JP2002234844A - Bone density improver and utilization thereof - Google Patents

Abstract

PROBLEM TO BE SOLVED: To obtain a bone density improver capable of improving the bone density and thereby having effects on prophylaxis of osteoporosis and a food and drink and a medicine comprising the bone density improver formulated therein. SOLUTION: This bone density improver is characterized as mainly comprising flavonoids, preferably at least one flavonoid selected from the group consisting of hesperidin, naringin and rutin or a derivative thereof. In particular, the hesperidin derivative is more preferably an α-glucosylated hesperidin and the naringin derivative is more preferably an α-glucosylated naringin. The rutin derivative is more preferably an α-glucosylated rutin. The flavonoids are preferably included together with at least one selected from the group consisting of a milk extract, a soybean hypocotyl extract, oligosaccharides, vitamins and minerals having improving effects on the bone density and salts thereof.

Description

DETAILED DESCRIPTION OF THE INVENTION

[0001]

TECHNICAL FIELD The present invention relates to a bone density improving agent containing mainly flavonoids and to its use. More specifically, the present invention provides a bone density enhancer containing flavonoids and the like, in which effects such as improvement of bone density can be obtained by ingesting the food as it is or added to foods, pharmaceuticals, etc. The present invention relates to the use in foods and pharmaceuticals, etc., containing the compound.

[0002]

BACKGROUND OF THE INVENTION As a method of treating osteoporosis, which is common in the elderly, with a drug, administration of calcium preparations, _three active vitamin D preparations, female hormone preparations and the like has been conventionally performed. To prevent the development of osteoporosis, diet,
It is effective to prevent bone density from decreasing by improving lifestyle including exercise. Particularly in postmenopausal women, the secretion of the female hormone estrogen is reduced, which increases the risk of developing postmenopausal osteoporosis in addition to menopausal disorders such as arteriosclerosis, hyperlipidemia, and hypertension . Therefore, it is desirable to proactively prevent such diseases.

[0003] However, no food has been proposed so far that can improve bone density and positively prevent the onset of osteoporosis. If the daily intake of foods or health foods can maintain or improve bone density and actively prevent the development of osteoporosis, or treat osteoporosis, its usefulness is high. For this reason, there has been a demand for a new health food or medicine that can easily and safely increase bone density and prevent osteoporosis.

[0004] The inventors of the present invention have conducted intensive studies and have surprisingly found that flavonoids improve bone density and are thus effective in preventing osteoporosis. In addition, among flavonoids, hesperidin, naringin, or a derivative thereof having increased solubility, particularly obtained from rutin or citrus, is easy to orally ingest and has excellent bone density improving effect. A bone mineral density enhancer containing a flavonoid and a substance having a bone mineral density improving action other than the above can be used as a pharmaceutical, and further added to general foods and drinks, health foods, functional foods and feeds. The present inventors have found that the use of such a compound can improve bone metabolism in a balanced and efficient manner, and completed the present invention.

Incidentally, statins which lower the blood cholesterol level by inhibiting the activity of 3-hydroxy-3-methylglutaryl-CoA (HMG-CoA) reductase have been known to reduce the risk of fracture in the elderly. It has been reported that it has a reducing effect and has an effect of suppressing bone resorption (JAMA, 283 (24), pp3205-3210 and pp3211).
-3216 (2000), J. Bone Miner Res 15 (4), pp650-620 (200
0)).

It has also been reported that citrus hesperidin or naringin inhibits HMG-CoA reductase and lowers blood and hepatic cholesterol (J. Nutr. 129, pp1182-). 1185 (1999)). However, even if these documents are scrutinized as to whether or not citrus hesperidins or naringins have an effect of inhibiting bone resorption similarly to statins, nothing is described or suggested.

[0007]

SUMMARY OF THE INVENTION An object of the present invention is to provide a bone density enhancer containing flavonoids and the like, which is effective for improving bone density and thereby preventing osteoporosis. . A further object of the present invention is to provide foods, drinks, medicines, feeds, and the like having an effect of improving bone density.

[0008]

SUMMARY OF THE INVENTION The bone density improving agent according to the present invention is characterized by containing a flavonoid and / or a derivative thereof. The bone density improving agent according to the present invention may contain the flavonoid and / or a derivative thereof together with a substance having a bone density improving effect.

[0009] The flavonoids and / or derivatives thereof contained in the bone density improving agent include hesperidin, naringin, rutin and derivatives thereof and hesperidin,
Naringin, hesperetin, an aglycone of rutin,
At least one from the group consisting of naringenin and quercetin
It is preferable that one is selected. Further, the flavonoid and / or a derivative thereof is hesperidin,
At least one selected from the group consisting of naringin, rutin and their derivatives or aglycones (hesperetin, naringenin, quercetin), and a substance having a bone density improving effect other than the milk extract, soybean hypocotyl extract, It is also preferable to include at least one selected from the group consisting of oligosaccharides, vitamins, minerals and salts thereof.

[0010] Further, in the above bone density improving agent, at least one selected from the group consisting of hesperidin, naringin, rutin and their derivatives or aglycones (hesperetin, naringenin, quercetin) is used as the flavonoid and / or a derivative thereof. 0.01
As a substance having a bone density improving effect of at least 70% by weight, at least one selected from the group consisting of milk extract, soybean hypocotyl extract, vitamins, minerals and salts thereof is 0.01 to It is characterized by containing 30% by weight.

In the above bone density improving agent, it is particularly preferable that the hesperidin derivative is α-glucosylated hesperidin, the naringin derivative is α-glucosylated naringin, and the rutin derivative is α-glucosylated rutin. preferable. Further, in the bone density enhancer, the milk extract is a milk-based protein or peptide, the soybean hypocotyl extract is isoflavone or saponin, the oligosaccharide is galacto-oligosaccharide, fructooligosaccharide or lactosucrose, vitamins Is a vitamin C, a vitamin K, a vitamin D or a vitamin D active form, and it is particularly preferred that the mineral is calcium, magnesium or a salt thereof.

The food and drink according to the present invention is characterized by containing the above-mentioned bone density improving agent. Further, the present invention is characterized in that the medicine according to the present invention or the above-mentioned bone density improver is added.

[0013]

DETAILED DESCRIPTION OF THE INVENTION Hereinafter, the bone density enhancer according to the present invention and its use will be described in detail. The bone density enhancer according to the present invention mainly contains flavonoids and / or derivatives thereof. In this specification, flavonoids and / or derivatives thereof are also collectively referred to as “flavonoids”. Similarly, “oligosaccharides” includes derivatives of oligosaccharides. “Vitamins” also include provitamins and their salts, and “minerals” also include their salts.

Flavonoids are a general term for chalcones, flavanones, flavonols, flavanols (catechins), and anthocyans.
Those exhibiting a wide variety of properties such as vitamin P action and estrogen-like action have been found. Hesperidin, which is often contained in citrus fruits and the like, and rutin, which is contained in naringin and buckwheat, are substances belonging to this flavonoid. Hesperidin, naringin, and rutin have so-called vitamin P-like actions such as strengthening capillaries and preventing bleeding. On the other hand, it has been found that it has the effect of lowering the amount of cholesterol and neutral lipids in blood, as well as improving arteriosclerosis, hypertension, etc. And its safety is high.

The type of flavonoids contained in the bone density improving agent of the present invention is not particularly limited, but is preferably hesperidin, naringin, rutin or a derivative thereof and hesperidin, naringin, and aglycone of rutin, hesperetin, naringenin, and quercetin. At least one selected from the group consisting of: In addition to these flavonoids, other flavonoids,
For example, esculin may be used as it is, or water-soluble α-glucosyl esculin may be used.

Hereinafter, among the flavonoids, hesperidin, naringin, rutin and derivatives thereof which are particularly preferably used will be described in detail. Hesperidin and its derivative Hesperidin have the following formula [I]:

[0017]

Embedded image

Hesperetin (5,7,
3'-Trihydroxy-4'-methoxyflavanone) 7
Position hydroxyl group, rutinose (L-rhamnosyl- (α1 →
6) -glucose) is β-linked. This hesperidin is contained in the immature pericarp of citrus fruits, and hesperidin and its derivatives have the effect of improving bone density, as well as vitamin P which exerts physiological actions such as strengthening of capillaries, prevention of bleeding and blood pressure regulation. It also has the function of Pharmaceuticals, cosmetics, etc. utilizing this vitamin P function have been provided so far. This hesperidin is soluble in an alkaline aqueous solution, but is sparingly soluble in water and acid. At room temperature, only 1 g (about 0.002 W / V) is added to 50 L of water.
%) Only melts. In the present invention, this hesperidin may be used as it is, but preferably a hesperidin derivative having improved solubility, such as the following “enzyme-treated hesperidin” or “monoglucosyl hesperidin-rich substance” may be used.

"Enzyme-treated hesperidin" is disclosed in JP-A-3-75.
It is prepared by the method described in JP-A-93. Α-glucosyl hesperidin as a main component is a compound in which n (1 to 20) glucoses (G) are successively α-1 and 4-linked at the 4-position of glucose of hesperidin represented by the formula [I]. . “Enzyme-treated hesperidin” is a mixture containing α-glucosyl hesperidin having different added glucose numbers.

"Enzyme-treated hesperidin" by the above method
Of hesperidin contained in the raw material solution in the preparation of
Up to 80% is converted to α-glucosyl hesperidin by enzyme treatment, but 20 to 60% remains as unreacted hesperidin. Unreacted hesperidin (hesperidin) increases solubility in aqueous solution when α-glucosyl hesperidin coexists, but unreacted hesperidin becomes insoluble in a short time when the ratio of unreacted hesperidin to α-glucosyl hesperidin is high And precipitate out. This phenomenon is inconvenient when the enzyme-treated hesperidin is used in the form of a liquid.

What solved such a problem was a "monoglucosyl hesperidin high content" which was disclosed in
It is prepared by the method described in JP-A-10-323196. Unreacted hesperidin has been converted to monoglucosyl hesperetin, has remarkably excellent water solubility, and does not cause cloudiness even after a long period of time. Naringin and its derivative Naringin have the following formula [II]:

[0022]

Embedded image

As shown by naringenin (5,
L-rhamnosyl- (α1 → 2) -glucose is β-linked to the hydroxyl group at the 7-position of (7,4′-trihydroxyflavanone). This naringin is contained in the immature pericarp of citrus fruits and has the effect of improving bone density, as well as physiological effects such as strengthening capillaries, preventing bleeding, regulating blood pressure, lowering cholesterol, etc. It has been found that it also has TNF inducing activity to maintain. For this reason, naringin and its derivatives are used in medicines as preventives for cardiovascular diseases and the like, and because they have antioxidant and ultraviolet absorption effects, they are used as foods and drinks as bittering agents, vitamin P enhancers, antioxidants, etc. , Is also used in cosmetics.

However, this naringin is also soluble in an alkaline aqueous solution, but is hardly soluble in water and acid.
At room temperature, only 1 g (about 0.1 W / V%) in 1 liter of water
Since it is only soluble to a certain extent, its field of application is limited. Accordingly, various methods for increasing the water solubility of naringin and derivatives thereof have been developed, and the following derivatives can also be used more preferably in place of naringin in the bone density enhancer according to the present invention.

"Enzyme-treated naringin" is disclosed in
It is prepared by the method described in Japanese Patent Publication No. This product contains 3 ″ -α-glucosylnaringin as a main component, which is a product obtained by adding a plurality of glucoses to the 3-position of glucose of naringin, and its 4′-position is also α-glucosylated. It often contains 3 ″, 4′-α-glucosyl naringin or 4′-α-glucosyl naringin in which only the 4′-position of naringin is α-glucosylated.

[0026] "Enzyme-treated monoglucosyl naringin" can also be used. It contains 3 "-α-monoglucosyl naringin as a main component and a small amount of unreacted naringin and contains 3", 4'-α-. Glucosyl naringin, 4'-
Almost no α-glucosyl naringin. 3 ″ -α-monoglucosyl naringin contained in “enzyme-treated monoglucosyl naringin” at a high content is 7% of naringin.
Only one glucose is added only to the 3 ″ -position of glucose in —O-neohesperidoside, and the 4′-position of naringenin is a phenolic hydroxyl group. In contrast, 3 ″, 4′-α -Glucosyl naringin or 4'-α
-In all cases of glucosyl naringin, the OH group at the 4'-position of naringin is blocked by a glucosyl group. For this reason, 3 ", 4'-α-glucosyl naringin and 4'-α-
Glucosylnaringine shows no increase in bitterness and shows almost no antioxidant ability. In the “enzyme-treated monoglucosyl naringin”, since the main components include 3 ″ -α-monoglucosyl naringin and a small amount of unreacted naringin, the types of compounds contained in the bone density improver are small, It is characterized by a relatively uniform molecular composition.

Rutin and its derivative Rutin have the following formula [III]:

[0028]

Embedded image

As shown in the above, quercetin is used as an aglycone, and L-rhamnosyl- (α1 →
6) -flavonol glycoside with β-linked glucose. This rutin is contained in buckwheat whole plant, fig, blue-green, tobacco leaf, etc., and has the same effect of improving bone density as hesperidin and naringin.In addition, physiological action as vitamin P, ultraviolet absorption, antioxidation, Coloring
It also has the effect of preventing fading.

This rutin is also soluble in an alkaline aqueous solution, but is poorly soluble in water and acid, and is only slightly soluble at room temperature in about 0.1 g in 1 liter of water. Have been. Therefore, various methods for increasing the water solubility of rutin and derivatives thereof have been proposed, and α-glucosylated rutin, which is a derivative with improved solubility, is replaced with rutin in the bone density enhancer according to the present invention. Therefore, it can be more preferably used.

“ΑG-rutin” (trade name, manufactured by Toyo Seikagaku Co., Ltd.) obtained by converting rutin to α-glucosyl is obtained by transferring glucose from starch, dextrin or the like to rutin by the transfer action of enzymes such as glycosidase and transglycosidase. It is a water-soluble rutin transferred to the 4-position and is a mixture of α-glucosyl rutin having different glucose numbers. “ΑG rutin” has improved solubility (water solubility, fat solubility) and improved stability such as heat resistance and long-term storage stability as compared with rutin. Other Substances Having Bone Density Improving Effect Other than the above-mentioned flavonoids, other substances having a bone density improving effect include a milk extract, a soybean hypocotyl extract, vitamins, and minerals. The bone density improving agent of the present invention may contain at least one of these substances in addition to the above-mentioned flavonoids contained as a main component. This improves the bone metabolism efficiency and balance from various aspects, that is, calcium supplement to the bone component,
It can be expected to promote bone formation and suppress bone destruction and absorption.

The basic peptide composition, which is a milk basic protein (milk basic protein) or its enzyme digest, increases osteoblasts (bone forming cells) and promotes collagen production by osteoblasts. It not only promotes bone formation, but also has the effect of suppressing the action of osteoclasts that destroy bone and preventing calcium from leaking from bone. It has also been clarified that casein calcium peptide (CCP) has an effect of promoting calcium absorption.

The effect of the soybean hypocotyl extract is due to the action of isoflavone and / or saponin contained as components. That is, isoflavones are known to have a structure similar to the female hormone estrogen and to exhibit an estrogen-like effect. As is inferred from the relationship between estrogen and bone density, the effect of isoflavones also acts as a substitute for estrogen.

Recent studies have reported that saponins also exert a similar effect on bone metabolism. Oligosaccharides are known to have an intestinal environment, promote the absorption of calcium and magnesium from the intestine, and reduce bone cholesterol, thereby improving bone density.

Vitamin C among the vitamins having a bone density improving effect is involved in formation of a collagen matrix and incorporation of BMP (Bone Morphogenetic Protein) into the matrix, and may be an essential vitamin for bone metabolism. It has been revealed. Vitamin K, among homologs of such K _1, K _2, particularly K ₂ have been primarily shown to be involved in the reduction of osteoclast and bone mineralization (i.e. deposition of calcium) .

[0036] Among the vitamin D, active substances derived from such D ₃ indicates the effect of Vitamin D. This active form promotes the biosynthesis of proteins that bind to calcium in the small intestinal mucosa and suppresses calcium excretion from the kidney. In addition, the active form promotes phosphate reabsorption from renal tubules and is involved in bone metabolism through the action of constantly maintaining serum calcium / phosphate concentrations.

Among the minerals, calcium (Ca) forms a component of bone as calcium carbonate. Magnesium is present in bone together with calcium as magnesium phosphate. In addition, magnesium has been shown to promote collagen production by osteoblasts. Both minerals have a certain quantitative relationship such that magnesium deficiency indicates a decrease in calcium content in bone.

Hereinafter, substances other than flavonoids used in the bone density improving agent of the present invention will be specifically exemplified, but it goes without saying that the substances are not limited to these. Milk basic protein is contained in milk whey. Details about the composition containing the milk-derived basic protein as well as details about the milk-derived basic peptide composition obtained by digesting the composition with proteolytic enzymes are described in Preparation from Milk or Raw Materials Derived from Milk. The method, including the method, is disclosed in JP-A-9-191858. Similarly, as the casein calcium peptide, one prepared from milk or the like can be used.

Soybeans are particularly high in isoflavones compared to other plants, and soybean hypocotyl extract is a preferred source of isoflavones and saponins. Specific preparation methods thereof are disclosed in Japanese Patent Publication No. 04-48417 (humidity control, heating, peeling, soybean hypocotyl collection), and Japanese Patent Publication No. 05-3.
No. 3016 (alkaline solution immersion / roasting / soybean hypocotyl treatment method) and Japanese Patent Publication No. 07-238089 (protein isolate containing a large amount of isoflavone compounds and a method for preparing the same).

As oligosaccharides, galactooligosaccharides,
Fructooligosaccharides, lactosucrose and the like can be used. As vitamin Cs having an effect of improving bone density, derivatives of ascorbic acid can be used in addition to ascorbic acid alone. Ascorbic acid is easily decomposed by the action of oxygen and light in a water-soluble state, and therefore, a relatively stable derivative thereof is more preferable. Suitable derivatives include derivatives in esterified or etherified form with monosaccharides, phosphoric acid, sulfuric acid, or alkyl compounds. These are converted to ascorbic acid enzymatically or non-enzymatically in vivo and exert their effects.

As vitamin K, K ₁ , K ₂ and K ₃ are known. Among them, preferred are vitamin K ₂ relating to bone metabolism, vitamin K ₂ -4 naturally occurring, like is preferable -7. In particular, vitamin K ₂ -4 is preferably used as a drug as a therapeutic agent for osteoporosis. For vitamin D, any known six such D ₇ from vitamin D ₂ may be used. Among them preferably used is D ₂ and D _3, but the active vitamin D _3, which is particularly improved intestinal absorption are preferred.

With respect to the above-mentioned vitamins, derivatives containing each provitamin can also be preferably used in the present invention. As the minerals, conventional calcium preparations including calcium chloride, calcium phosphate, calcium carbonate, calcium lactate, eggshell, fish bone meal and the like, and conventional magnesium preparations including magnesium oxide, magnesium silicate, magnesium stearate and the like can be used. Further, dolomite (a main component of which is calcium magnesium carbonate) which is a natural material containing calcium and magnesium in ideal ratios as bone minerals can also be preferably used.

These bone density improving agents are already commercially available and can be easily obtained. Since both are of biological origin, they can be safely used because side effects are rarely seen at ordinary doses and use forms. Bone Density Improving Agent In the bone density improving agent according to the present invention, there is no particular limitation on which flavonoid is used and in what ratio as long as it contains flavonoids. For example, any one or more of the above-mentioned hesperidin and its derivatives, naringin and its derivatives, and rutin and its derivatives, or a mixture containing these in any mixing ratio may be used. In a bone density improving agent containing only flavonoids as a component having a bone density improving action, flavonoids, that is, flavonoids and / or derivatives thereof, can be contained in an arbitrary amount.
It may be included in a range of less than 100% by weight. In the bone density enhancer according to the present invention, the flavonoids are preferably used in an amount of 0.01 to 90% by weight, more preferably from the viewpoint of ease of use.
It is blended in a ratio of 0.1 to 80% by weight.

In the bone density improving agent according to the present invention, in addition to the case where the flavonoids are contained alone as described above, a substance having a bone density improving action other than the flavonoids may be added together with the flavonoids. Good. In this case, the flavonoids are contained in an amount of 0.01 to 70% by weight, preferably 0.1 to 50% by weight, and a substance other than the flavonoids, which has a bone density improving action, is contained in an amount of 0.01 to 30% by weight, preferably 0 to 30% by weight. It is desirable to contain it in a ratio of 0.1 to 20% by weight.
More specifically, the amount of the substance having a bone density improving action other than the flavonoids is determined by the total amount of the bone density improving agent (100%).
flavonoids; 0.01 to 70
g, preferably 0.1 to 50 g, milk basic protein or calcium casein peptide; 0.01 to 20 g, preferably 0.1 to 15 g, soybean hypocotyl extract; 0.01 to 20 g, preferably 0.1 to 15 g, oligosaccharides (galacto-oligosaccharides) 0.1-50 g, preferably 1.0-20 g, vitamin K; 25-3000 μg, preferably 50-500 μg, vitamin D; 25-2000 IU, preferably 5
0-200 IU, vitamin C; 0.001-1 g, preferably 0.01-
0.5 g, calcium; 0.01 to 10 g, preferably 0.01 to 5
g, magnesium; 0.01 to 5 g, preferably 0.1 to 2 g, desirably alone or in combination.

The bone density improving agent according to the present invention may contain other substances as long as the object of the present invention is not impaired. For example, various amino acids and vitamins may be added to enhance nutrition and nourishment. In particular, by adding vitamin C, a synergistic effect can be exhibited in vitamin P action such as enhancement of capillary resistance. In addition, sweeteners, bulking agents,
One or two or more of various components such as a flavoring agent can be blended as required.

For example, sweetness such as starch syrup, glucose, maltose, sugar, isomerized sugar, palatinose, stevia extract and enzyme-treated stevia, L-asparatylphenylalanine methyl ester, glycyrrhizin, acesulfame K, sucralose, saccharin, trehalose, maltitol, etc. Ingredients: various organic acid salts such as citric acid, succinic acid, lactic acid, malic acid, and gluconic acid; flavors such as various flavors; extenders such as dextrin, starch, lactose, and cyclodextrin; Further, various additives generally used for foods and pharmaceuticals, for example, arbitrary components such as thickeners, dispersants, gelling agents, and pigment preparations can be included.

The dosage form of the bone density enhancer according to the present invention is not particularly limited, and powdery flavonoids may be used as they are, or may be mixed with fillers and excipients as needed to obtain granules. It can be used by molding into a spherical shape, a cube, a tablet shape, or the like. Further, it may be used as a paste or a liquid product, and the concentration of the liquid product can be appropriately adjusted for convenience in use. The agent for improving bone density according to the present invention can be provided or used in two or more divided forms as required. The performance and form of the container filled with the bone density improver are not particularly limited.

When the flavonoids contained in the bone density improver according to the present invention are α-glucosylated products of the above-mentioned flavonoids, the solubility in water and the like is extremely good, and therefore, beverages, seasonings, etc. Can be satisfactorily added to the liquid. The obtained bone density improver in a solution state is excellent in stability, and almost no formation of flocs (agglomerates) such as precipitation of flavonoids is recognized even during long-term storage.

Method for Producing Bone Density Improver Hesperidin or a derivative thereof, naringin or a derivative thereof, and rutin or a derivative thereof used in the bone density enhancer of the present invention can be commercially available products. For example, glucosylated derivatives of these flavonoids include “αG Hesperidin” ^™ and “α
Gnaringin ^™ , αG rutin ^{™ and the} like can be used.

Hesperidin or its derivative, naringin or its derivative, rutin or its derivative used in the bone density improving agent of the present invention can also be prepared by the following method. As for “enzyme-treated hesperidin”, JP-A-3-7593 discloses a process in which hesperidin is reacted with a glycosyltransferase (an enzyme having α-glucosyltransferase activity) in the presence of a partially degraded starch (α-glucosyl sugar compound). A method is disclosed.

"Monoglucosyl hesperidin high content"
Is disclosed in JP-A-10-323196.
When an enzyme having α-L-rhamnosidase activity is allowed to act on a solution containing α-glucosyl hesperidin and unreacted hesperidin, α-glucosyl hesperidin remains almost unchanged and unreacted hesperidin is hydrolyzed. Then, rhamnose is separated and converted into monoglucosyl hesperetin, which gives an enzyme-treated hesperidin which is remarkably excellent in water solubility and does not cause cloudiness even after a long period of time.

As a method for producing “enzyme-treated naringin”, Japanese Patent Application Laid-Open No. 4-13691 discloses an enzyme having a glycosyltransferase (α-glucosyltransferase) in the presence of partially degraded starch (α-glucosyl sugar compound). For example, cyclodextrin glucanotransferase (CGTase) or the like) to produce α-glucosyl naringin represented by the above formula [II], and fractionating the α-glucosyl naringin, discloses a method for α-glucosyl naringin. Have been.

The method for producing "enzyme-treated monoglucosyl naringin" is based on the method of producing naringin with a glycosyltransferase in the presence of a partially degraded starch, the main components of which are 3 "-α-glucosyl naringin and 3", A solution containing 4′-α-glucosyl naringin, 4′-α-glucosyl naringin, unreacted naringin, etc., is added with α-glucosidase,
Alternatively, by reacting α-glucosidase and glucoamylase. According to this method, “enzyme-treated monoglucosyl naringin” containing a high content of 3 ″ -α-monoglucosyl naringin can be prepared easily and with high yield.

A method for producing “α-glucosylated rutin” is disclosed in Japanese Patent Publication No. 2926411. These flavonoids do not need to be highly purified, and extracts derived from various plants including them, or partial products thereof, and enzyme-treated products may be used as they are.

Since many flavonoids are available in powder form, they are weighed in a predetermined amount and further added to substances such as milk-basic protein, casein calcium peptide, soybean hypocotyl extract, vitamin C, D, If there are mineral preparations such as K, calcium, magnesium and the like, they are also mixed in a predetermined amount to prepare a bone density improving agent. In the case of forming a paste or granules or molding, a necessary amount of water or the like may be added and kneaded, and if necessary, concentration and drying may be performed. In the case of a liquid product, it may be dissolved in a solvent such as water. Uses of Bone Density Improving Agent The most useful application examples of the bone density improving agent according to the present invention will be described below, but the uses of the bone density improving agent are not limited thereto.

The above-mentioned bone density improving agent is used as a drug for improving bone density, a general food, a health food, a functional food, a fortified food, or as a drug raw material by paying attention to other medicinal effects such as vitamin P. Is mentioned. In the case of being used as a medicine, a utilization form utilizing various drug effects of flavonoids in addition to the effect of improving bone density can be considered. For example,
In addition to exerting the effect of improving bone density, it can be used as a component raw material of conventional drugs for treating circulatory diseases such as for strengthening blood vessels, preferably while maintaining the physiological action of vitamin P. Examples of such pharmaceuticals include vitamin P enhancers; prophylactic or therapeutic agents for circulatory diseases and susceptibility diseases (anti-sensitivity disease agents); and the like.

Many of the bone density improving agents according to the present invention have an antioxidant effect in addition to a bone density improving effect.
If added to pharmaceuticals, etc., in addition to the effect of improving bone density, antioxidant effects of foods, pharmaceuticals, etc. can be expected. Therefore, by adding a bone density improver to foods, pharmaceuticals and the like, generation of off-flavor and off-flavor, discoloration or generation of toxic substances, etc. can be effectively prevented, and its quality or nutritional value can be maintained. In a drug orally administered for improving bone density or for treating the above-mentioned various diseases, the effect of improving taste and the antioxidant effect are also enhanced. Such pharmaceuticals include, for example, enteral nutrition, supplemental nutrition, drench, syrup and the like.

In foods and drinks (including health foods, functional foods, nutritionally enhanced foods, etc.) intended to increase or prevent bone density, for example, they also exhibit the functions of antioxidants and anti-fading agents. In this case, the type, form, and amount of the food to which the bone density improver is added can be arbitrarily selected. In order to use the bone mineral density enhancer of the present invention in general foods and drinks, luxury goods, medicines and the like as described above, the bone mineral density enhancer is added at an appropriate stage in the process until the product is completed. can do. For example, when adding a bone density improver, mixed with other compounding ingredients,
It may be kneaded, kneaded, penetrated, dissolved, sprayed, applied, sprayed, injected, or the like with a bone density improver in food or drink, or may be immersed in food or drink with a liquid bone density improver. For this purpose, a conventionally known method is appropriately adopted.

Improvement of Prevention and Treatment of Osteoporosis When the bone mineral density enhancer of the present invention is taken into humans or other animals, the flavonoid derivatives and the like contained in the bone mineral density enhancer are in vivo. Under the action of the enzyme, the flavonoid derivative is converted back to a flavonoid, exhibiting a physiological action of the flavonoid itself and exerting an action of improving bone density. For example, when the bone density improver contains the flavonoid derivatives α-glucosylsperidin, α-glucosylnaringin, α-glucosylrutin, etc., when these are returned to the original hesperidin, naringin, rutin in the body, Vitamins in addition to density-enhancing action
Various functions as P will also be exhibited. Other functions include lowering cholesterol and neutral lipids in the blood. The bone density enhancer can effectively prevent the development of osteoporosis. That is, in patients with osteoporosis, bone density is reduced in accordance with the severity, and the pathology and bone density have a close relationship, so the ingestion of the bone density enhancer according to the present invention causes the onset of osteoporosis. Can be prevented. In addition, it can be used for the purpose of prevention and / or treatment of various bone diseases and bone strengthening. Further, in the bone density improving agent of the present invention, when the flavonoids and at least one other substance having a bone metabolism improving effect are incorporated together, the effect of improving bone metabolism in a balanced manner with efficiency from various aspects is expected. it can.

The form for ingesting the bone density improving agent of the present invention is
When ingested as a drug or food, the dose and usage are not the same. However, the origin of the active ingredient of the bone density improver is a compound derived from a natural product, which is extracted from a plant that has been used for food since long ago, and is extremely excellent in safety.

[0061]

The bone mineral density enhancer according to the present invention is contained directly when the bone mineral density enhancer is absorbed into the body by directly ingesting the food or medicine or food containing the bone mineral density enhancer. In addition to exerting the various effects of vitamin P contained in the flavonoids used, it is expected to have the effects of lowering blood cholesterol and improving bone density.

Further, in addition to using each of the substances having an effect of improving bone density other than the flavonoids together with the above-mentioned flavonoids, a mixture thereof can be contained together with the flavonoids. In such a case, the agent for improving bone density of the present invention can be expected to have a synergistic effect due to the combined use, or a well-balanced comprehensive improvement effect on bone metabolism based on the action of each active ingredient.

When the bone density enhancer according to the present invention is incorporated into a food or drink or a pharmaceutical product, in addition to the effect of ingesting the bone density enhancer, the food or drink and the pharmaceutical product have an antioxidant effect.
It also has the effect of preventing fading and improving flavor.

[0064]

EXAMPLES Hereinafter, the present invention will be described more specifically with reference to examples, but the present invention is not limited to these examples. Unless otherwise specified,% means weight%.

[0065]

[Example 1]-About magnesium (Mg) deficient rat-<Method> 30 male rats of 4 weeks old SD strain were randomly divided into 6 groups, and the rats of each group were allowed to freely eat the following diet and water. For 4 consecutive weeks.・ N group: normal diet for commercial rats ・ NH group: 1 untreated hesperidin in the diet to be administered to the above N group
Diet added at a rate of 0 mg / g ・ NE group: Diet to which the enzyme-treated hesperidin was added at a rate of 14 mg / g (10 mg / g as hesperidin) to the diet to be administered to the above-mentioned N group ・ L group: a normal magnesium content Low-magnesium (low-Mg) diet reduced by 95% from diet-LH group: low-mag diet to be administered to the above L group, untreated hesperidin added at a rate of 10 mg / g-LE group: to the above L group 14 mg / g enzyme treated hesperidin (10 mg / mg hesperidin)
g) Food added in g) After the rearing, the rats were sacrificed, the femur was collected, and the bone density (BMD) of the entire femur was measured using Dual Energy X-ray abso.
It was measured by rptiometry (DXA). The significance test between the groups was performed by the ANOVA method. <Results> The feed intake of each group was the same, and the weight gain was significantly smaller in the three groups deficient in Mg than in the normal Mg diet group.
There was no significant difference in body weight gain among the three Mg-deficient groups.

As shown in FIG. 1, the bone density of the whole femur was reduced by the Mg-deficient diet, but recovered by ingestion of either hesperidin. It is known that when rats are fed a low Mg diet, cholesterol levels in the blood increase, but in this case, as shown by the above results, the bone density of the femur significantly decreases. However, it can be seen that ingestion of hesperidin improves bone density to normal levels.

When hesperidins were added to the normal diet and given, the bone density was almost the same level as the control group N as shown in the NH group and NE group.

[0068]

Example 2-Concomitant effect of flavonoids and other substances having an effect of improving bone density-<Method> As shown in Table 1, 32 SD male rats of 3 weeks of age were used as test animals. A group (N group) who took a normal magnesium (Mg) diet based on the AIN-93 composition,
"Low Mg diet" single intake group (L group), low Mg diet + 1.4% enzyme treated hesperidin + 0.25% soybean hypocotyl extract intake group (LHI group),
A total of 4 groups (8 per group) consisting of a low Mg diet + 1.4% enzyme treated hesperidin + 0.1% milk basic protein intake group (LHM group)
Restricted feeding was performed so that the feed intake of each group was equal. The feed was bred for 6 weeks, with the Mg content being 0.085% on a normal Mg diet and the low Mg being 0.006% in the first half and 0.008% in the second half.

After the rearing, the bone density of the femur was measured by the DXA method. <Test results> The bone density of the femur was L
Low Mg diet + 1.4% enzyme treated hesperidin + 0.
The LHI group with 25% soybean hypocotyl extract intake and the LHM group with low Mg diet + 1.4% enzyme-treated hesperidin + 0.1% milk basic protein showed significantly higher values (Fig. 2).

[0070]

[Table 1]

[0071]

[Example 3]-About OVX mice-<Method> 30 ddy female mice of 7 weeks old were randomly divided into 5 groups, and the mice in each group were subjected to the following treatment, and then given food and water were given freely. They were fed for 4 consecutive weeks in a fed form. Sham group: Sham operation consisting of laparotomy, manipulation of ovarian surgery (OVX) manipulation and suturing was performed, and then normal mouse chow and water were given. OVX group: OVX surgery was performed, followed by normal mouse chow and water. -OVX-A group: OVX operation was performed, and thereafter, food and water supplemented with 0.5% untreated hesperidin were added to normal mouse food. -OVX-B group: OVX operation was performed, and then a normal mouse food supplemented with 0.7% enzyme-treated hesperidin and food were given. -OVX-Es group: OVX operation is performed, and then normal mouse food and water are given, and 17β estradiol (0.1 μg /
g / day) was administered subcutaneously.

The mouse was sacrificed, and the femur was collected. The measurement of the bone density and the test for significant difference were carried out in the same manner as in Example 1. <Results> There was no significant difference in feed intake between the groups, but the weight gain was smaller in the OVX-Es group than in the other groups.

As shown in FIG. 3, the bone mineral density of the femur was reduced by OVX, and the bone mineral density was improved to the bone density shown in the Sham group by ingestion of either hesperidin. all right. It should be noted that even when the female hormone estrogen was administered instead of the hesperidins, the bone density was improved to the level of the sham group.

[0074]

Example 4 Production of Beverage A beverage of the present invention was prepared having the composition shown in Table 2 and containing enzyme-treated hesperidin and another substance having an effect of improving bone density.

[0075]

[Table 2]

[0076]

Example 5 Production of Jelly A jelly of the present invention containing the enzyme-treated hesperidin and another substance having an effect of improving bone density was prepared in the composition shown in Table 3.

[0077]

[Table 3]

[0078]

Example 6 Production of Biscuit Biscuits of the present invention were prepared with the composition shown in Table 4 and containing both enzyme-treated hesperidin and other substances having an effect of improving bone density.

[0079]

[Table 4]

[0080]

Example 7 Production of Tablets Tablets of the present invention were prepared by mixing the enzyme-treated hesperidin and other substances having an effect of improving bone density with the composition shown in Table 5, followed by press molding.

[0081]

[Table 5]

[0082]

Example 8 Production of Feed A feed for dog breeding of the present invention was prepared with the composition shown in Table 6 and containing enzyme-treated hesperidin and other substances having an effect of improving bone density.

[0083]

[Table 6]

[Brief description of the drawings]

FIG. 1 shows the effect of lowering bone density (BMD) of the entire femur and improving hesperidin intake when rats are fed a low magnesium (Mg) diet. Each data is
It is expressed as mean ± standard deviation. * Indicates risk factor 5 for group L
% Indicates that a significant difference is observed.

FIG. 2 shows that when a low-magnesium (Mg) diet is fed to rats, bone mineral density (BMD) of whole femur is reduced, and enzyme-treated hesperidin and other substances having an effect of improving bone density are included. Show the effect. Each data is expressed as mean ± standard deviation. The asterisk indicates that a significant difference is observed at a risk rate of less than 5% for the L group.

FIG. 3 shows the results of reduced bone mineral density (BMD) of whole femurs in ovarian surgery (OVX) mice improved by ingestion of hesperidins. Each data is expressed as mean ± standard deviation. The mark a indicates that a significant difference is observed at a risk rate of less than 5% with respect to the sham (Sham) operation group.
The mark “b” indicates a risk factor of 5 for the group that underwent ovarian surgery (OVX).
% Indicates that a significant difference is observed.

──────────────────────────────────────────────────の Continued on the front page (51) Int.Cl. ⁷ Identification symbol FI Theme coat ゛ (Reference) A23L 1/30 A23L 1/30 B 4C088 Z A61K 31/353 A61K 31/353 31/702 31/702 35 / 20 35/20 35/78 35/78 J 45/00 45/00 A61P 19/08 A61P 19/08 (72) Inventor Junichi Takagi 18-20 Nihonbashi Koami-cho, Chuo-ku, Tokyo Toyo Refinery Co., Ltd. (72) Inventor Takashi Yumoto 1-4-6 Iwasaki Nishi, Ichihara-shi, Chiba Prefecture Toyo Refinery Co., Ltd. Chiba Plant F-term (reference) 2B150 DB04 DC15 DD01 DD11 DE01 DE13 DE14 DE16 DH03 DH05 DH35 4B018 MD03 MD04 MD07 MD23 MD31 MD58 MD71 ME05 4C084 AA19 MA02 ZA96 4C086 AA01 AA02 BA08 EA11 MA01 MA02 MA04 NA14 ZA96 4C087 BB39 MA02 MA52 NA05 ZA96 ZC75 4C088 AB59 AC04 MA02 MA52 NA05 ZA96 ZC75

Claims (8)

[Claims] 1. A bone density improving agent comprising a flavonoid and / or a derivative thereof. 2. The agent for improving bone density according to claim 1, wherein said flavonoid and / or a derivative thereof are combined with a substance having an effect of improving bone density. 3. The method according to claim 1, wherein the flavonoid and / or its derivative is at least one selected from the group consisting of hesperidin, naringin, rutin and their derivatives or aglycones (hesperetin, naringenin, quercetin). The bone density enhancer according to claim 1. 4. The above-mentioned flavonoid and / or its derivative selected from at least one selected from the group consisting of hesperidin, naringin, rutin and their derivatives or aglycones (hesperetin, naringenin, quercetin), and other bone mineral density. The substance having an improving effect is characterized by containing at least one selected from the group consisting of milk extract, soybean hypocotyl extract, oligosaccharides, vitamins, minerals and salts thereof. Item 3. The bone density improving agent according to Item 2. 5. The hesperidin derivative is α-glucosylated hesperidin, the naringin derivative is α-glucosylated naringin, and the rutin derivative is α-glucosylated naringin.
The bone density enhancer according to claim 3 or 4, which is glucosylated rutin. 6. The milk extract is a milk basic protein or peptide, the soybean hypocotyl extract is isoflavone or saponin, the oligosaccharide is galactooligosaccharide, fructooligosaccharide or lactosucrose, and the vitamins are vitamin C. The bone mineral enhancer according to claim 4, wherein the mineral is calcium, magnesium or a salt thereof, wherein the mineral is calcium, magnesium or a salt thereof. 7. A food or drink comprising the bone density improving agent according to any one of claims 1 to 6. A pharmaceutical or feed comprising the bone density improving agent according to any one of claims 1 to 6.