JP5157007B2 - Bone strengthening agent - Google Patents

Description

The present invention relates to a bone formation promoter, a bone resorption inhibitor, a bone strength increasing agent characterized by containing thioctic acid and creatine, and a bone formation promoting action, a bone resorption suppressing action, and a bone strength increasing action. Of these, the present invention relates to an osteoporosis preventive / ameliorating agent based on at least one action, and also relates to an oral composition characterized by containing at least one of the above-mentioned agents.

Bone is a living body support and a reservoir for minerals such as calcium and phosphorus, and plays an important role in the ionic regulation mechanism of body fluids. The bone tissue looks static at first glance, but there is active metabolism, and bone remodeling (remodeling) in which bone resorption and bone formation occur continuously is always performed. Osteoclasts derived from hematopoietic stem cells are involved in bone resorption, and osteoblasts derived from undifferentiated mesenchymal cells are involved in bone formation. In normal bone tissue, the balance between bone formation and bone resorption is maintained. However, if the balance is lost due to some cause and bone resorption is relatively increased, the bone mass is remarkably lowered and various diseases such as osteoarthritis and osteoporosis are induced.

Osteoporosis is defined as a disease characterized by a decrease in bone mass and a change in the fine structure of bone tissue, resulting in a weakened bone and consequently an increased risk of fracture. In particular, postmenopausal women who have had their ovaries removed are more likely to develop osteoporosis due to increased bone resorption associated with decreased secretion of female hormones. Moreover, in elderly people, bone resorption is relatively higher than bone formation due to a decrease in bone turnover, and osteoporosis is likely to occur.

When osteoporosis becomes severe, it becomes easy to break even with a light impact, resulting in a bedridden state. The cause of bedriddenness in Japan is due to falling fractures as well as stroke and senility. In today's aging society, the prevention and improvement of osteoporosis is a very important issue in order to maintain the quality of life.

In order to prevent osteoporosis, it is indispensable to sufficiently increase bone mass from a young age, and it is recommended to actively take minerals such as calcium and magnesium, vitamin D, and the like. For the treatment of osteoporosis, bone resorption inhibitors such as bisphosphonates, estrogens and calcitonin are mainly used. However, it is known that bisphosphonate has low bioabsorption efficiency, and absorption is significantly reduced depending on the intake timing of meals. In addition, side effects of gastrointestinal symptoms have been reported. Side effects such as increased risk of breast cancer and cardiovascular disorders have been reported for estrogens. Therefore, there has been a demand for the development of a simple oral composition that has fewer side effects and that effectively prevents and improves osteoporosis.

Thioctic acid is α-lipoic acid, 1,2-diethylene-3-pentanoic acid, 1,2-diethylene-3-valeric acid, 1,2-dithiolane-6-pentanoic acid or 1,2-dithiacyclopentane. It is also referred to as -3-valeric acid, etc., and is synthesized in vivo in animals and plants and microorganisms, and is bioavailable as one of various coenzymes of pyruvate dehydrogenase complex and 2-oxoglutarate dehydrogenase complex. It is known to catalyze the reaction.

As a function of thioctic acid and its reduced form dihydrothioctic acid (6,8-dimercapto-octanoic acid), a strong antioxidant power has been attracting attention in recent years. Superoxide radical, hydroxy radical, peroxy radical, singlet oxygen It reacts easily with reactive oxygen species such as, reacts easily and loses the action of the reactive oxygen species, reduces damage to living tissues, protects cell membranes by interacting with vitamin C and glutathione, It is said to have the effect of regenerating vitamin E. The pharmacological action of thioctic acid is known to be effective for pathological models of oxidative stress such as tissue damage during ischemic reperfusion, diabetes, cataracts, neurodegeneration, radiation damage, inflammatory diseases and the like.

Creatine is a kind of amino acid having another name of 1-methylguanidinoacetic acid or methylglycosiamine. Biosynthesized from ornithine and arginine in vivo, reversibly converted to creatine phosphate, deeply related to ATP production, creatine intake increases creatine phosphate content in muscle, improves exercise performance and fatigue Is known to mitigate. Regarding the influence on bone metabolism, it has been reported that creatine is ingested while carrying out resistance exercise, resulting in an increase in muscle mass resulting in promotion of bone formation (Non-patent Document 2). In addition, when rats are ingested with creatine under exercise, the bone mineral content, bone density, and bone strength of the femur tend to increase (Patent Document 1).

In addition, oysters have a dietary experience that has been provided for daily use, and as nutrients there are glycogen, taurine, amino acids, vitamin groups (A, B ₁ , B ₂ , B ₆ , E, etc.), minerals Products (zinc, calcium, iron, magnesium, iodine, etc.), so they are marketed as seasonings such as oyster extract, oyster oil, oyster sauce, and powders, tablets, capsules, ampoules, etc. It is used as a food and drink for nourishment, health maintenance and disease prevention.

JP 2001-120226 A P. D. Chiribeck et al., The Journal of Nutrition, Health & Aging, Vol. 9, No. 5, pp. 352-355, 2005

In view of the present situation, the present inventors have efficiently promoted bone formation, suppressed bone resorption, or increased bone strength, and bone formation promotion action, bone resorption suppression action or bone strength. An object of the present invention is to develop a preventive and / or ameliorating agent for osteoporosis based on an increasing action and to provide a composition in an aspect that can be effectively used industrially.

In order to solve the above-mentioned problems, the present inventors have conducted extensive studies on the relationship between various raw materials and the ability to promote bone formation, ability to suppress bone resorption, ability to increase bone strength, and ability to prevent and improve osteoporosis. The present invention has been completed by finding that when thioctic acids and creatine are used in combination, the above-mentioned effects are manifested, and that this can be effectively used in the fields of foods and drinks, feeds, cosmetics, pharmaceuticals, etc. .

That is, the first feature of the present invention is an osteogenesis promoter comprising thioctic acids and creatine as active ingredients, and the second feature comprises thioctic acids and creatine as active ingredients. The third feature is a bone strength increasing agent containing thioctic acid and creatine as active ingredients, and the fourth feature is effective thioctic acid and creatine. It is contained as a component and is in an osteoporosis prevention / amelioration agent based on at least one of a bone formation promoting effect, a bone resorption suppressing effect, and a bone strength increasing effect.

In each of the above-mentioned agents, the thioctic acid is one or two selected from the group consisting of thioctic acid, dihydrothioctic acid, their optical isomers, salts, esters, amides, their cyclodextrin inclusions and lipid coatings. Desirably more than seeds. The creatine is preferably one or more selected from the group consisting of creatine salt, creatine hydrate, creatine citrate, tricreatine malate, creatine pyruvate and phosphocreatine.

The fourth feature of the present invention is that each of the above-mentioned agents is further used in combination with oyster meat or oyster meat extract.

The fifth feature of the present invention resides in an oral composition formed by blending at least one of the above-mentioned agents, and the oral composition is preferably a food or drink.

The bone formation promoter, bone resorption inhibitor, bone strength enhancer, and osteoporosis prevention / improving agent of the present invention are excellent in quality stability, and when taken orally, the active ingredient is digested and decomposed in the body. Is effective in promoting osteogenesis, promoting osteogenesis, suppressing bone resorption, and / or increasing bone strength, and is extremely effective in preventing and improving osteoporosis based on at least one of these actions. Useful for maintaining and improving the quality of life. For this reason, the osteogenesis promoter, bone resorption inhibitor, bone strength enhancer and osteoporosis prevention / amelioration agent of the present invention are in the form of each agent in the fields of food and drink, feed, pharmaceuticals, etc. It can be effectively used in a form in which the above-mentioned agents are contained in various products in the field.

The present invention is described in detail below. First, the osteogenesis promoter, bone resorption inhibitor, bone strength increasing agent, and osteoporosis prevention / amelioration agent of the present invention is characterized by containing thioctic acids and creatine as active ingredients.

Here, the origin and type of thioctic acids are not particularly limited, and natural product extracts of organs such as livers of cattle and pigs, and chemical synthetic products starting from ethylene and adipic acid esters are known. It may be collected and manufactured by the method described above. Since thioctic acid has an asymmetric carbon, optically enantiomers (R-enantiomer and S-enantiomer) exist. However, the thioctic acid according to the present invention may be any one of them or a mixture in any ratio. Also, a racemic mixture or a racemate may be used. In the industrial production level, it is easy to use a commercially available racemate that is inexpensive and easily available, and it is desirable to use the racemate because the desired effect of the present invention is more strongly expressed.

As the thioctic acids, various derivatives in addition to the above thioctic acid can be used as appropriate, but reduced forms such as dihydrothioctic acid, optical isomers including racemates, salts, esters and amides thereof, and these It is desirable that it is one or more selected from the group consisting of cyclodextrin inclusions and lipid coatings. Specific examples of the reduced form of thioctic acid include dihydrothioctic acid, dihydrolipoic acid, 6,8-dimercapto-octanoic acid and the like. Similarly, optical racemates include R, S-thioctic acid, R, S-dihydro. Thioctic acid and the like, such as R-thioctic acid, S-thioctic acid, R, S-thioctic acid, R-dihydrothioctic acid, S-dihydrothioctic acid, potassium salt such as R, S-dihydrothioctic acid, sodium salt , Calcium salts, magnesium salts, and the like such as R-thioctic acid, S-thioctic acid, R, S-thioctic acid, R-dihydrothioctic acid, S-dihydrothioctic acid, R, S-dihydrothioctic acid Dihydric alcohol (ethylene glycol, propylene glycol, butanediol, neopentyl glycol, glycerin, erythritol Partial ester or complete ester or glycerides (monoglyceride, diglyceride, triglyceride) with monoglycerin or other monomers or polymers, or higher alcohols having 10 to 22 carbon atoms (decanol, lauryl alcohol, myristyl alcohol, cetanol, stearyl alcohol) And amides such as R-thioctic acid, S-thioctic acid, R, S-thioctic acid, R-dihydrothioctic acid, S-dihydrothioctic acid, R, monoester with oleyl alcohol, isostearyl alcohol, behenyl alcohol, etc.) , S-dihydrothioctic acid, etc., mono-, di- or tri-alkylamines (alkyl residues are methyl, ethyl, propyl, isopropyl, etc.), mono-, di- or tri-alkanolamines (alkyl) Nord residues can be exemplified methanol, ethanol, propanol, various amides derived from isopropanol). In addition, this invention is not limited at all by these illustrations.

Examples of the cyclodextrin inclusion products include inclusion products of α-, β-, γ-, or δ-cyclodextrins, cyclodextrins such as methylated products, hydroxyalkylated products, etc., and the above-mentioned various thioctic acids or derivatives thereof. be able to. The lipid coating is a coating of the outer surface of one or more crystals, powders and / or particles selected from the group consisting of the above-mentioned various thioctic acids or derivatives thereof and these cyclodextrin inclusion products with lipids. It means what you do. The embodiment of the cyclodextrin inclusion and lipid coating is more desirable for achieving the desired effect of the present invention because it suppresses thermal alteration (decomposition, polymerization, discoloration, etc.), moisture absorption or oxidative modification of thioctic acids. is there.

In addition, the lipids in the above-described lipid coating may be acceptable as long as they are acceptable in the industrial field in which the product of the present invention is used, such as general edible oils or industrial fats, fatty acid glycerides, fatty acids, fatty acids. Esters, fatty acid amides, higher alcohols, waxes, sterols, glycolipids, phospholipids and the like can be used alone or in combination. Of these, lipids having a melting point of about 30 ° C. or higher are preferable in consideration of coating workability and physical properties of the coating (stability, solidification, fluidity, meltability, solubility, etc.). More preferred forms are lipids having a melting point of about 40 ° C. to about 70 ° C., and still more preferred forms are lipids having a melting point of about 40 ° C. to about 60 ° C. When the melting point is less than about 30 ° C., the coating may not be able to maintain a solid state during use, and may form a lump or impair flowability. On the other hand, if it exceeds about 70 ° C., the thioctic acids themselves may be deteriorated due to the influence of heat treatment and mechanical energy when producing the agent or composition of the present invention.

A known method can be used to coat thioctic acids with lipids. That is, ball mill, flash blender (powder granule mixer), V-type mixer, high-speed mixer, high-speed paddle mixer, heat-melt mixer, ultrasonic super-humidified liquid-type mixer, tumbler mixer, pressure extruder, etc. The thioctic acid crystals, powder and / or particles and the heated and melted lipids are uniformly mixed, cooled and solidified, and then pulverized. A method of coating by spraying or dripping the lipids which have been formed, and stirring and mixing the thioctic acids of the above-mentioned form and particulate lipids at high speed, and bringing them into contact or colliding with each other, thereby producing crystals, powders and / or thioctic acids. Alternatively, a method in which particulate lipids are uniformly attached to the entire surface of the particle and coated is possible. In the present invention, among these, thioctic acid crystals, powders and / or particles and particulate lipids having a specific melting point or higher are mixed with high-speed stirring, and both are brought into contact with or collided with each other to obtain the thioctic acid of the above form. A method of uniformly coating particulate lipids on the entire surface of acids is preferable.

The ratio of thioctic acids to lipids is generally about 0.05 parts by weight to about 10 parts by weight, more preferably about 0.1 parts by weight to about 5 parts by weight with respect to 1 part by weight of thioctic acids. . If the lipids are less than about 0.05 parts by weight, the coating state is not sufficient and it is difficult to achieve the desired effect. Conversely, if the lipids exceed about 10 parts by weight, the thioctic acid content in the coating is low, In the scene where it is used, the blending rate and the like are limited, and the practical value may be impaired.

Further, when the lipid coating is applied to a water-based composition such as a beverage, an embodiment in which the outer surface is further coated with a hydrophilic substance is even more desirable. Here, the hydrophilic substance means a substance that further coats the outer surface of the coating with lipids and has a coating film-forming ability having an affinity with an aqueous substance. Specific examples include polysaccharides (xanthan gum, guar gum, Tamarind seed gum, psyllium seed gum), starch and modified starch, yeast cell wall components, glucan, mannan, shellac, sodium alginate, gelatin, carrageenan, pullulan, carboxymethylcellulose, soybean protein, whey protein, zein, etc. Can do. More preferably, it is one or more selected from the group consisting of polysaccharides, starch, yeast cell wall components, shellac, gelatin, soybean protein, zein and mannan, and more preferably yeast cell wall components, shellac and gelatin. is there.

In order to coat such a hydrophilic substance, a method according to the above-described method for coating lipids may be employed. That is, the hydrophilic substance is appropriately dissolved in water, ethanol, or other solvent to form a liquid, and this is attached to the outer surface of thioctic acid previously coated with lipids and dried to coat the hydrophilic substance. A film can be formed. The coating thus obtained becomes a double-coated structure having a hydrophilic substance as the outermost layer. When this is used for foods, drinks, feeds, cosmetics, pharmaceuticals, etc., the affinity with aqueous raw materials and ingredients is increased, It becomes easy to prepare a homogeneous composition of thioctic acids with low water solubility.

Next, creatine can be used for each of the above-mentioned agents of the present invention regardless of whether its origin is a natural product or a chemically synthesized product. As specific examples, creatine salts (calcium salt, potassium salt, Sodium salt, magnesium salt, iron salt, zinc salt, etc.), creatine hydrated salt (monohydrate, etc.), creatine citrate, tricreatine malate, creatine pyruvate, phosphocreatine, etc. Species or two or more species can be appropriately selected and used. Of these, creatine calcium salt, creatine monohydrate and tricreatine malate are more preferable, and creatine monohydrate is most preferable. In addition, these creatines are desirably high-purity products in consideration of industrial products to which the respective agents are applied, for example, characteristics of foods and drinks and drugs, palatability, intake amount, and the like.

Each of the above-mentioned agents of the present invention, that is, an osteogenesis promoter, a bone resorption inhibitor, a bone strength increasing agent and an osteoporosis prevention / ameliorating agent contains thioctic acids and creatine, and the ratio of both is However, thioctic acids: creatine is preferably 9 to 1: 1 to 9 (weight ratio), more preferably 3 to 5: 7 to 5. .

Other features of the bone formation promoter, bone resorption inhibitor, bone strength enhancer, and osteoporosis prevention / amelioration agent of the present invention include the addition of oyster meat or oyster meat extract in addition to thioctic acids and creatine. is there.

Here, the oyster meat may be edible if the raw oyster is provided for edible use, and may not be edible if it does not contain toxic or harmful substances. It is not limited by the time. Specific examples of oysters include oysters, American oysters, European oysters, oysters, lobsters, and Portuguese oysters. The aspect of the oyster meat used for each of the above-mentioned agents of the present invention is preferably a raw oyster meat dried by a conventional method or its powder from the viewpoint of storage stability and handleability. Dried oyster meat generally has glycogen: 30 to 40% by weight, taurine: 3 to 5% by weight, vitamin E: 50 to 75 ppm, vitamin B ₁ : _{2 to 5} ppm, vitamin B ₂ : 5 to 10 ppm, vitamin B ₆ : 3-5 ppm, niacin: 60-90 ppm, pantothenic acid: 20-40 ppm, vitamin C: 150-200 ppm, calcium: 4,000-5,500 ppm, magnesium: 3,500-4,500 ppm, iron: 75-130 ppm, Zinc: 500 to 900 ppm, copper: 30 to 70 ppm, manganese: 15 to 25 ppm and the like.

The oyster meat extract is a liquid or obtained by extracting raw or dried oyster meat with water and / or a solvent such as edible alcohol at normal temperature or under heating, at normal pressure or under pressure, and removing the residue. A solid extract. A part of the raw oyster meat nutrients is extracted from the oyster meat extract. In the present invention, for example, oyster meat extract obtained by extracting oyster meat with an acidic aqueous solution or extracting a water extraction residue of oyster meat with ethanol to increase the concentration of mineral components can be used.

The ratio of thioctic acids and creatine and oyster meat or oyster meat extract to be contained in each agent of the present invention is generally thioctic acids and creatine: oyster meat or oyster meat extract = 1: 0. 001 to 1, more preferably 1: 0.01 to 0.5. Below this range, the desired effect of the present invention is not affected, and on the contrary, the desired effect exceeding the predetermined amount is not recognized.

The osteogenesis promoter, bone resorption inhibitor, bone strength enhancer and osteoporosis prevention / amelioration agent of the present invention are the thioctic acids and creatine mentioned above, more preferably further combined with oyster meat or oyster meat extract, If necessary, various excipients, stabilizers, colorants, fragrances, etc. that can be used in the preparation are subjected to processing such as mixing, dispersion, emulsification, dissolution, etc. by conventional methods, and powders, granules, pellets, tablets It can be prepared by processing into any form such as capsule, liquid and the like. The osteogenesis promoter, bone resorption inhibitor, bone strength enhancer, and osteoporosis prevention / improving agent of the present invention is preferably about 10 mg to about 1000 mg of thioctic acid intake per day for humans (body weight 50 kg). Is about 30 mg to about 500 mg, more desirably about 50 mg to about 200 mg, which can be taken into the body by any method such as oral ingestion and tube administration.

The bone formation promoter, bone resorption inhibitor, bone strength enhancer and osteoporosis prevention / amelioration agent of the present invention can be used as various products in food and drink, pharmaceuticals, feed, cosmetics and other industrial fields, Or it can utilize also in the aspect used as a part of compounding raw material of this various products. In particular, it is preferably used in the form of an oral composition, and is suitable for food and drink use. Examples of these are described below, but the present invention is not limited thereby.

Specific examples of food and drink include beverages such as vegetable juice, fruit juice drink, soft drink, tea, soup, jelly, pudding, yogurt, cake premix product, confectionery, sprinkle, miso, soy sauce, sauce, dressing, mayonnaise, Vegetable cream, seasonings for grilled meat sauce and noodle soup, noodles, udon, soba noodles, spaghetti, processed meat and fish products such as ham and sausage, hamburger, croquette, boiled, jam, milk, cream, butter, spread and cheese In addition to various processed foods such as powdered, solid or liquid dairy products, margarine, bread, cakes, cookies, chocolate, candy, gummi, gum, etc., powdered, granular, pills, tablets, Soft capsule, hard capsule, paste or liquid nutritional supplement, food for specified health use, functional food, healthy food , Mention may be made of the diet or the like of the concentrated liquid diet and dysphagia for food.

In order to produce these foods and drinks, one or more appropriately selected from known raw materials and the bone formation promoter, bone resorption inhibitor, bone strength enhancer, and osteoporosis prevention / amelioration agent of the present invention. Or a part of a known raw material may be replaced with at least one of the above-mentioned agents of the present invention and produced by a known method. For example, the hyaluronic acid production enhancer of the present invention and, if necessary, glucose (dextrose), dextrin, lactose, starch or processed product thereof, excipients such as cellulose powder, vitamins, minerals, fats and oils of animals, plants and seafood, Proteins (proteins derived from animals and plants and yeast, hydrolysates thereof), carbohydrates, pigments, fragrances, antioxidants, surfactants, other edible additives, powders and extracts containing various nutritional functional ingredients, etc. Mixed with edible materials and processed into powders, granules, pellets, tablets, etc., processed into general foods of the above examples by conventional methods, mixed liquids such as gelatin, sodium alginate, carboxymethyl cellulose, etc. It is suitable to be used as a dietary supplement or health food by forming a capsule by coating with a coating agent or by processing into a beverage (drink) form. That. In particular, tablets, capsules and drinks are desirable.

The ratio of the agent of the present invention to be blended in such food or drink depends on the form of the food or drink, the purpose of use, the content of thioctic acids and creatine in the agent of the present invention, the type and ingredients of other compounding ingredients, etc. Although it is difficult to define uniformly, thioctic acids and creatine are used so that the thioctic acid content in the food and drink is about 0.01% to about 50% by weight, more preferably about 1% to about 30% by weight. The prescription may be designed by appropriately combining oyster meat or oyster meat extract and other raw materials for food and beverage production, and the desired food and beverage may be prepared according to conventional methods. If the thioctic acid content is less than about 0.01% by weight, a large amount of food and drink must be consumed in order to expect the desired effect of thioctic acids, while about 50% by weight is the maximum thiocto in terms of food and drink design. The acid content.

Next, although an Example is given and this invention is demonstrated in detail, this invention is not limited by this. In each example,%, part and ratio are based on weight unless otherwise specified.

Production Example 1
(1) Cyclodextrin clathrate inclusion powder of thioctic acid 10 g of thioctic acid (trade name: ALIPURE (registered trademark), racemic product) manufactured by Cargill, USA, α-cyclodextrin (manufactured by Wacker Chemie, Germany, product) Name: CAVAMAX (R) W6) 100 g was suspended in an aqueous solution dissolved in 1 L of ion-exchanged water, and dissolved by stirring at 30 to 35 ° C. for 8 hours. Next, this was allowed to stand at 5 ° C. for 12 hours, and the resulting precipitate was recovered and dried under reduced pressure at room temperature to obtain a cyclodextrin inclusion product (thioctic acid content: 19% by weight).

Production Example 2
(2) Thioctic acid lipid coating Crystal powder of thioctic acid (trade name: ALIPRE (registered trademark), racemic body) 200 g and powdered rapeseed oiled oil (manufactured by Kawaken Fine Chemical Co., Ltd., melting point) : 60 ° C., average particle size of about 20 μm) 190 g is charged into a fine particle coating granulator (Powrec Co., Ltd., model: MP-25SFP), and mixed and mixed for 30 minutes at a rotating speed of 1000 rpm of a stirring and mixing fan blade. The two raw materials were brought into contact with each other and collided to obtain a thioctic acid lipid coating having an average particle size of about 100 μm.

Production Example 3
(3) Double coating of thioctic acid A part of the thioctic acid lipid coating described in Production Example 2 was charged into a fine particle coating granulator (manufactured by POWREC Co., Ltd., model: MP-01SFP) and stirred and flowed. The surface of the thioctic acid lipid-coated particles is coated by spraying a dispersion containing 7.7% yeast cell wall (manufactured by Kirin Brewery Co., Ltd., trade name: Yeast Wrap (registered trademark)). I got a thing.

Production Example 4
300 g of edible oyster meat produced in Hiroshima Prefecture is shredded with a mixer, 5 L of water is added thereto and stirred at 80 to 90 ° C. for 2 hours, and then the residue is filtered and the extract is collected, and then dried under reduced pressure to extract oyster meat extract The final 65.7 g was obtained. This oyster meat extract contained glycogen: 41.2%, taurine: 4.3%, calcium: 870 ppm, magnesium: 6,050 ppm, zinc: 570 ppm, manganese: 25 ppm.

Test example 1
Using the components according to the present invention, the effects on bone formation, bone resorption and bone strength were examined by the following methods. In addition, the test substance which is a component according to the present invention includes (1) thioctic acid (referred to as sample 1), (2) thioctic acid cyclodextrin inclusion product (referred to as sample 2) obtained in Production Example 1, (3) ) Thioctic acid lipid coating obtained in Production Example 2 (referred to as sample 3), (4) thioctic acid double coating obtained in Production Example 3 (referred to as sample 4), (5) creatine (referred to as sample 5) ), (6) Oyster meat extract powder obtained in Production Example 4 (referred to as sample 6), (7) 1: 2 mixture of sample 1 and sample 5 (referred to as sample 7), (8) Sample 2 and sample 1: 1 mixture of 5 (referred to as sample 8), (9) 1: 1 mixture of sample 3 and sample 5 (referred to as sample 9), (10) 1: 1 mixture of sample 4 and sample 5 (referred to as sample 8) (Referred to as sample 10), (11) 1: 2: 0.05 mixture of sample 1, sample 5 and sample 6 (referred to as sample 11), (12) sample 2 and sample 5 1: 1: 0.2 mixture with sample 6 (referred to as sample 12), (13) 1: 1: 0.2 mixture of sample 3, sample 5 and sample 6 (referred to as sample 13), (14) A mixture of sample 4, sample 5 and sample 6 was 1: 1: 0,5 (referred to as sample 14). Here, thioctic acid is a product manufactured by Cargill, USA, trade name: ALIPURE (registered trademark), racemate, and creatine are manufactured by Degussa, Germany, product names: CREAPURE (registered trademark), creatine monohydrate.

4-week-old Wistar male rats (purchased from Nippon SLC Co., Ltd., average body weight: 110 g) were preliminarily raised for 1 week, and 6 animals were used for each type of test substance. Control group, test substance (sample 7 to sample) 14) Divided into administration group and comparison test substance (sample 1 to sample 6) administration group. Each group of rats was given the standard diet (AIN-76A) shown in Table 1 twice a day at a predetermined time, the control group was given physiological saline, and the test substance administration group was the test substance (thioctic acid dose). 100 mg / kg body weight), and in the comparative test substance administration group, the comparative test substance (100 mg / kg body weight as the thioctic acid dosage, 200 mg / kg body weight as the creatine dosage, or 100 mg as the oyster meat extract powder dosage / Kg body weight) dissolved or dispersed in physiological saline, each was orally administered once a day and reared for 2 weeks.

Two weeks after the breeding, the rats were decapitated and blood collected, and using the serum, alkaline phosphatase (ALP) activity, which is a typical bone formation marker, and tartrate-resistant phosphatase (TRAP), which is a typical bone resorption marker. ) Activity was measured. The ALP activity was measured by a conventional method using a lab assay ALP kit (manufactured by Wako Pure Chemical Industries, Ltd.) and obtained as a p-nitrophenol equivalent (nmol / L), and the TRAP activity was determined by an ALP & TRAP assay kit (Takara). The amount was measured as a p-nitrophenol equivalent (nmol / L) using a conventional method. In addition, the right femur of the rat was removed, the muscle adhering to the bone was removed, and the maximum load (N) was measured by performing a bending test using a bone strength tester (manufactured by Muromachi Kikai Co., Ltd., TK-252C). The bone strength per 100 g body weight before slaughtering (N / 100 g body weight) was calculated. For these results, the influence of each test substance on bone formation is shown in Table 2, the influence on bone resorption is shown in Table 3, and the influence on bone strength is shown in Table 4.

From Table 2, serum ALP activity was not significantly different from the control group when thioctic acid, cyclodextrin inclusion product of thioctic acid, creatine and oyster meat extract were each administered alone. When thioctic acid and creatine are used together (sample 7), when cyclodextrin inclusion product of thioctic acid and creatine are used together (sample 8), when thioctic acid, creatine and oyster meat extract powder are used together ( In the sample 11), and when the cyclodextrin inclusion product of thioctic acid and creatine are used in combination (sample 12), the serum ALP activity is significantly higher than that in the control group and each single administration group. Was confirmed. From this, it became clear that the combined use of thioctic acids and creatine and the combined use of thioctic acids, creatine and oyster meat extract synergistically promote bone formation.

From Table 3, serum TRAP activity was not significantly different from the control group when thioctic acid, thioctic acid lipid coating, creatine and oyster meat extract were each administered alone. When using acid and creatine together (sample 7), when using a lipid coating of thioctic acid and creatine (sample 9), when using thioctic acid, creatine and oyster meat extract powder together (sample 11), In addition, when the thioctic acid lipid coating and creatine were used in combination (Sample 13), it was confirmed that the serum TRAP activity was significantly lower than that of the control group and each single administration group. From this, it became clear that the combined use of thioctic acids and creatine and the combined use of thioctic acids, creatine and oyster meat extract powder synergistically suppress bone resorption.

From Table 4, the bone strength of the femur was not significantly different from the control group when thioctic acid, a double coating of thioctic acid, creatine and oyster meat extract were each administered alone. However, when thioctic acid and creatine are used together (sample 7), when thioctic acid double coating and creatine are used together (sample 10), when thioctic acid, creatine and oyster meat extract powder are used together ( In sample 11) and when thioctic acid double coating and creatine were used in combination (sample 14), it was confirmed that the bone strength was significantly higher than in the control group and each single administration group. It was done. This revealed that the combined use of thioctic acids and creatine and the combined use of thioctic acids, creatine and oyster meat extract powder synergistically increased bone strength.

Prototype example 1
(1-1) Capsule type osteogenesis promoter, bone resorption inhibitor, bone strength increasing agent, or osteoporosis prevention improving agent (part 1)
Thioctic acid (manufactured by Cargill, USA, trade name: ALIPURE (registered trademark), racemic body) 50 parts, creatine monohydrate (manufactured by Degussa, Germany, trade name: CREAPURE (registered trademark)), 100 parts, beeswax 30 And 50 parts of purified fish oil were mixed and homogenized, and then subjected to a capsule filling machine to prepare a gelatin-coated soft capsule preparation having an internal volume of 300 mg per grain by a conventional method. This capsule preparation can be orally ingested as a bone formation promoter, bone resorption inhibitor, bone strength increasing agent for food use or pharmaceutical use, or at least one of bone formation promoting action, bone resorption inhibiting action and bone strength increasing action It can be used as an osteoporosis prevention and improvement agent based on the above.

Prototype example 2
(1-2) Capsule type osteogenesis promoter, bone resorption inhibitor, bone strength increasing agent, or osteoporosis prevention / improving agent (part 2)
A prototype gelatin-coated soft capsule preparation having an internal volume of 300 mg per grain was produced in the same manner as in Prototype Example 1 except that 50 parts of thioctic acid was replaced with 75 parts of the cyclodextrin inclusion product obtained in Production Example 1.

Prototype example 3
(1-3) capsule type osteogenesis promoter, bone resorption inhibitor, bone strength increasing agent, or osteoporosis prevention / improving agent (part 3)
In Prototype Example 1, 50 parts of thioctic acid was replaced with 50 parts of the thioctic acid lipid coating obtained in Production Example 2, and the same treatment was performed except that 10 parts of oyster meat extract powder obtained in Production Example 4 was used in combination. A gelatin-coated soft capsule preparation with an inner volume of 250 mg per tablet was prepared.

Prototype example 4
(2-1) Tablet-type osteogenesis promoter, bone resorption inhibitor, bone strength enhancer, or osteoporosis prevention / improving agent (part 1)
Thioctoic acid (manufactured by Cargill, USA, trade name: ALIPURE (registered trademark), racemic form) 50 parts, creatine monohydrate (manufactured by Degussa, Germany, trade name: CREAPURE (registered trademark)), 100 parts, crystalline cellulose After 25 parts, 20 parts of corn starch and 1 part of magnesium stearate were uniformly mixed, this mixture was subjected to a direct compression tableting machine to produce a plain tablet having a diameter of 7 mm, a height of 4 mm, and a weight of 150 mg / piece. A tablet was produced by forming a shellac film with a coating machine. This tablet can be orally ingested as a bone formation promoter, bone resorption inhibitor, bone strength increasing agent for food use or pharmaceutical use, or at least one of bone formation promoting action, bone resorption suppressing action and bone strength increasing action. It can be used as an osteoporosis prevention and improvement agent based on this.

Prototype example 5
(2-2) Tablet-type osteogenesis promoter, bone resorption inhibitor, bone strength increasing agent or osteoporosis prevention / improving agent (part 2)
A prototype tablet of 8 mm in diameter and 150 mg in weight was made in the same manner except that 50 parts of thioctic acid in Example 4 was replaced with 100 parts of the thioctic acid lipid coating obtained in Production Example 2.

Prototype Example 6
(2-3) Tablet-type osteogenesis promoter, bone resorption inhibitor, bone strength increasing agent, or osteoporosis prevention / improving agent (part 3)
In Prototype Example 4, 50 parts of thioctic acid was replaced with 50 parts of the thioctic acid double coating obtained in Production Example 3, and the same treatment except that 20 parts of oyster meat extract powder obtained in Production Example 4 was used in combination. Thus, one tablet with a diameter of 8 mm and a weight of 150 mg was made as a trial.

Prototype example 7
(3-1) Beverage powder type bone formation promoter, bone resorption inhibitor, bone strength enhancer or osteoporosis prevention / improving agent (part 1)
100 parts of thioctoic acid cyclodextrin inclusion product obtained in Production Example 1, 100 parts of creatine monohydrate (manufactured by Degussa, Germany, trade name: CREAPURE®), 700 parts of anhydrous crystalline glucose, 60 parts of citric acid 40 parts of malic acid, 50 parts of baking soda and 20 parts of lemon flavor were mixed by a conventional method to produce a powder for beverages. This is a bone formation promoter, bone resorption inhibitor, bone strength increasing agent for food use that can be dispersed or dissolved in an appropriate amount of drinking water and ingested, or bone formation promoting action, bone resorption suppressing action and bone strength increasing action. It can be used as an osteoporosis prevention and improvement agent based on at least one action.

Prototype Example 8
(3-2) Beverage powder type bone formation promoter, bone resorption inhibitor, bone strength enhancer or osteoporosis prevention / improving agent (part 2)
In Prototype Example 7, the same procedure except that 100 parts of cyclodextrin inclusion complex of thioctic acid is replaced with 70 parts of thioctic acid used in Prototype Example 1 and 20 parts of oyster meat extract powder obtained in Production Example 4 is used in combination. After processing, a beverage powder was produced.

Prototype Example 9
(4) Add 2 parts of kefir grains (manufactured by Nippon Kefir Co., Ltd.) to 500 parts of commercially available milk for yogurt-like foods and ferment it at 26 ° C. for 24 hours to make a fermented milk product. A yogurt-like food was prepared by adding 5 parts of thioctic acid and 20 parts of creatine monohydrate and 0.5 parts of orange flavor and mixing well. This product could be eaten in the same way as commercially available yogurt without any discomfort due to the flavor and texture.

The combined use of thioctic acids and creatine, more preferably the combined use of thioctic acids, creatine and oyster meat has an effect of promoting bone formation, an effect of suppressing bone resorption or an effect of increasing bone strength. Effective use in the industrial field as a means for promoting bone formation, suppressing bone resorption, increasing bone strength, or for preventing or improving osteoporosis based on any of the above effects it can.

Claims (6)

  A bone resorption inhibitor comprising thioctic acid and creatine as active ingredients.   A bone strength increasing agent comprising thioctic acid and creatine as active ingredients. The agent according to claim 1 or 2, wherein the thioctic acid is a cyclodextrin inclusion product and / or a lipid coating of thioctic acid. The agent according to claim 1 or 2, wherein the creatine is creatine hydrate. The agent according to any one of claims 1 to 4, further comprising oyster meat or oyster meat extract in combination. An oral composition comprising the agent according to any one of claims 1 to 5 (excluding food and drink) .