JP2008013473A - Muscle hypofunction inhibitor - Google Patents

Abstract

<P>PROBLEM TO BE SOLVED: To provide a medicine and a food and drink, having excellent actions of suppressing amyotrophy, suppressing brawn hypofunction accompanied thereby and suppressing bedridden state caused by exercise ability decrease, and excellent in safety. <P>SOLUTION: An amyotrophy inhibitor and a brawn hypofunction inhibitor, comprising catechin as an active ingredient is provided. And the above-mentioned myoatrophy inhibitor, which amyotrophy is disuse amyotrophy or sarcopenia, is provided. <P>COPYRIGHT: (C)2008,JPO&INPIT

Description

  The present invention relates to a pharmaceutical or a food or drink that exhibits an effect of suppressing muscle function deterioration such as muscle atrophy or muscle strength reduction.

  In general, muscle atrophy in which muscle mass and muscle strength decrease include disuse muscle atrophy and sarcopenia. When muscle atrophy occurs, muscle function declines accordingly.

  In particular, elderly people have muscle atrophy and a decrease in muscle strength due to aging, and are more likely to suffer muscle damage or fracture. When the patient is placed in a resting state for the treatment or medical treatment or restricted by activities such as fixing the cast, disuse muscle atrophy and muscle function decrease rapidly.

  Elderly people are likely to fall into such a vicious circle and become bedridden in the worst case. Therefore, in order to improve life function, extend healthy life expectancy, and maintain quality of life (QOL), encourage some exercise. It is important to prevent disuse muscular atrophy and decline in muscle function, to maintain exercise ability, and to keep the body function generally good (10 items to zero bedridden, Ministry of Health and Welfare, 1990) ).

  Until now, attempts to prevent muscle atrophy and muscle function decline have been limited to continuation of moderate exercise or physical therapy for rehabilitation at normal times, and a more effective suppression method has been desired.

  From such a viewpoint, not only exercise and physical therapy, but also a search for a component that can prevent muscle atrophy and the accompanying decrease in muscle function and eventually bedridden. For example, prevention of aging by cystine and theanine (Patent Document 1), suppression of muscle atrophy by fruit polyphenol (Patent Document 2), suppression of muscle protein degradation by lycopene (Patent Document 3), reduction of muscle oxidative stress by superoxide dismutase (Patent Document) 4) etc.

On the other hand, catechins contained in green tea, black tea, and the like have an inhibitory effect on cholesterol elevation (Patent Document 5), an inhibitory action on blood sugar increase (Patent Document 6), an endurance improving action (Patent Document 7), and an inhibitory effect on muscular dystrophy. (Non-Patent Document 1) and the like have been reported to have physiological benefits. However, the effects of catechins on disuse muscular atrophy and associated muscular function decline have never been known.
International Publication No. 2005-123058 Pamphlet JP 2001-89387 A JP 2004-59518 A JP 2006-62976 JP-A-60-156614 JP-A-4-539918 JP 2005-89384 A Dorchies OM et al, AJP-Cell Physiol, 616-25, 2006

  An object of the present invention is to provide a highly safe pharmaceutical product or food or drink useful for bedridden prevention by suppressing muscle function decline or muscle atrophy.

  Then, when this inventor examined the component derived from a natural product, it discovered unexpectedly that catechins have the outstanding muscular-atrophy suppression and muscular-strength suppression effect also under action restriction | limiting.

That is, this invention provides the bedridden preventive agent which uses catechin as an active ingredient.
Moreover, this invention provides the muscle function fall inhibitor which uses catechin as an active ingredient.
Moreover, this invention provides the muscular atrophy inhibitor which uses catechin as an active ingredient.
Moreover, this invention provides use as a muscular function fall inhibitor, a muscular-atrophy inhibitor, and / or a bedridden preventive agent of catechin.
Moreover, this invention provides use for manufacture of the muscle function fall inhibitor of catechins, a muscular atrophy inhibitor, and / or bedridden prevention agent.
Furthermore, the present invention is characterized by containing catechins and acting on the suppression of muscle function decline and / or muscle atrophy, and the indication that it is used for suppressing muscle function decline, muscle atrophy and / or bedridden prevention. The food / beverage provided is provided.

  That is, according to the present invention, it is possible to provide highly safe food and drink, pharmaceuticals and the like that suppress a decrease in muscle function and exhibit bedridden prevention effects.

In the present invention, “muscle atrophy” refers to a decrease in muscle mass due to a decrease or reduction in muscle cells, such as cast fixation by prolonged bed rest or fracture, or exposure to microgravity (disused muscles). Atrophy) and those associated with aging (called sarcopenia). Therefore, “suppression of muscle atrophy” refers to suppressing the decrease in muscle mass associated with inactivity and aging.
Further, in the present invention, “muscle function decrease” means that muscles structurally or qualitatively change with muscle atrophy, resulting in a decrease in muscle strength and exercise capacity. Therefore, “suppression of muscular function deterioration” refers to suppression of a decrease in muscular strength and exercise capacity associated with muscle atrophy.
In addition, the term “bedridden” as used herein refers to those that are created from a bedridden state in which, for example, the amount of exercise is extremely reduced in the treatment or medical treatment of stroke or fracture of the elderly, and the muscle function is further reduced. 10 articles to zero bedridden, Ministry of Health, 1990).

  Catechin in the present invention is a generic term for non-epimeric catechins such as catechin, catechin gallate, gallocatechin and gallocatechin gallate, and epimeric catechins such as epicatechin, epigallocatechin, epicatechin gallate and epigallocatechin gallate. It is preferable to contain one or more of these. The catechins are preferably non-polymers.

  The catechins used in the present invention can generally be obtained by direct extraction from tea leaves or by concentrating or purifying the tea extract, but those derived from other raw materials, column purified products and chemicals It may be a synthetic product.

The tea extraction is carried out by adding water or hot water or an extraction aid to these tea leaves made from tea leaves obtained from the genus Camellia, such as C. sinensis, C. assamica, or hybrids thereof, followed by stirring extraction, etc. This can be done. Moreover, you may use together the method of extracting in so-called non-oxidative atmosphere, ventilating inert gas, such as boiling deaeration and nitrogen gas, and removing dissolved oxygen. Examples of the extraction aid include organic acids such as sodium ascorbate or organic acid salts thereof.
The tea leaves produced are: (1) Green teas such as Sencha, Bancha, Gyokuro, Tencha, Kamasencha; (2) Iron Kannon, color types, golden katsura, wushuiwa tea, etc. (3) Fermented teas such as Darjeeling, Uba, and Keyman called black tea are included.

Concentration of the tea extract can be performed by concentrating the extract, and purification of the tea extract can be performed by purification using a solvent or a column. Various forms such as a solid, an aqueous solution, and a slurry are exemplified as the form of the concentrate or purified product of the tea extract.
For example, the tea extract can be prepared by a method exemplified in detail in JP-A-59-219384, JP-A-4-20589, JP-A-5-260907, JP-A-5-306279, etc. it can. Commercial products can also be used, such as Mitsui Norin Co., Ltd. “Polyphenone”, ITO EN “Teafuran”, Taiyo Kagaku Co., Ltd. “Sunphenon”, Suntory Co., Ltd. Or the like.

The catechins in the tea extract are present as non-polymers and dissolved in a liquid or as solids adsorbed or included in a suspension of fine tea powder.
Moreover, content of the catechin in the said extract is 30-98 mass%, Preferably it is 40-90 mass%. Moreover, the content rate of catechins in these total polyphenols is 10 mass% or more in the amount of catechin immediately after manufacture, Preferably it is 20 mass% or more.

  In addition, most of the catechins in tea leaves exist as epi-catechins, and these epi-catechins can be converted to non-epi-isomers that are stereoisomers by treatment with heat, acid, alkali, etc. Can do. Accordingly, when non-epimeric catechins are used, an extract from green tea, semi-fermented tea or fermented tea or a concentrate of tea extract is made into an aqueous solution, for example, 40 to 140 ° C., 0.1 It can be obtained by heat treatment for min to 120 hours. Moreover, you may use the concentrate of the tea extract with high non-epicatechin content. They may be used alone or in combination.

  As shown in Examples below, catechins have the effect of suppressing the decrease in muscle mass and the decrease in maximum muscle strength that occur under behavioral restrictions such as tenotomy and tail suspension treatment, the muscle function decrease inhibitor muscle, the suppression of atrophy In order to produce a bedridden preventive agent (hereinafter referred to as “muscle function lowering inhibitor, etc.”) that suppresses bedridden conditions caused by agents and muscle function decline, and for producing muscle atrophy inhibitor, etc. Can be used. The muscular atrophy inhibitor, etc. is used to reduce the amount of exercise due to life under restricted activities such as bed rest, cast casts, sitting, etc., reduce overload on the body, and suppress muscular atrophy and muscle function decline due to aging. It is useful as a food or drink for humans or animals or a pharmaceutical product that exhibits the effect. In addition, when used as a food or drink, the concept is a physiological function of suppressing muscle atrophy, suppressing muscle weakness, or bedridden prevention, and a food or drink displaying such effect, such as food for the sick, food for the elderly, specific It can be applied to special-purpose food and drinks such as insurance foods and functional foods.

  The catechins of the present invention are used for the suppression of muscle atrophy, but are preferably used for the suppression of muscular atrophy associated with aging and disuse muscular atrophy, particularly disuse muscular atrophy. It is used for suppression of muscular weakness caused by atrophy.

When using the muscle function lowering inhibitor or the like of the present invention as a pharmaceutical product, for example, oral solid preparations such as tablets and granules, orally, enteral or tube use such as elixirs, syrups and suspensions It can be set as a liquid formulation.
Oral solid preparations are prepared by adding excipients, binders, disintegrating agents, lubricants, coloring agents, flavoring agents, flavoring agents, etc. to catechins, and then adding tablets, coated tablets, granules by conventional methods. An agent, a powder, a capsule, etc. can be manufactured. Examples of the excipient include sugars such as lactose and saccharose, amino acids such as glycine, and cellulose. Examples of the lubricant include silicon dioxide, talc, magnesium stearate, and polyethylene glycol, and examples of the binder include starch, gelatin, methyl cellulose, and polyvinyl pyrrolidone. Disintegrants include starch and agar.
In addition, liquid preparations can be used to produce oral liquids, elixirs, syrups, suspensions and the like by conventional methods with the addition of flavoring agents, buffering agents, stabilizers, flavoring agents and the like.

Moreover, when using the muscle function fall inhibitor of this invention, etc. as food-drinks, for example, cheese (natural, process), ice cream, yogurt and other dairy products, sauce, soup, sprinkles, Japanese confectionery (seibei etc.) ), Confectionery (potato chips, pudding, jelly, gummy candy, candy, drop, caramel, chocolate, chewing gum, etc.), baked confectionery (castella, cake, donuts, biscuits, cookies, crackers, etc.), various beverages, etc. It can be.
When manufacturing food and drink, various raw materials used in general food and drink can be blended with catechins and processed and manufactured by ordinary methods.

  Beverages include carbonated drinks (soft drinks), non-carbonated drinks (fruit juice drinks, nectar drinks, vegetable drinks, etc.), soft drinks, sports drinks, near water, diet drinks, tea, coffee, cocoa, alcoholic drinks, etc. However, a wider range of beverages can be provided by combining with other beverage components.

The beverage is preferably a packaged beverage filled in a container. Examples of the packaged beverage include a non-tea-based packaged beverage described in Japanese Patent Publication No. 3749494 and a tea described in Japanese Patent Application Laid-Open No. 2002-272373. A system-packed drink can be illustrated. An example of the composition is shown below.
The container-packed beverage contains the non-polymer component (A) non-epi-catechins and (B) epi-catechins, and the content thereof per 500 mL of the container-packed beverages,
Component (A) = total amount 5-2250 mg,
Component (A) + (B) = total amount 50-2500 mg,
Mass ratio (A) / (B) = 0.1-9.0
Containing.

  Non-polymeric component (A) non-epimeric catechins dissolved in water and component (B) epimeric catechins that are also non-polymeric and dissolved in water, total per 500 mL of beverage An amount of 50 to 2500 mg is contained, preferably 460 to 2500 mg, more preferably 500 to 1300 mg, still more preferably 600 to 1300 mg, and particularly preferably 640 to 800 mg from the viewpoint of taste.

Component (A) is contained in an amount of 5 to 2250 mg per 500 mL of beverage, preferably 90 to 2250 mg, more preferably 140 to 2250 mg, and particularly preferably 140 to 1880 mg from the viewpoint of stability.
In the beverage, the content of catechins in the total polyphenol is 10% by mass or more, preferably 20% by mass or more immediately after production.

  Furthermore, the mass ratio of component (A) to component (B) is (A) / (B) = 0.1-9.0, preferably 0.25-9.0, more preferably 0.43. -5.67, especially 0.67-5.67 are preferred from the point of taste and stability.

  Further, when the content of catechins is 30 to 98% by mass, preferably 40 to 90% by mass, selected from epigallocatechin gallate, gallocatechin gallate, epigallocatechin, and gallocatechin, it is presented as a beverage. The taste is even better, and it is preferable without the astringency that pulls behind. Here, one or more types of epigallocatechin gallate, gallocatechin gallate, epigallocatechin, and gallocatechin are contained, but usually all are contained.

  The pH of the beverage is preferably 3 to 7, preferably 4 to 7, particularly 5 to 7 at 25 ° C. in terms of taste and chemical stability of catechins.

  The beverages described above are antioxidants, fragrances, various esters, organic acids, organic acid salts, inorganic acids, inorganic acid salts, inorganic salts, pigments, emulsifiers, preservatives, seasonings, sweeteners in accordance with catechins. Additives that may be added in the formulation such as acidulant, fruit juice extract, vegetable extract, nectar extract, pH adjuster, quality stabilizer, etc., may be used alone or in combination as appropriate.

  Containers to be used are provided in normal forms such as molded containers (so-called PET bottles) based on polyethylene terephthalate, metal cans, paper containers combined with metal foil and plastic films, bottles, etc. can do. A drink here means what can be drunk without dilution.

  For example, if the container can be heated and sterilized after being filled into a container like a metal can, the container is manufactured under sterilization conditions defined in the Food Sanitation Law. For PET bottles and paper containers that cannot be sterilized by retort, sterilize under the same conditions as above, for example, after sterilizing at high temperature and short time with a plate heat exchanger, etc. The method is adopted. Moreover, you may mix | blend another component with the filled container under aseptic conditions. Furthermore, after sterilization by heating under acidic conditions, the pH can be returned to neutrality under aseptic conditions, or after sterilization by heating under neutral conditions, the pH can be returned to acidic conditions under aseptic conditions.

Examples of the food for patients include enteral nutrients and concentrated liquid foods (food) that are administered to elderly people who are difficult to supplement with an appropriate amount of nutrition or those who are in bed rest.
Enteral nutrients and concentrated liquid foods can be produced by mixing catechins with raw materials for nutritional compositions and using conventional methods. Specifically, catechins and various raw materials are dissolved and mixed in an appropriate solvent, homogenized with a homogenizer, etc., filled into various containers such as retort and plastic, and then liquid, semi-solid by a known sterilization method. Or a solid preparation can be obtained. Moreover, after homogenizing with a homogenizer etc. as mentioned above, a powdery formulation can also be obtained by well-known spray drying etc.

An example of a nutritional composition is a nutritional composition containing protein, saccharides, fat, trace elements, vitamins, emulsifiers, fragrances and the like. Examples of protein sources include proteins such as milk protein, soy protein, egg albumin, etc., which are well-balanced in amino acids, but are not limited to these degradation products, egg white oligopeptides, soy hydrolysates, etc. A mixture of these may also be used.
The administration (intake) amount of the nutritional composition is preferably 10 to 50 kcal / kg body weight per day for an adult in terms of calories as a nutritional agent.

  The amount of catechins contained in the muscle atrophy inhibitor of the present invention varies depending on the use form, but in the case of food or pet food, it is usually 0.01 to 5% by mass, and further 0.05 to 5% by mass In particular, the content is preferably 0.1 to 1% by mass. In the case of pharmaceuticals other than the above, for example, oral solid preparations such as tablets, granules and capsules, oral liquid preparations such as oral liquids and syrups, etc., usually 0.01 to 95% by mass, and further 5 to 95% by mass. %, Particularly 10 to 95% by mass.

  The dose (effective intake) of the muscle atrophy inhibitor of the present invention is preferably 100 to 3000 mg / 60 kg body weight per day, particularly 250 to 2000 mg / 60 kg body weight, more preferably 250 to 1000 mg / 60 kg body weight. Is preferred. It is clear that the dose varies depending on the age, weight, symptom level, etc. of the patient to be administered.

  The sample used in Examples 1 and 2 was a green tea extract having a total catechin amount of 81%. The composition of catechins is as follows: gallocatechin (7%), gallocatechin gallate (4%), epicatechin (9%), epigallocatechin (23%), epicatechin gallate (12%), epigallocatechin gallate ( 41%) and others (4%).

Example 1 Efficacy of catechins in Tenotomy treated mice Male Balb / c mice (9 weeks old) were preliminarily raised for 1 week and grouped into 3 groups (non-treated group, control group, catechin group) based on body weight. The groups were divided (each group n = 8). Thereafter, each group of mice was fed a feed prepared with the formulation shown in Table 1 for 2 weeks.

  After feeding the above feed for two weeks, the control group and the catechin group were subjected to tenotomy treatment on the hindlimb Achilles tendon of the mouse, and the tension load on the muscle group (such as the soleus muscle) belonging to the hindlimb calf region was removed. Muscles with reduced tension exhibit disuse muscle atrophy, which reduces muscle mass and strength. The untreated group did not receive tenotomy treatment.

Measurement of muscle strength in isolated muscles Two weeks after the tenotomy treatment, breeding with the test diet was continued, and the mice were subjected to dissection. The soleus muscle was removed from the mouse and fixed to a transducer (WPI: FORT100) in a Krebs solution at 37 ° C. (aeration conditions: 95% -oxygen, 5% -carbon dioxide). Thereafter, electrical stimulation (0.2 msec, 40 Hz) was applied to measure the maximum muscle strength. FIG. 1 shows the wet mass of the soleus muscle, and FIG. 2 shows the measurement results of muscle strength.

Example 2 Effectiveness of catechins in tail suspension treated mice Male Balb / c mice (9 weeks old) were preliminarily raised for 1 week and divided into 3 groups (non-treated group, control group, catechin group) based on body weight. (Each group n = 8). Thereafter, each group of mice was fed the test feed prepared with the formulation shown in Table 1 above for 2 weeks.

  After feeding the test diet for 2 weeks, mice in the control group and the catechin group were subjected to tail suspension treatment, and the gravity load on the hind limb muscle group (such as the soleus muscle) was eliminated. Muscles with reduced load exhibit disuse muscle atrophy and muscle mass and strength decrease. The untreated group did not receive tail suspension treatment.

Measurement of muscle strength in the isolated muscle For 10 days after the tail suspension treatment, the animals were kept on the test feed and subjected to dissection. The soleus muscle was removed from the mouse and fixed to a transducer (WPI: FORT100) in a Krebs solution at 37 ° C. (aeration conditions: 95% -oxygen, 5% -carbon dioxide). Thereafter, electrical stimulation (0.2 msec, 40 Hz) was applied to measure the maximum muscle strength. FIG. 3 shows the wet mass of the soleus muscle, and FIG. 4 shows the measurement results of the muscle strength.
From the results of Test Examples 1 and 2, the ingestion of catechins suppressed muscle atrophy and also suppressed muscle weakness. In Tests 1 and 2, almost no improvement in muscle mass and muscle strength was observed due to pre-treatment administration of catechins. From this, it is clear that catechins have an effect of suppressing muscle atrophy and muscle function decline accompanying a decrease in muscle activity, and can be said to be useful as a bedridden inhibitor or a muscle function decline inhibitor.

Example 3 Various Formulation Examples Formulation Example 1 Beverage for suppression of muscle function decline / muscular atrophy suppression / bedridness prevention (hereinafter referred to as suppression of muscle function decline, etc.) The formulation of the present invention is tea with the formulation and conditions shown in Table 2. It was prepared as a system beverage. Table 3 shows the composition of catechins in this beverage. The storage stability and flavor of this beverage were good.

Formulation Example 2 Enteral nutrient for suppression of muscle function decline etc. In the formulation shown in Table 4, the formulation of the present invention was sealed in a retort container as an enteral nutrient, sterilized according to a conventional method of high-pressure steam sterilization, and prepared . Minerals, Na, K, Ca, Mg , P, Cl, organic or inorganic salt mixture such as Fe, vitamins, vitamins A, D, E, vitamin _{B 1, B 2, B 6} , B 12, C A mixture of niacin, pantothenic acid, etc. was used in an amount consistent with national nutrition requirements.

Formulation Example 3 Jelly Food for Suppressing Muscle Function Reduction The formulation of the present invention was prepared as a jelly food. Carrageenan and locust bean gum mixed gelling agent 0.65%, grapefruit 50% concentrated juice 5.0%, citric acid 0.05%, vitamin C 0.05%, theavigo (DSM Nutritional Products) 0. 54% was mixed, water was added to this to adjust to 100%, and the mixture was dissolved at 65 ° C. Further, a small amount of grapefruit flavor was added and kept at 85 ° C. for 5 minutes, sterilized, and dispensed into a 100 mL container. A jelly food containing catechins having good mouth meltability, fruit flavor and good texture when placed in the mouth, gelled by cooling to 5 ° C. while allowing to cool for 8 hours. It was.

Formulation Example 4 Vitamin internal use liquid for suppressing muscle function deterioration etc. The preparation of the present invention was prepared as a vitamin internal use liquid. Taurine 800mg, sucrose 11000mg, caramel 50mg, sodium benzoate 30mg, vitamin B1 nitrate 5mg, vitamin B2 20mg, vitamin B6 20mg, vitamin C 2000mg, vitamin E 100mg, vitamin D3 2000IU, nicotinamide 20mg, polyphenone 70S (Mitsui Norin) ) 540 mg was added to an appropriate amount of purified water for dissolution, adjusted to pH 3 with an aqueous phosphoric acid solution, and further purified water was added to make the total volume 50 mL. This was sterilized at 80 ° C. for 30 minutes to obtain a vitamin oral solution containing catechins.

Formulation Example 5 Chewable tablet for suppressing muscle function deterioration etc. The formulation of the present invention was prepared as a chewable tablet. Ascorbic acid 180 mg, citric acid 50 mg, aspartame 12 mg, magnesium stearate 24 mg, crystalline cellulose 120 mg, lactose 274 mg, Tearfuran 90S (Itoen) 540 mg in a formula (daily dosage 1200 mg) in the Japanese Pharmacopoeia (General Formula “Tablet”) According to the same manner, tablets were produced to obtain chewable tablets containing catechins.

Formulation Example 6 Tablets for Inhibition of Muscle Function Reduction etc. The formulation of the present invention was prepared as a tablet by a conventional method based on the following formulation. Ingredient blending amount (mass%): Polyphenone 70S (Mitsui Norin) 20, Sodium malate 20, Palatinose 20, Ascorbic acid 20, Vitamin mix (manufactured by Nippon Fragrance Chemicals) 5, Crystalline cellulose 5, Sucrose ester 4, Silicon dioxide 1. Eggshell calcium 5.

Soleus mass (mg) in the control and catechin groups in the tenotomy treatment and in the non-treatment group. Maximum muscle strength (g) of the control and catechin groups in the tenotomy treatment and the untreated group. The soleus mass (mg) of the control group and the catechin group in the tail suspension treatment and the non-treatment group. Maximum muscle strength (g) of the control group and catechin group in the tail suspension treatment and the non-treatment group.

Claims (7)

  A muscle function lowering inhibitor containing catechins as an active ingredient.   A muscle atrophy inhibitor comprising catechins as active ingredients.   The inhibitor according to claim 2, wherein the muscle atrophy is disuse muscle atrophy or sarcopenia.   Bedridden preventive agent containing catechins as active ingredients.   Use of catechins as a muscle function lowering inhibitor, muscle atrophy inhibitor and / or bedridden prevention agent.   Use of catechins for the production of a muscle function lowering inhibitor, a muscle atrophy inhibitor, and / or a bedridden preventing agent.   A food / beverage product containing catechins, which acts to suppress muscle function deterioration and / or muscle atrophy, and is labeled for use to suppress muscle function deterioration, muscle atrophy and / or bedridden prevention.