JP5006577B2 - Lifestyle-related disease remedy - Google Patents

Description

  The present invention relates to a life-style related disease improving agent, and particularly to improvement of sustained effect of polyphenols which are active ingredients thereof.

    In recent years, with the progress of an aging society, an increase in lifestyle-related diseases has become a problem. In particular, obesity after middle age is considered to be a cause of lifestyle diseases such as hypertension, diabetes and arteriosclerosis. In other words, energy consumption due to lack of exercise is decreasing compared to an increase in calories due to excessive food intake, and the balance of calorie regulation is lost, causing obesity.

  On the other hand, with the aging of society, not only heart diseases and cerebrovascular diseases but also the incidence of cancer has increased, and the development of substances that treat or prevent this has been desired.

  It is known that polyphenols, particularly tea catechins, have an improving action against lifestyle-related diseases such as hypertension. In addition, anthocyanins, which are other polyphenols, are also known to exhibit physiological activities such as antioxidant action.

However, since polyphenols have a short duration in vivo, it has been necessary to ingest them many times during the day in order to obtain such physiological functions. For example, when 100 mg of epigallocatechin in tea catechin is orally ingested by a healthy person, it reaches a maximum blood concentration after 1-2 hours, then gradually decreases, and after 12 hours, it is known that it almost disappears from the blood. (See, for example, Non-Patent Document 1). In addition, these polyphenols have a low absorption rate and are not sufficient to obtain useful physiological functions when taken from normal foods, so if they are not consumed in large amounts and frequently, useful functions can be expressed. I know it ’s not there.
Furthermore, such polyphenols are known to cause water-insoluble precipitation with animal or plant proteins, and this is reported to reduce the absorption of polyphenols (non-patent literature). 2-5).
Nakagawa, T. et al., Biosci. Biotech. Biochem., 61, 1981-1985 (1997) J. Agric. Food Chem. Vol 44, 80-85 (1996) Shokuko, vol48, 913-917 (2001) Shokuko, vol51, 18-22 (2004) Shokuko, vol51, 623-632 (2004)

As described in Non-Patent Document 1 above, in order to obtain the physiological function, polyphenols have no in vivo persistence, and therefore need to be ingested frequently and in large quantities. However, such polyphenols are not only bad in taste, but frequent intake of high concentrations of polyphenols also imposes a heavy burden on the stomach and intestines.
On the other hand, as described in Non-Patent Documents 2 to 5 above, polyphenols form a complex with animal or vegetable proteins, and if these are taken simultaneously from the diet, useful physiological effects are weakened. Can be considered.
In other words, a lifestyle-related disease-improving agent that can sustain the effects of polyphenols, a material that can improve lifestyle-related diseases in anticipation of an aging society in the future, can be effective even with low ingestion frequency, and can improve compliance. It has been demanded.
This invention is made | formed in view of the subject of the said prior art, The objective is to aim at the improvement of the effect sustainability of polyphenol.

As a result of various studies on the sustainability of the effects of polyphenols to solve such problems, the present inventors surprisingly formed a complex with milk protein to release polyphenols in the digestive tract. The inventors have found that the physiological activity can be expressed for a long time, and have completed the lifestyle-related disease improving agent of the present invention.
That is, the lifestyle-related disease improving agent according to the present invention is characterized by containing a complex of polyphenols and milk protein.
In the improving agent, it is preferable that the polyphenols are catechins or anthocyanins.
In the improving agent, the milk protein preferably contains whey protein.

  The lifestyle-related disease improving agent of the present invention can release polyphenols in the stomach or intestine by complexing with milk protein, and can maintain the action of physiological activity for a long time.

  The polyphenols used in the present invention include tea catechins and anthocyanins, all of which exhibit physiological activities such as blood pressure lowering action and antioxidant action.

As the tea catechin source, green tea or gyokuro that has been cooked and cooked as it is after picking the tea leaves that are its raw materials may be used, or oolong tea of semi-fermented tea or black tea of fermented tea may be used. . Furthermore, you may use the post-fermented tea puer tea fermented with microorganisms. In addition, as anthocyanins, foods containing anthocyanins such as berries such as blueberries, granberries and raspberries, beans such as black beans, potatoes such as purple potato and red potato, onion, red cabbage, eggplant skin, etc. Any can be used.
Moreover, as protein which forms a complex with polyphenols, milk proteins, such as raw milk, skim milk, skim milk powder, and the component protein, can be mentioned typically, Casein, whey protein, etc. may be used.

  In using these polyphenols, tea leaves, fruits, and skins may be used as they are, and further, extracts extracted by water extraction, hot water extraction, alcohol extraction, supercritical extraction, or the like may be used. Moreover, those extracts may remain in a liquid state, or a dry solid may be used.

  In order to prepare a complex of polyphenols and milk protein, these may be mixed, and individual properties may be in a solution state, or the solids thereof may be mixed as they are. Moreover, you may use what collect | recovered the precipitate obtained by mixing those solutions as a composite_body | complex. When mixing, 0.01 to 100 parts of milk protein is mixed with 1 part of polyphenol, more preferably 0.1 to 10 parts. Is preferable. When mixing as a solution, a mixer may be used, and some additive may be added to the solution.

Thus, the lifestyle-related disease improving agent of the present invention contains the above complex, and the administration route of such an improving agent may be either oral administration or intrarectal administration, but oral administration is preferred. The dose of such an improving agent to a person cannot be generally stated depending on the administration method, patient's symptoms, age, etc., but the dose of polyphenol is 10 to 500 mg / kg, particularly preferably 50 to 200 mg / kg. It is preferable to adjust so that it is usually 0.1 to 10 g, preferably 1 to 5 g, preferably 1 to 3 times a day.
The improving agent of the present invention is usually administered in the form of a preparation. As the carrier and auxiliary agent used in the preparation, a substance that is commonly used in the preparation field and does not react with the improving agent is used.

  Specifically, for example, lactose, glucose, mannitol, dextrin, cyclodextrin, starch, sucrose, magnesium aluminate metasilicate, synthetic aluminum silicate, sodium carboxymethylcellulose, hydroxypropyl starch, carboxymethylcellulose calcium, ion exchange resin, methylcellulose , Gelatin, gum arabic, hydroxypropylcellulose, hydroxypropylmethylcellulose, polyvinylpyrrolidone, polyvinyl alcohol, light anhydrous silicic acid, magnesium stearate, calcium stearate, talc, tragacanth, bentonite, bee gum, titanium oxide, sorbitan fatty acid ester, sodium lauryl sulfate Glycerin, fatty acid glycerin ester, purified lanolin, glycerogelatin Polysorbate, macrogol, vegetable oils, waxes, liquid paraffin, white petrolatum, fluorocarbons, nonionic surfactants, propylene glycol, and the like.

  Examples of the dosage form include tablets, capsules, granules, powders, syrups, suspensions, suppositories, ointments, creams, gels, patches, inhalants and the like. These preparations are prepared according to a conventional method. In the case of a liquid preparation, it may be dissolved or suspended in water or other appropriate medium at the time of use. Tablets and granules may be coated by a known method.

  These preparations preferably contain the above complex in an amount of 0.01% by weight or more, and further 0.5 to 70% by weight. These formulations may also contain other therapeutically valuable ingredients. In addition, examples of foods specifically targeted when the composition is used by adding to other foods include, but are not limited to, the following.

(1) Agricultural and hydro-acid processed products Harusame, Koshian, Konnyaku, Bread, Noodles (immediate noodles, pasta, raw noodles, dried noodles), rice cakes, cereal foods, processed soybean products (tofu, soy milk, natto, frozen tofu), hydroxy acid processed products [ Kneaded products, (crab flavor) salmon, (fish meat) ham, (fish meat sausage), (fish meat) winner, sprinkle, tea sauce, egg-containing food (soup, salmon, etc.), canned (oil sardine, yakitori), retort Food (curry, stew, spaghetti)
(2) Dairy milk, processed milk, lactic acid bacteria beverages, butter, cheese, condensed milk, powdered milk (3) confectionery cake, mousse, (powder) dessert, ice cream, rice cake, chocolate, gummy, candy, cookies, wafers, jelly ( 4) Seasoning miso, soy sauce, umami (flavor) seasoning, (powder) natural seasoning, sauce, dressing, grilled meat sauce, mirin, curry, stew, spice, spice, yogurt (5) Beverage soft drink (carbonated drink) , Fruit drinks, sports drinks, nutrition drinks), taste drinks (coffee, cocoa, wort)
(6) Health food (dietary supplement)
[1] Saponin-containing foods (Ginseng root-containing foods, Ezokogi-containing foods)
[2] Sugar-containing food [oligosaccharide (fructo-oligosaccharide-containing food, isomalt-oligosaccharide-containing food, galactooligosaccharide-containing food), polysaccharide (shiitake-containing food, mucopolysaccharide, protein-containing food, chondroitin sulfate-containing food, mannambo ) Contained foods), Chitin and chitosan-containing foods]
[3] Mineral-containing foods (calcium-containing foods, alfalfa-containing foods, prunes extract foods, β-carotene-containing foods)
[4] Oils and fats-containing foods Vitamin E-containing oils and fats [wheat (wheat, pigeon) germ oil, soybean germ oil, rice germ oil] eicosapentanoic acid-containing foods, soybean lecithin-containing foods, γ-linolenic acid-containing foods (evening primrose oil, Borage oil), docosahexaenoic acid-containing food [5] protein-containing foods soy protein-containing foods, casein, whey protein, koji processed foods [6] taurine oyster processed foods, shijimi processed foods (7) other processed foods, abnormal amino acid metabolism Food, liquid food (disease food)

  Next, the present invention will be described more specifically with examples. In addition, although the physiological activity was shown about the blood pressure lowering effect, it is not limited to this. In addition, the results are shown as mean ± standard error, and statistical differences were determined by student t-test for statistical processing (P value of less than 0.05 was considered significant).

<Example 1>
A complex of green tea polyphenol (“Sunphenon BG” manufactured by Taiyo Kagaku Co., Ltd.) and milk protein was obtained as follows. That is, 194.4 g of green tea polyphenol (“Sanphenon BG” manufactured by Taiyo Kagaku Co., Ltd.) and 300 g of milk protein obtained by dialyzing skim milk powder (manufactured by Meiji Dairies) with a dialysis membrane are suspended in 1 L of physiological saline to obtain a complex. It was.

(Measurement of blood pressure lowering effect)
A 20-week-old SHR (n = 4) in which the above-mentioned tea polyphenol complex is dissolved in physiological saline is orally administered using a sonde needle so that the tea polyphenol is 162 mg / kg. Was measured over time by the tail-cuff method, and the maximum antihypertensive value in systolic blood pressure was examined. The results are shown in FIG.

<Comparative Example 1>
The same evaluation as in the examples was performed using only green tea polyphenol (“Sunphenon BG” manufactured by Taiyo Kagaku Co., Ltd.).

  As shown in FIG. 1, in the group administered with the complex of tea polyphenol and milk protein of the example, the blood pressure gently decreased after administration, and the blood pressure decreased significantly even 8 hours after administration, and it lasted for a long time. The blood pressure lowering effect was shown. In the tea polyphenol single administration group of Comparative Example 1, a transient blood pressure lowering effect was observed 2 hours after the administration, but then it quickly increased to the original blood pressure value.

<Example 2>
[Effect of milk protein on blood pressure lowering effect of tea catechin]
In view of the results of Example 1 and Comparative Example 1, the present inventor conducted further detailed studies on the effects of tea catechins, milk proteins, and complexes thereof.
In this example, skim milk powder was manufactured by Meiji Dairies. In order to remove the effects of lactose contained in about half of the skim milk powder, the skim milk powder was dialyzed, freeze-dried milk protein (300 mg / kg), and tea catechin (160 mg / kg Sanphenon BG, manufactured by Taiyo Chemical Co., Ltd.) A mixture in a normal saline solution was orally administered to SHR, and blood pressure was measured every 2 hours by the Tail Cuff method (MK-2000, manufactured by Muromachi Kikai).
In the tea catechin alone administration group, a transient blood pressure lowering effect was observed in which both blood catechin 50 mg / kg and 160 mg / kg administration groups had the lowest blood pressure 2 hours after administration and then increased (FIG. 2). ). On the other hand, as shown in FIG. 3, the tea catechin + milk protein administration group showed a continuous blood pressure lowering effect from 2 hours to 8 hours after administration. In addition, milk protein alone showed a weak blood pressure lowering effect 2 to 4 hours after administration, but it recovered to the pre-administration level after 8 hours, and the milk protein + tea catechin group was sustained. The blood pressure lowering effect is thought to be due to a synergistic action rather than a simple additive action of milk protein and tea catechin.

Further, even when skim milk powder containing lactose (280 mg / kg) and tea catechin were mixed and orally administered, the blood pressure lowering action was sustained (FIG. 4). Since this skim milk powder contains 35% protein, 100 mg / kg of milk protein was administered, and even 1/3 of the amount of milk protein in the above experiment was sustained by interaction with tea catechin. It became clear to give.
The cause of such a specific action in the present invention has not yet been fully clarified, but when milk protein is administered as a catechin complex, it is digested by digestive tract proteases in the body. It is considered that catechin is gradually released and a continuous blood pressure lowering effect can be obtained.

<Example 3>
[Sustained blood pressure lowering action by casein and whey protein]
Next, to clarify whether casein, which accounts for 80% of milk protein, or whey protein, which accounts for 20%, is important for sustaining the blood pressure lowering action of catechin, lactate casein (manufactured by Nippon Protein) and separated milk It was examined using a purified protein (WPI, manufactured by DAVISCO INTERNATIONAL). First, in the case of a mixture of 240 mg / kg casein equivalent to 300 mg / kg milk protein and tea catechin, blood pressure decreased 2 hours after administration, but the blood pressure lowering effect began to disappear after 6 hours. The blood pressure lowering effect was weaker than that of milk protein (FIG. 5). On the other hand, in the administration of a mixture of catechin and 240 mg / kg whey protein, as in the case of the mixed administration of milk protein 300 mg / kg, no blood pressure lowering effect was observed 2 hours after administration, and blood pressure decreased 6 hours after administration. The effect was recognized (FIG. 6). In addition, 60 mg / kg whey protein corresponding to the amount contained in 300 mg / kg milk protein was observed to have a sustained blood pressure lowering effect equivalent to 240 mg / kg. From the above, it is considered that whey protein having a small abundance ratio rather than casein, which is the main component of milk protein, has a larger contribution to the blood pressure lowering sustaining action. One possible cause is that casein is digested more rapidly than whey protein, so the duration is short.

<Comparative example 2>
Next, when 300 mg / kg separated soy protein (SPI, manufactured by Fuji Oil Co., Ltd.) and tea catechin in the same amount as milk protein were mixed and administered to SHR, no blood pressure lowering effect was observed (FIG. 7). . This means that the blood pressure lowering effect of catechin and soy protein disappeared by mixing them. This may be because soy protein forms a strong complex with tea catechin, so that its digestion in the body is inhibited, and the release of blood pressure-lowering peptides derived from catechin and soy protein is inhibited.
From the above, it was found that the effect of maintaining the blood pressure lowering action of catechin is an action specific to milk protein. As its mechanism, milk protein, especially whey protein, forms a complex based on moderate affinity with catechin, and releases catechin as it is gradually digested in the body, and its intestinal absorption It is considered that a delayed blood pressure lowering effect is exhibited.

<Example 4>
[Persistence of blood pressure lowering action by β-lactoglobulin and α-lactalbumin]
Furthermore, the present inventor examined the persistence of the blood pressure lowering action of each catechin of β-lactoglobulin and α-lactalbumin, which are the main components of whey protein. First, in the case of a mixture of 60 mg / kg β-lactoglobulin and 162 mg / kg green tea polyphenol (tea catechin), blood pressure decreased continuously until 6 hours after administration. Reached 8 hours later. On the other hand, in the case of a mixture of 60 mg / kg α-lactalbumin and 162 mg / kg green tea polyphenol, the blood pressure did not decrease until 6 hours after administration, and the blood pressure remained high at -15 mmHg even after 8 hours. Was.
From the above points, both whey proteins α-lactalbumin and β-lactoglobulin showed a high effect on sustaining the effect of polyphenols, but it is understood that the sustained effect of α-lactalbumin is particularly remarkable.

It is a graph which shows the blood pressure fall value in each time after each administration of tea catechin and tea catechin and milk protein complex. It is explanatory drawing of the blood pressure lowering effect of tea catechin alone. It is explanatory drawing of the influence of milk protein on the blood pressure lowering effect of tea catechin. It is explanatory drawing of the influence of skim milk addition on the blood pressure lowering effect of tea catechin. It is explanatory drawing of the influence of casein with respect to the blood pressure lowering effect of tea catechin. It is explanatory drawing of the influence of whey protein with respect to the blood pressure lowering effect of tea catechin. It is explanatory drawing of the influence of soy protein on the blood pressure lowering effect of tea catechin. It is explanatory drawing of the influence of (alpha) -lactalbumin and (beta) -lactoglobulin on the blood pressure lowering effect of tea catechin.

Claims (2)

Hypertension improving agent characterized by containing green tea polyphenol or tea catechins, a complex with milk protein. The hypertension improving agent according to claim 1, wherein the milk protein contains whey protein.