JP4771064B2 - Coffee-like supplements and supplements - Google Patents

Description

  The present invention relates to supplements and supplements containing roasted coffee ingredients, which are health promoting ingredients, and more preferably to coffee-like supplements and coffee-like supplements.

Coffee products have a unique flavor, and are loved as a luxury product for relaxing the stress and so on in modern society. On the other hand, there is a concern that a large intake of conventional coffee products increases the risk of cardiovascular disease (for example, see Non-Patent Document 1).
Further, decaffeinated coffee (hereinafter simply referred to as “decaffeinated coffee”) has been widely consumed in order to avoid the above-mentioned concerns and caffeine stimulation. However, the umami component and the fragrance component are lost in an arbitrary caffeine extraction process such as a water extraction method, and the decaf product has a disadvantage that the flavor is inferior.
On the other hand, the Maillard reaction product, which is known to be contained in a minute amount as an aroma and flavor component in roasted coffee beans, is melanoidin formed by reacting amino acids and reducing sugars such as glucose and fructose by roasting. Examples of such a brown substance, which can be obtained by adding water to glucose and alanine and dissolving them, followed by heating reaction.
Like the Maillard reaction product, roasted coffee is known to contain vitamin B ₃ (nicotinic acid and nicotinamide) and is effective in vitamin B ₃ deficiency (pellagra). Has also been studied (for example, see Non-Patent Documents 2 to 4).
The physiological action of vitamin B ₃ is an action as a coenzyme NAD, which is activation of a metabolic pathway that produces energy. Nicotinic acid as the above-mentioned vitamin is commercially available as an over-the-counter drug, and it displays an action of promoting carbohydrate / lipid metabolism. On the other hand, nicotinic acid, approved as a ethical drug, is a therapeutic drug for hyperlipidemia, and its pharmacological characteristics are improved lipid metabolism, in particular, increased blood HDL-C concentration, resulting in hyperlipidemia and diabetes. It is effective for prevention and treatment (see, for example, Non-Patent Document 5). Nicotinic acid has the strongest HDL-C-elevating action among existing pharmaceuticals.

As a side effect, nicotinic acid is known to have a phenomenon in which the blood lipid concentration once lowered when the administration is continued increases rapidly by reaction (hereinafter simply referred to as a rebound phenomenon). FIG. 12 is a graph showing the rebound phenomenon of nicotinic acid obtained by oral administration to Wistar male rats as described later in the Examples section.
As is clear from the figure, in the system in which nicotinic acid was administered, the blood lipid concentration once decreased was rebounded, after 1 hour at a dose of 5 mg / kg, after 2 hours at 10 to 20 mg / kg, and 50 mg / kg. Then, it rises sharply after 4 hours, far exceeding the blood concentration when not administered.
In addition, the same result as the above was confirmed also about the human.
In order to reduce the side effects of nicotinic acid as an ethical drug, Acipimox (trade name, manufactured by Italian Pharmacia / currently Pfizer) was developed using nicotinic acid as a model (see, for example, Non-Patent Document 6). ), Used in the treatment of hyperlipidemia, mainly in Europe (not approved in Japan and the US).

Among the above-mentioned hyperlipidemias, it is effective and general to use a statin drug in pharmacological treatment of patients whose blood total cholesterol is high. However, the disadvantage of statin drugs is that they have little effect on raising HDL-C. Recently, when statins and nicotinic acid are used in combination, HDL-C rises more strongly than when used alone (see, for example, Non-Patent Documents 13 to 15). In particular, the method using a low amount of nicotinic acid (Non-patent Document 13) is safe and can be administered for a long period of time, has little rebound phenomenon peculiar to nicotinic acid, and is effective.
That is, if the total cholesterol level in the blood is kept low and the HDL-C level is controlled to a high level, diabetes and arteriosclerosis can be prevented, and lethal cardiovascular diseases caused by those lifestyle-related diseases It is believed that the risk of developing cerebral infarction can be reduced. Table 1 shows examples of drugs having a cholesterol-lowering action and drugs that increase HDL-C.

On the other hand, recently, it has been epidemiologically proved that coffee has an effect of preventing the onset of type 2 diabetes (see, for example, Non-Patent Documents 7 to 11). However, the mechanism by which the effect is manifested is completely unknown (in particular, see Non-Patent Documents 9 to 11).
There were no reports on nicotinic acid or nicotinamide contained in coffee to prevent hyperlipidemia, obesity, or diabetes, but some of the compounds contained in roasted coffee are known as the above medicinal products. Contains the same components as nicotinic acid and nicotinic acid amide.
However, nicotinic acid was not sufficiently contained in roasted coffee products other than French and Italian (for example, see Non-Patent Document 12).
In addition, conventional roasted coffee commercial products are known to contain trace amounts of Maillard reaction products as described above, but they contain caffeine and are the main ingredients of coffee's original aroma and flavor. However, you should avoid drinking too much. It was not possible to obtain a product enriched with nicotinic acid and Maillard reaction products at an increased content suitable for diabetes prevention. Moreover, there has been no safe supplement or supplement that reduces the risk of cardiovascular disease of conventional coffee products and has a diabetes-preventing effect.
J. Nutr. 134: 2381-2386 (2004) Agric. Biol. Chem. 49 (12), 3467-3471, 1985 Nutritional and Toxicological Consequence of Food Processing, 49-59, M. Friedman, Plenum Press, New York, 1991 Eur. J. Med. Chem. 15: pp 157-163 (1980) Arch. Int. Med. 2004; 164, 697-705 Clin. Pharmacol. Ther. (1980) Vol. 28, Number 6, 790-795 Lancet 2002, 360: 1477〜1478 Lancet 2003, 361: 702-704 Annals of Internal Medicine, 2004; 140: 1-8 Journal of Internal Medicine, 2004; 255: 89-95 JAMA. 2004; 291: 1213-1219 Anal.Sci., 20, 325〜328 (2004) Am. Heart J. 2002: 143, 514-8 Am. J. Cardiol. 2004: 93, 307-12 Am. J. Cardiol. 2004: 94, 306-11

It is an object of the present invention to provide a coffee-like supplement and a supplement containing a relatively reduced amount of caffeine and an increased proportion of nicotinic acid, which is a health promoting component, and Maillard reaction product. Specifically, an object of the present invention is to provide supplements and supplements that prevent diabetes and reduce the risk of cardiovascular disease.
In addition, the object of the present invention is to supplement the taste and aroma of blended coffee by controlling the amount of caffeine to a relatively low level by blending with any coffee (especially any decaf product) as a blend component. It is to provide supplements that improve.

High temperatures up to 220 ° C are good for making nicotinic acid-rich products from green coffee beans, but relatively low temperatures below 200 ° C are good for making Maillard reaction products. Accordingly, the present inventors have found that the content of nicotinic acid and Maillard reaction product can be increased at the same time, and have realized a supplement suitable for the prevention of diabetes and the like.
Furthermore, as a result of extensive research, the present inventors have converted the components of the blood lipids that are reduced by liver metabolism when the Maillard reaction product contained in the roasted coffee beans is absorbed into the body, It was found that this metabolite prevents the rebound phenomenon of nicotinic acids and lowers blood lipids. The present invention has been made based on these findings. That is, the present invention
(1) Coffee-like supplement 10g per at least one nicotinic acid compound 3mg more represented by the following general formula A, and metabolism of the Maillard reaction product or the Maillard reaction product represented by any one of the following general formula B1~B3 A coffee-like supplement containing at least 30 mg of at least one product,
(In general formula A, X represents a hydroxyl group, an amino group or a methoxy group.)
(In the general formulas B1 to B3, R ^{11 to} R ¹³ , R ^{21 to} R ²⁴ and R ^{31 to} R ³⁴ each represent a hydrogen atom or a methyl group, provided that R ²¹ may be an aldehyde group.)

(2) metabolites of the Maillard reaction product is a supplement features that (1) above, wherein that a compound represented by any one of the following general formulas C1 ~ C3,

(In the Formula ^{C1~C3, R 41 ~R 43, R} 51 ~R 53 and ^R 61 ^{to R 64} each represent a hydrogen atom or a methyl group.)
(3) The supplement according to (1) or (2), which is derived from roasted coffee,
(4) The content of the nicotinic acid compound, the Maillard reaction product and / or the metabolite of the Maillard reaction product is an increased ratio with respect to the standard amount of caffeine from roasted coffee beans, respectively. The supplement of any one of the items (1) to (3),
(5) A coffee-like supplement containing 30 mg or more of chlorogenic acid, 3 mg or more of nicotinic acid compound and 10 mg or more of Maillard reaction product per 10 g of the total amount of roasted coffee bean-derived components, wherein the nicotinic acid compound has the following general formula A coffee-like supplement, wherein the Maillard reaction product is a compound represented by any one of the following general formulas B1 to B3:
(In general formula A, X represents a hydroxyl group, an amino group or a methoxy group.)
(In the Formula ^{B1~B3, R 11 ~R 13, R} 21 ~R 24 and ^R 31 ^{to R 34} each represents a hydrogen atom or a methyl group. ^{However, R 21} may be an aldehyde group.)
(6 ) The coffee-like supplement according to (5 ), further containing 1 mg or more of chlorogenic acid lactone,
( 7 ) 3 mg or more of at least one nicotinic acid compound represented by the following general formula A per 10 g of coffee-like supplements and the metabolism of the Maillard reaction product represented by any one of the following general formulas B1 to B3 A coffee-like supplement containing at least 30 mg of at least one product,
(In general formula A, X represents a hydroxyl group, an amino group or a methoxy group.)
(In the general formulas B1 to B3, R ^{11 to} R ¹³ , R ^{21 to} R ²⁴ and R ^{31 to} R ³⁴ each represent a hydrogen atom or a methyl group, provided that R ²¹ may be an aldehyde group.)

( 8 ) The food supplement according to ( 7 ), wherein the metabolite of the Maillard reaction product is a compound represented by any one of the following general formulas C1 to C3:

(In the Formula ^{C1~C3, R 41 ~R 43, R} 51 ~R 53 and ^R 61 ^{to R 64} each represent a hydrogen atom or a methyl group.)
( 9 ) Supplementary food according to ( 7 ) or ( 8 ), which is derived from roasted coffee,
( 10 ) The content of the nicotinic acid compound, the Maillard reaction product and / or the metabolite of the Maillard reaction product is an increased ratio with respect to the standard amount of caffeine from roasted coffee beans, respectively. The supplement of any one of the items ( 7 ) to ( 9 ),
( 11 ) A coffee-like supplement containing 30 mg or more of chlorogenic acid, 3 mg or more of nicotinic acid compound and 10 mg or more of Maillard reaction product per 10 g of the total amount of roasted coffee bean-derived ingredients. A coffee-like supplement, which is a compound represented by formula A, and wherein the Maillard reaction product is a compound represented by any one of the following general formulas B1 to B3:
(In general formula A, X represents a hydroxyl group, an amino group or a methoxy group.)
(In the Formula ^{B1~B3, R 11 ~R 13, R} 21 ~R 24 and ^R 31 ^{to R 34} each represents a hydrogen atom or a methyl group. ^{However, R 21} may be an aldehyde group.)
(12 ) The coffee-like supplement according to ( 11 ), further containing 1 mg or more of chlorogenic acid lactone, and ( 13 ) at least one nicotinic acid compound represented by the following general formula A, and the following general formulas B1 to B3: The Maillard reaction product represented by any of the above, or a metabolite of the Maillard reaction product is mixed, and the content of the nicotinic acid compound is 3 mg or more per 10 g of coffee-like supplement or coffee-like supplement. A method for producing a coffee-like supplement or coffee-like supplement, wherein the content of the metabolite of the product or Maillard reaction product is 30 mg or more,
(In general formula A, X represents a hydroxyl group, an amino group or a methoxy group.)
(In the general formulas B1 to B3, R ^{11 to} R ¹³ , R ^{21 to} R ²⁴ and R ^{31 to} R ³⁴ each represent a hydrogen atom or a methyl group, provided that R ²¹ may be an aldehyde group.)
Is to provide.
The supplement and supplement of the present invention are supplements and supplements each containing nicotinic acid, Maillard reaction products, and / or metabolites of Maillard reaction products, preferably 3 mg or more (more preferably 4 mg) of nicotinic acid per 10 g. And 30 mg or more (more preferably 50 mg or more) of the Maillard reaction product.
In the present invention, coffee-like includes not only coffee bean-derived supplements and supplements, but also coffee fragrances and flavors obtained by mixing the above components (including synthetic products).

The supplements and supplements of the present invention (hereinafter also referred to as supplements) are rich in nicotinic acid, Maillard reaction products and / or Maillard reaction product metabolites.
The supplement of the present invention utilizes the lifestyle habit of drinking coffee most directly, for example, by including a supplement made of ingredients derived from a specific roasted coffee bean in foods that are routinely used in lifestyle Thus, it is possible to prevent the onset of type 2 diabetes and arteriosclerosis and reduce the risk of developing cardiovascular disease in a long life.
The supplement of the present invention reduces the risk of increased blood pressure, which is said to reduce the effect of excessive intake of caffeine and to increase by excessive drinking in conventional coffee if blended in a predetermined amount with coffee as a blend component and taken in daily life It can also be a blended coffee that can reduce the risk of cardiovascular disease and heart disease and promote health. And it can use as a blend component which has the flavor peculiar to a Maillard reaction product, and can taste the original fragrance and flavor of coffee by blending with a decaf product.
When the supplement of the present invention is blended with coffee, the type 2 diabetes prevention effect is 1 to several cups a day, which can be equivalent to 7 to 10 cups of conventional coffee.
The supplement of the present invention prevents the rebound phenomenon of nicotinic acid by sustaining the slow-acting blood lipid concentration lowering effect by the liver metabolite of the Maillard reaction product, and supplementing the immediate-acting blood lipid concentration lowering effect by nicotinic acid. Blood lipid concentration can be reduced, and HDL-C is increased.

The present invention is described in detail below.
The present invention relates to a supplement containing ingredients contained in coffee that is widely favored as a favorite product by many people, and by adjusting the intake and addition amount of the supplement, it has a medicinal effect over a long period of time. It is extremely preferable that

First, although the roasting method of the coffee beans used for manufacture of the supplement of this invention is demonstrated, this invention is not limited to this.
The type of green coffee beans used for the production of the supplement of the present invention is not particularly limited, but it is preferable to contain 300 mg or more of trigonelline to be converted into nicotinic acid in 100 g of green beans as described above, more preferably, Trigonelline contains 400 mg or more in 100 g of raw beans. Examples thereof include Indonesian species, Brazilian species, and Colombian species, and preferred are Indonesian species and Brazilian species. You may use the bean which blended several kinds.
With reference to FIG. 3, roasting conditions used for manufacturing the supplement of the present invention will be described.
As will be described later in the Example section, this figure shows roasted green coffee beans (Brazilian variety) at 180 to 220 ° C., and the nicotinic acid content measured every 10 minutes is expressed as a percentage (%) with respect to the trigonelline content. It is a figure which shows the result represented.
As is clear from FIG. 3, the maximum content of nicotinic acid is temperature-dependent, and as a result of repeated experiments on the relationship of time X (min) until reaching the maximum ratio of nicotinic acid at a certain temperature Y ° C., the following formula I was able to derive 1.

Formula 1
X = 240−Y
However, Y is 180-230 degreeC.

The roasting time of green coffee beans, which is preferable for the production of the supplement of the present invention, is the time for producing nicotinic acid in the maximum amount (2-5 mg per 10 g roasted beans) in the range of 180 to 230 ° C. Thus, the preferred roasting time according to the present invention is a function inversely proportional to the temperature, for example, 20 to 60 minutes in the range of 180 to 220 ° C, and 40 to 60 minutes in the range of 180 to 200 ° C.
For example, since the proportionality constant of Equation 1 is 1, when starting roasting at 180 ° C., increasing the temperature at a constant rate, and finishing roasting at 220 ° C., it takes 40 minutes to roast. This will maximize nicotinic acid production.
Further, as apparent from FIG. 3, the amount of nicotinic acid produced at 180 ° C. or lower is very small, which is not preferable for exhibiting blood lipid lowering action. In addition, at this temperature, it takes time to increase the amount of nicotinic acid produced, and the Maillard reaction product once produced volatilizes.
For example, FIG. 5-1 is a diagram showing the change over time in the amount of Maillard reaction product produced at a roasting temperature of 200 ° C., as will be described later in the Examples section. The amount of Maillard reaction product produced is 20 to 30 minutes. It becomes maximum and decreases after that.
Furthermore, if it exceeds 230 degreeC, carbonization of coffee beans will advance, and if time is taken, a taste will be impaired.
Therefore, for the production of the supplement of the present invention, the roasting temperature is preferably 180 ° C to 230 ° C for 15 to 60 minutes, more preferably 200 ° C to 230 ° C for 15 to 25 minutes, and further preferably. 200 ° C. to 220 ° C., 15 to 25 minutes.
Under the roasting conditions described above, roasted coffee beans containing 3 mg or more of nicotinic acid and 30 mg or more of Maillard reaction product per 10 g of roasted beans can be produced.
The roasting for producing the supplement of the present invention is preferably dry roasting in order to apply heat uniformly and constantly to the coffee beans.
Because of the roasting as described above, it is difficult to raise the temperature of the entire coffee bean uniformly to the roasting temperature. Therefore, it is preferable to perform preheating at, for example, 100 to 150 ° C. before roasting as described above. The remaining heat time is preferably 5 to 20 minutes, but in the case of a small amount of coffee beans (for example, about several hundred g), it may be within 5 minutes.
In the production of the supplement of the present invention, the roasted coffee beans obtained as described above contain at least one type A compound (nicotinic acid compound) and at least one type B compound (Maillard reaction product) from normal levels. This is preferable because it is contained at a higher concentration.

Although the specific example of the compound relevant to the preventive effect of diabetes onset etc. contained in the supplement of this invention below is shown, it is not limited to the following example.
The compound for preventing the onset of type 2 diabetes contained in the supplement of the present invention is produced in the coffee roasting process or derived from the produced compound. Specifically, at least one type A compound (nicotinic acid compound) and at least one type B compound (Maillard reaction product) contained in the roasted coffee are not contained in the roasted coffee. It is at least one type C compound that is produced in the body by a metabolic reaction after drinking coffee.
As typical examples of Group B compounds that are active ingredients in Maillard reaction products of roasted coffee, 15 types have been known so far, and in detail, types B-1, B-2, and B-3 Examples of the compounds include C-1, C-2 and C-3 compounds having blood lipid lowering action by metabolic reaction. Preferred among the Group B compounds and the Group C compounds are the Group B-1 compounds and the Group C-1 compounds, respectively.

A preferable compound contained in the supplement of the present invention from the viewpoint of blood lipid lowering action is nicotinic acid (1a), 2,5-dimethylpyrazine (2c) or pyrrol-2-aldehyde (3a) in the above formula. More preferably, it is nicotinic acid (1a) or 2,5-dimethylpyrazine (2c).
The A-type compound, B-type compound (Maillard reaction product), and / or C-type compound (metabolite) contained in the supplement of the present invention are limited to those obtained from the roasted coffee beans described above, respectively. It may be produced by any organic synthetic method or biochemical method.

The case where the A to C compounds are added to any liquid food or drink (coffee, soft drink, etc.) or hydrophilic solution (for example, an aqueous solution or an alcohol solution) at the time of manufacturing or eating or drinking the supplement of the present invention will be described.
Since the nicotinic acid compound of class A is non-volatile and water-soluble, it can be simply dissolved.
Since the Group B compound is water-soluble but has strong volatility, when a concentration of a coffee extract or a freeze-drying step is included, it may be simply dissolved after those steps. As an exception in the group B compound, the tetramethylpyrazine (2f) is poorly soluble in water and may be dissolved as a salt such as phosphate.
The C-type compound is water-soluble, but has weak volatility, so it may be simply dissolved according to the B-type compound.
Next, the case where the A to C compounds are added to any solid food (bread, biscuits, etc.) or solid at the time of production or at the time of eating or drinking will be described.
In this case, it is preferable to add solid (crystalline) compounds of class A and class C. This is because the Group B compound is liquid or unstable even if it is a solid because of its low melting point. When adding a solid compound, it may be simply added and mixed well. When added to an aqueous solution supplement, it may be simply dissolved in the final manufacturing process.
Further, the supplement of the present invention may be a mixture of only A to C compounds alone or in combination. In this case, it is preferable to devise measures such as preventing moisture absorption or using a desiccant in the container and the storage method.

From the viewpoint that the effect of reducing the delayed action lipid concentration by the liver metabolite of the Maillard reaction product complements the effect of reducing the immediate action lipid concentration by nicotinic acid, the supplement of the present invention comprises at least one nicotinic acid compound and at least one Maillard reaction product. It is preferable to contain the composition. Therefore, it is preferable to use the roasted coffee beans as a raw material for supplements.
For example, the roasted coffee beans may be used as a supplement of the present invention by blending with other arbitrary coffee beans.
When the supplement of the present invention contains the above-mentioned composition, the molar ratio of nicotinic acid: Maillard reaction product is 3 or more with respect to nicotinic acid 1, more preferably with respect to nicotinic acid 1. The Maillard reaction product is 5 or more, more preferably 1:10 to 1:20. Furthermore, depending on the type of roasted beans and the roasting conditions, the amount of nicotinic acid may be 100 mg or more / roasted beans 10 g with respect to a minute amount (almost 0) of nicotinic acid.
In the production of the supplement of the present invention, the method for grinding roasted coffee beans is not particularly limited, the roughness of the ground beans is not particularly limited, and the extraction method from the beans is not particularly limited. Such ground bean powder may be used as it is as a supplement of the present invention, may be used as a blending component of blended coffee, or a food added as it is as a supplement of the present invention.
A roasted coffee bean ground bean powder is extracted with water at an arbitrary temperature to obtain a coffee extract, the coffee extract is concentrated under reduced pressure, and powdered by freeze-drying or spray-drying is also used as a supplement of the present invention. Alternatively, a food to which the powder is added may be used as the supplement of the present invention. The coffee extract may be used as the supplement of the present invention, and a food to which the coffee extract is added may be used as the supplement of the present invention.
In particular, in order to improve the recovery rate of Maillard reaction products, it may be extracted from ground bean powder by a supercritical extraction method. From the same viewpoint, any method such as a column concentration method or a droplet alternating current distribution extraction method may be used.
Supplementary food of the present invention has a preventive effect such as coffee-like diabetes, coffee, milk, soft drinks, bread, biscuits and any other food and drink, depending on the characteristics and purpose of each food and drink, in the manufacturing process, Moreover, it can be added appropriately at the time of eating and drinking. Moreover, the supplement of this invention is good also as a tablet, a granule, a powder etc. by arbitrary formulation methods.

  In particular, when the supplement of the present invention is added to coffee, various forms are possible according to the user's preference. For example, it can be added to sweeteners such as sugar, dairy products such as cream, etc., which many people usually use by adding to coffee, or its own powder can be added alone. There is no particular restriction on the coffee to be added, black coffee may be used, any kind of milk added with dairy ingredients, sugars, fragrances, etc., coffee extract concentrated and freeze-dried powder coffee, bottle or can Instant coffee packed in The supplement of the present invention may be added in the production process of these coffees, or can be used even if added appropriately during drinking. It is preferable to add appropriately at the time of eating and drinking from the viewpoint of adjusting the incense generated when the coffee beans are extracted with hot water with the supplement of the present invention. Furthermore, addition to soft drinks other than coffee and drinks as quasi drugs is also preferred.

Next, although the aspect which adds the supplement of this invention to coffee is demonstrated, this invention is not limited to this.
From the viewpoint of reducing blood free fatty acid concentration and increasing HDL-C without fail, when a cup of coffee is drunk, the total amount of Group A compounds, Group B compounds, and / or Group C compounds is 50 to 100 mg. It is preferable to do so. Specifically, it is preferable to contain 5 mg or more of nicotinic acid and 50 mg or more of Maillard reaction product per cup of coffee.
Here, the amount of the Maillard reaction product is more than three times the amount of nicotinic acid in order to prevent the rebound phenomenon of nicotinic acid by the Maillard reaction product liver metabolite as described later in the Examples section. is there. As a result, a low concentration of blood lipid can be maintained.
In the present specification, a cup of coffee is about 100 to 150 ml, and the roasted bean powder necessary for that is 10 to 20 g, but it may be smaller or larger.

  For example, the nicotinic acid compound and Maillard reaction product contained per cup of coffee (10 g of roasted coffee beans) are quantitatively analyzed by an arbitrary method such as the NMR measurement method or the HPLC method described later in the Examples section. Thus, the supplement of the present invention containing the nicotinic acid compound and the Maillard reaction product can be supplemented as a blending component for the nicotinic acid compound and for the Maillard reaction product, the amount insufficient for 50 mg. . Further, for example, only pyrazine carboxylic acid may be selected from the group C compounds and added as a supplement containing 25 mg of pyrazine carboxylic acid.

Moreover, even if the content of nicotinic acid per cup of coffee (10 g of roasted coffee beans) is 5 mg or less, only the metabolite (C compound) of the Maillard reaction product that does not contain the nicotinic acid compound and the Maillard reaction product. You may add as a supplement containing.
The intake of the supplement of the present invention is preferably 30 mg to 150 mg per day in terms of the total amount of Group A compounds, Group B compounds, and / or Group C compounds. Compared to 3g per day (see Arch. Int. Med. 2004; 164, 697-705), which is the maximum clinical dose of nicotinic acid, it is safe enough to be equivalent to 1 / 100th to 20th. It can be said that it is content. Compared with the daily clinical dose of 50 mg (see Am. Heart J. 2002: 143, 514-8), it is 1 to 3 times 1.7 times lower in blood free fatty acid concentration. It can be said that this is an amount that reliably increases HDL-C.

In conventional coffee, the amount of Maillard reaction product relative to the standard amount of caffeine is 0.3 to 0.6 times in molar ratio, but the supplement of the present invention can be more than twice, preferably 3 to 3 times. It can be 5 times or more.
The constant amount of caffeine referred to in the present specification and claims is a standard amount of caffeine in roasted coffee beans, and is a value in the range of 90 to 150 mg in 10 g of roasted coffee beans. is there.
In addition, it has been shown that conventional coffee increases the risk of cardiovascular disease if it is swallowed in anticipation of lowering the risk of diabetes (for example, 800 mL or more per day) (J. Nutr. 134: 2381- 2386, 2004).
It is known that if diabetes is prevented, the risk of cardiovascular disease will eventually decrease, so the causative agent of cardiovascular disease caused by conventional heavy drinking of coffee is different from the components that prevent diabetes Think of things (eg caffeine).
However, if the supplement of the present invention is added to coffee in an amount that does not increase the risk of cardiovascular disease (for example, 400 to 800 mL per day), for example, as a blend component and taken daily for a long time, cardiovascular disease Reduces risk and prevents the development of diabetes.

For nicotinic acid drugs, when taking a pharmacological amount of a compound over a long period of time, if the daily dose is excessive, the risk of developing side effects increases (facial flushing due to nicotinic acid, rebounding) Phenomenon). It is preferable to write information necessary to prevent this in the direct container of the product in order to ensure the purpose of drinking the product as well as ensuring the safety of the consumer.
Next, the mechanism by which the ingredients in the supplement of the present invention prevent the onset of diabetes will be described.

As described above, trigonelin contained in green coffee beans is converted into nicotinic acid by roasting and absorbed into the body as nicotinic acid. On the other hand, in the present invention, carbohydrates, fats and proteins contained in green coffee beans undergo a Maillard reaction by roasting, the reaction products obtained are absorbed into the body, undergo liver metabolism, and the liver metabolites are lipids in blood. Preventing the onset of diabetes by reducing the concentration.
FIG. 1 shows the molecular mechanism of blood lipid lowering action using nicotinic acid binding protein HM74 as a membrane receptor in the present invention.
As shown in FIG. 1, nicotinic acid (A compound) and the liver metabolite of the Maillard reaction product (C compound) are transferred to the receptor HM74 present in the adipocyte membrane constituting the adipose tissue. Bind (some are known). At this time, the compound C is a ligand that binds to the HM74 receptor to a greater or lesser extent regardless of C1 to C3.
Ligand bound HM74 activates the G protein and then inactivates adenyl cyclase (Ac). This suppresses biosynthesis of cAMP and PKA and inhibits phosphorylation of hormone-acting lipase. Ultimately, the rate of neutral fat hydrolysis is reduced, resulting in a decrease in free fatty acids and triglycerides released from the adipose tissue into the blood. Although not shown in FIG. 1, a decrease in blood free fatty acid suppresses LDL synthesis in the liver and enhances HDL-C synthesis, so that in individuals with excess BMI (body mass index), systemic carbohydrate / Lipid metabolism is improved.
The relationship between blood lipid (including free fatty acids) reduction and type 2 diabetes treatment / prevention is described in “Hypertriglyceridemia Handbook” pp148-160, Pharmaceutical Journal (1998), M. Lavezzari, et. al., J. Int. Med. Res. 17: 373-380 (1989), P. Tornvall, et.al., J. Int. Med. 230: 415-421 (1991), etc. .

Next, the health promotion method by the combination of the supplement of the present invention and the cholesterol-lowering drug treatment will be described.
The compound that binds to the HM74 receptor increases blood HDL-C concentration as an effect not observed with a statin drug alone when used in combination with a statin drug (Am. Heart J. 2002: 143, 514). -8, Am. J. Cardiol. 2004: 93, 307-12, Am. J. Cardiol. 2004: 94, 306-11 etc.).
As described above with reference to Table 1, the total cholesterol level in the blood is lowered by the combination of drugs I and II in Table 1 in the hyperlipidemic drug treatment for the patient group whose HDL-C is lower than the standard value. Therefore, the effect of increasing HDL-C is expected and clinical trials are being conducted.
Therefore, according to this combination, the supplement of the present invention is not intended for pharmacological treatment for patients, for example, it is basically healthy or only the blood total cholesterol level is slightly high in a health checkup. For this reason, it can be applied to a healthy person who is taking the drug of I alone. Table 2 shows a comparison between the drug treatment using the two-drug combination and the health promotion method using the supplement of the present invention.

By ingesting the supplement of the present invention containing a large amount of HM74 receptor ligand, these healthy persons can promote health. In this case, if the person taking the medicine of I takes the supplement of the present invention, the effect of increasing HDL-C is strongly expressed. In addition, even if a healthy person who is not taking the drug of I is taking health care such as restricting intake of foods containing a large amount of cholesterol, by taking the supplement of the present invention, HDL -The effect of increasing C is strongly expressed. That is, when a healthy person takes the supplement of the present invention, the same health promotion effect as that of a two-drug combination therapy in a hyperlipidemic patient can be safely achieved.
When the present invention is used for such applications, if it is added so that the daily intake as nicotinic acid is 50 mg or more, a synergistic effect of increasing HDL-C can be obtained in addition to the therapeutic effect of the combination drug. It will be. Since the number of times of drinking coffee varies from person to person, in order to make the amount of HM74-binding component per day a certain amount, rather than using coffee prepared by adding ingredients in advance, It is more effective to add supplements.

Next, as another embodiment of the supplement or supplement of the present invention, a supplement or supplement obtained by blending coffee beans having different roasting conditions will be described.
As conventional coffee roasting methods, mainly light roasting, medium roasting and deep roasting are known. Depending on the degree of roasting, the contained components are different, or even if the components are the same, the content varies greatly, and coffee beans with different roasting conditions contain different pharmacologically active components. Conventional blended coffee is manufactured by mixing and roasting green beans with different varieties, production areas, and shipping ports at an appropriate ratio, and coffee beans with different roasting conditions are not blended. Conventional blended coffees contain some of these pharmacologically active ingredients, but little or no other ingredients.

Supplements or supplements made by blending coffee beans with different roasting conditions according to the present invention are prepared by changing the roasting conditions for any of the following components (a) to (c) that promote health such as diabetes prevention. It is formed by mixing at least two kinds selected from a plurality of roasted coffee beans increased with respect to a certain amount of caffeine in the roasted coffee beans.
(A) chlorogenic acid (b) chlorogenic acid lactone, and (c) at least one nicotinic acid compound and at least one Maillard reaction product. Supplements or supplements obtained by blending coffee beans with different roasting conditions of the present invention include: Roasted coffee beans in which the component (a) is increased with respect to a certain amount of caffeine in the roasted coffee beans by changing the roasting conditions, and roasted coffee beans in which the component (b) is increased, and It is preferable to mix roasted coffee beans with an increased amount of the component (c).
One of the above components (a) to (c) may be blended with at least two types of ground bean powder that is increased with respect to a certain amount of caffeine in the ground beans, or at least the increased amount A blend of two coffee extracts may be used. The raw beans may be the same or different from each other.
The supplement or supplement made by blending coffee beans with different roasting conditions of the present invention can contain both components that disappear by roasting and components that are newly produced by roasting in any proportion. Multiple components that cannot be obtained by a conventional blending method or a single roasting can be contained at the same time.
For example, chlorogenic acid can be 30 mg or more, nicotinic acid compound 3 mg or more and Maillard reaction product 10 mg or more per 150 ml of coffee extract, and chlorogenic acid lactone can be 1 mg or more.

The supplement or supplement obtained by blending coffee beans having different roasting conditions of the present invention is preferably formed by mixing at least two roasted coffee beans of the following (d) to (f).
(D) Raw coffee beans were roasted at 180-220 ° C. for 1-6 minutes (hereinafter sometimes simply referred to as shallow roast), preferably roasted at 180-210 ° C. for 1-5 minutes. Coffee beans,
(E) Raw coffee beans were roasted at 190-225 ° C. for 7-14 minutes (hereinafter sometimes simply referred to as medium roasting), preferably roasted at 215-225 ° C. for 10-14 minutes Coffee beans, and (f) coffee beans obtained by roasting raw coffee beans at 200 to 230 ° C. for 15 to 30 minutes (hereinafter sometimes simply referred to as deep roasting), preferably 20 to 30 at 220 to 230 ° C. Coffee beans roasted for a minute.

Roasted coffee beans are chlorogenic acid in the above-mentioned (d) shallow roasting conditions, chlorogenic acid lactone is in the roasting conditions in (e) above, and nicotinic acid and Maillard reaction products are in the deep roasting conditions in (f) above. Increase to a certain amount of caffeine.
For example, when the roasted coffee beans of (d) and (f) above are blended, the contents of chlorogenic acid, at least one nicotinic acid compound and at least one Maillard reaction product are each constant in the roasted coffee beans. The amount of chlorogenic acid lactone can be increased with respect to a certain amount of caffeine in roasted coffee beans. Can be increased.
Although there is no restriction | limiting in particular in a blend ratio, From a viewpoint of the content ratio of said each component, shallow roasting: medium roasting: deep roasting = 0.5-1.5: 2.5-3.5: 1.5-2. 5 is preferred.
Eating and drinking many components that promote health such as diabetes prevention at the same time is expected not to be a simple additive effect of each component but to be expressed as a synergistic effect as described later. For this purpose, a product containing as many kinds of useful components as possible having different pharmacological action points is preferable.
Since supplements or supplements obtained by blending coffee beans with different roasting conditions according to the present invention contain multiple components at the same time, their synergistic effects and interactions can be expressed.
Here, pharmacologically known synergistic effects will be explained. When two drugs having the same drug effect but different action points are used at the same time, the strength of the drug effect is determined when each is used alone. It expresses beyond the sum of its strengths. Such synergistic effects are widely applied in clinical practice. For example, acarbose that suppresses postprandial hyperglycemia and sulfonylurea that promotes insulin secretion are often applied to slightly refractory diabetes.

As a pharmacological action of chlorogenic acid, it has been known in animal experiments that glucose absorption in the gastrointestinal tract is delayed (MF McCarty. A chlorogenic acid-induced increase in GLP-1
production may mediate the impact of heavy coffee consumption on diabetes risk.
Med. Hypotheses 64: 848-853, 2005).
The enhancement of insulin sensitivity of chlorogenic lactone is described in J. Shearer, et al., Quinides of roasted coffee enhance insulin action in conscious rats. J. Nutr. 133: 3529-3532 (2003).
The glucose absorption inhibitory action of chlorogenic acid and the insulin sensitivity enhancing action of chlorogenic acid lactone are clearly and sufficiently different in their pharmacological action points, and their effects are complementary to each other. That is, suppression of glucose absorption should be sufficient to suppress a slightly elevated blood glucose level if an increase in insulin sensitivity occurs simultaneously with suppression of an increase in postprandial blood glucose level.
Moreover, the interaction in which the Maillard reaction product eliminates the rebound phenomenon of nicotinic acid is as described above.
Therefore, supplements or supplements obtained by blending coffee beans having different roasting conditions according to the present invention are considered to have a synergistic enhancement of diabetes prevention effect.

Hereinafter, the present invention will be described in more detail based on examples, but the present invention is not limited to these examples.
<1> HPLC analysis method of nicotinic acid contained in roasted coffee beans The Maillard reaction product, which is the scent of coffee products, shall be produced at a roasting temperature of 200 ° C. The optimum roasting time for heat conversion of trigonelline to nicotinic acid was determined as 40 minutes using Equation 1. Under these conditions, 200 g of green coffee beans (Brazilian variety) were roasted and ground in a coffee mill for 20 seconds. 10 g of the obtained powder was soaked with 30 ml of hot water. Centrifugation was performed at 3000 rpm for 5 minutes, and 1 ml of the supernatant was poured into Sep-Pak PlusCl8 (trade name, manufactured by Waters) and eluted with 3 ml of acetonitrile / purified water (7/93). 5 μl of the eluate was analyzed by HPLC. The experimental conditions are as follows. Liquid feed pump (trade name BIP-1 / manufactured by JASCO), multi-wavelength ultraviolet absorption detector (brand name MULTI-320 / manufactured by JASCO), data analysis microcomputer (brand name Vectra386 / 20N / manufactured by Hewlett Packard) ) And an analytical column (trade name Capcell PakC18ACR / manufactured by Shiseido Co., Ltd.), and a moving bed solvent (acetonitrile / pH 2.0 phosphate buffer (6/94)) was fed at a flow rate (1 ml / min).
FIG. 2 is a chromatogram obtained as a result. In the figure, AU on the vertical axis is an absorbance unit.
In FIG. 2, peak P1 indicates nicotinic acid. The UV absorption spectrum indicated by this peak was completely consistent with that of the nicotinic acid standard. When quantitative analysis was performed by using a calibration curve method with the broken line as the base, the nicotinic acid content in 10 g of roasted coffee beans as a sample (corresponding to 1 cup of roasted coffee beans) was 3.28 mg.
A few cups of coffee with this content corresponded to the daily requirement for nicotinic acid as a vitamin. In addition, 30 cups are required to reach the daily dose as a therapeutic drug for hyperlipidemia (the lower limit is ll4 mg per day), but even a small amount can be expected to have a preventive action as a health food.
Furthermore, in epidemiological studies, a statistically significant decrease in the risk of developing diabetes was observed when drinking 7 cups of coffee per day, but the amount of nicotinic acid for the 7 cups of coffee in Figure 2 above was calculated to be 26 mg. Is equivalent to 24% of the daily dose used for the treatment of hyperlipidemia, so that it can fully be expected to have an effect of preventing diabetes.

<2> Roasting time for maximizing nicotinic acid production at an arbitrary roasting temperature By an experimental operation similar to the HPLC method in <1> above, Agric. Biol. Chem 49 ( 12), 3467-3471, 1985, and Nutritional and Toxicological Consequence of Food Processing, 49-59, M. Friedman, Plenum Press, New York, 1991 In accordance with the roasting method described in the knitting, the roasting temperature was set between 180 and 220 ° C every 10 ° C, and the nicotinic acid content was measured every 10 minutes of roasting time.
FIG. 3 is a graph showing the relationship between the nicotinic acid content (mg) in roasted coffee with respect to 1 g of trigonelline content in green beans and the roasting time on the horizontal axis. is there.
As is clear from FIG. 3, the maximum content of nicotinic acid is temperature-dependent, and the above equation 1 is expressed as an empirical formula showing the relationship of time X (minutes) until reaching the maximum ratio of nicotinic acid at a certain temperature Y ° C. It was possible to derive from FIG.

<3-1> Roasting conditions suitable for the production of Maillard reaction products
A sample obtained by extracting 20 g of coffee beans (Brazilian seed) roasted at 200 ° C. for 20 minutes with 100 ml of hot water was measured with a 500 MHz NMR apparatus. The results are shown in Fig. 4-1. In the figure, the signal group of 2.2 to 2.5 ppm is derived from the Maillard reaction product, and includes, for example, a set of singlet (singlet) of the structure N = C—CH ₃ common to the group B compounds. FIG. 4-2 is a spectrum obtained by extracting an aqueous coffee solution with deuterated chloroform (CDCl ₃ ). 4-3 is a partially enlarged view of the spectrum of FIG. 4-2 in the range of 2.0 to 2.5 ppm.
As is clear from FIG. 4-1, a signal derived from pyrrole-2-aldehyde was confirmed among the group B compounds. The content of pyrrol-2-aldehyde can be easily measured by NMR spectrum, but quantitative analysis of other compounds is virtually impossible. Therefore, focusing on N = C—CH ₃ which is a partial structure common to these compounds, quantitative analysis by NMR spectrum was performed.
Standard products of Group B compounds were purchased, and 0.5 mg of each was added to 1.O ml of an aqueous coffee solution, and 500 MHz NMR was measured. All N = C—CH ₃ signals were observed in the range of 2.2 to 2.5 ppm.
As is clear from FIGS. 4-2 and 4-3, the approximate content can be predicted when compared with the methyl group of the coexisting main component caffeine, but when calculated using the integral value, 14 mg per 10 g of roasted beans Content.
Further, after the CDCl ₃ NMR measurement, the measurement sample was allowed to stand, and the mixture of caffeine (odorless) and the Maillard reaction product in which CDCl ₃ was volatilized had a coffee-specific scent (four subjects). On the other hand, the aqueous layer after the above coffee aqueous solution was extracted with deuterated chloroform (CDCl ₃ ) did not have coffee aroma.
Further, the black coffee extracted from the coffee beans roasted at 200 ° C. for 20 minutes described above was rich in fruity aroma, had no bitterness, and hardly felt sourness. The coffee-specific aroma gradually increased when roasted at 200 ° C. or higher, or when roasted at 200 ° C. for 20 minutes or longer. As a result, the fragrance and flavor were good at 220 ° C. for about 20 to 25 minutes. On the other hand, when the temperature reached 230 ° C. for 25 minutes or longer, the appearance was scorched, and bitterness and sourness were added.

<3-2> NMR Quantitative Analysis of Nicotinic Acid and Caffeine in Roasted Coffee Bean Hot Water A case where roasting is performed at 220 ° C. for 20 minutes, both of which have good aroma and flavor, will be described.
10g of Brazilian coffee beans roasted at 220 ° C for 20 minutes were crushed in a coffee mill for 20 seconds after cooling, 90 ml of hot water was added and stirred well, 10 ml was taken into a centrifuge tube and centrifuged at 3000 rpm for 5 minutes. . About 0.5 ml of the supernatant was removed from the liquid surface, and 1 μl of a 1% HCl aqueous solution was added thereto, and a 500 MHz NMR spectrum was measured. FIG. 4-4 is a spectrum showing the result. 4-5 is a partially enlarged view of the spectrum of FIG. 4-4 near 9 ppm. In FIG. 4-5, singlet lines based on the 2-position protons of trigonelline (single line pt) and nicotinic acid (single line pn) were observed at 9.06 ppm and 8.95 ppm, respectively. When 50 μg of nicotinic acid was added to this sample, the ratio of the obtained integrated value of the peak area and the integrated value of FIG. 4-4 was calculated, and the amount of nicotinic acid per 10 g of roasted coffee beans was calculated, 3.28 mg Met. For example, in order to add nicotinic acid to the coffee beans so that the total amount of nicotinic acid is 5 mg, 1.72 mg per 10 g may be added.
Further, in FIG. 4-4, when calculated from the ratio of the integrated value of the 2-position proton of nicotinic acid at 8.95 ppm and the integrated value of the methyl group proton of 3.22 ppm of caffeine, caffeine per 10 g of roasted coffee beans The amount was 147 mg.

<3-3> NMR Quantitative Analysis of Maillard Reaction Product in Roasted Coffee Bean Hot Water Extract The set of single lines observed at 2.2 to 2.5 ppm in FIG. 4-4 is the Maillard reaction as described above. It is a signal group of a partial structure common to products (for example, a methyl group (N = C—CH ₃ ) adjacent to a nitrogen atom). Add 0.5 ml of heavy chloroform to the sample used in the measurement of Fig. 4-4, stir for 1 minute with a vibration mixer, centrifuge at 3000 rpm for 5 minutes, separate the heavy chloroform layer, and re-measure NMR tube And a 500 MHz NMR spectrum was measured. When the integral value of the signal group observed at 2.2 to 2.5 ppm of the obtained spectrum was calculated by comparing with the integral value of the methyl group signal of caffeine, the Maillard reaction product in 10 g of roasted coffee beans The content of was 52 mg. When this value is compared with the nicotinic acid content in the section <3-2>, it corresponds to 15 times. Moreover, even if it increases so that the nicotinic acid content of this coffee may be 5 mg per 10g like <3-2> term, the ratio is about 10 times. Therefore, it is not necessary to add a further Maillard reaction product for the purpose of preventing the nicotinic acid rebound phenomenon when drinking this coffee.

<3-4> Maillard reaction product content molar ratio to caffeine content (comparison with conventional coffee)
FIG. 4-6 a) is a partially enlarged view of 2.2 to 3.5 ppm of the NMR spectrum shown in FIG. 4-4. FIG. 4-6 b) is an NMR spectrum (2.2 to 3.5 ppm) of a solution obtained by hot water extraction of a commercially available roasted coffee made from Brazilian coffee beans.
In Fig. 4-6 a) and Fig. 4-6 b), S1 and S1 'are signal groups derived from the Maillard reaction products observed at 2.2 to 2.4 ppm (for example, Maillard reaction products) as described above. Represents a single line of methyl groups adjacent to the nitrogen atom), and S2, S2 ′, S3, and S3 ′ are signals of the two methyl groups of caffeine.
The ratio of the signal intensity of S2 or S3 to the signal intensity of S1 (the ratio of the signal intensity of S2 ′ or S3 ′ to the signal intensity of S1 ′ for conventional roasted coffee) is the caffeine to Maillard reaction product content. This corresponds to the molar ratio (molar ratio of methyl groups).
In FIG. 4-6 b) for conventional commercially available roasted coffee, the ratio is about 1: 0.8. On the other hand, in FIG. 4-6 a) about the present invention, it is about 1: 3.
Since the caffeine content does not change by roasting, the coffee of the present invention in FIGS. 4-6 a) contains a relatively large amount of Maillard reaction products, and the difference is 3.9 times. If coffee with a relatively high content of Maillard reaction product relative to caffeine is drunk, a large amount of Maillard reaction product can be consumed while suppressing the intake of caffeine.
That is, the coffee-derived supplement of the present invention reduces the effect of caffeine on the human body, and can enhance the preferable action of nicotinic acid and Maillard reaction product as compared with this.

<3-5> Component content of supplement obtained by lyophilization 10 g of roasted coffee beans obtained in <3-2> is pulverized and extracted with 90 mL of hot water. It was dissolved again in 90 ml of hot water. About 0.5 ml of the solution was taken in an NMR measuring tube and measured at 500 MHz. The contents of nicotinic acid and Maillard reaction product were calculated according to the items <3-2> and <3-3> and found to be 3.00 mg and 7.8 mg, respectively. Therefore, for example, in order to increase the contents of nicotinic acid and Maillard reaction product to 5 mg and 50 mg, respectively, 2 mg and 42.2 mg may be added.

<3-6> Correlation between roasting time and Maillard reaction product content Next, in order to know the effect of roasting time at a roasting temperature of 200 ° C., the same as described above every 5 minutes after the start of roasting. Extraction with hot water by operation, NMR measurement, the ratio of signal intensity derived from the Maillard reaction product to the signal intensity of caffeine (region of 2.2 to 2.5 ppm), and the relationship with roasting time is shown in FIG. Show.
As apparent from FIG. 5-1, almost no signal in the region of 2.2 to 2.5 ppm was observed in the green beans. When roasting at 200 ° C., a signal group based on the Maillard reaction product was detected, and it was found that the production amount of the Maillard reaction product at 200 ° C. was maximized in 20 to 30 minutes. Referring to FIG. 3, the maximum production time of nicotinic acid at 200 ° C. is 40 minutes. However, judging from FIG. 5-1, the Maillard reaction product is rather decreased at this time.

<3-7> Correlation between content of each component (caffeine, trigonelline, chlorogenic acid, chlorogenic acid lactone, nicotinic acid, Maillard reaction product) and roasting time Furthermore, 3, 5, 10, 15, after the start of roasting At 20, 25 and 30 minutes, 5 coffee beans being roasted were extracted and extracted with hot water by the same operation as described above, and an NMR spectrum of 500 MHz was measured. For each time spectrum, the reference signal of caffeine is a singlet of 3.28 ppm derived from a methyl group, trigonelline is a singlet of 9.06 ppm derived from a proton at position 2, and chlorogenic acid is derived from a proton at position 6. 6.75ppm double line, sucrose is derived from 5.31ppm double line derived from glucose 1st position proton, chlorogenic acid lactone is derived from 4.48ppm single line derived from methoxy group proton, nicotinic acid is derived from 2nd position proton The single line of 8.95 ppm, the Maillard reaction product, the percentage of caffeine signal height of each signal height was determined using the 2.37 ppm singlet derived from N = C—CH ₃ group. The results are shown in FIG.
As is clear from FIG. 5-2, the components in the green beans decrease with time, but there are components that are newly produced by changing. Specifically, the components that decrease are trigonelline, chlorogenic acid, and sucrose, and the components that are produced are chlorogenic acid lactone, nicotinic acid, and Maillard reaction products. In about 10 minutes of medium roasting, sucrose decreased to 1/10 or less, indicating that the Maillard reaction was in progress. It can be seen that chlorogenic acid and trigonelline are already halved, and instead chlorogenic acid lactone is produced in about 10 minutes of roasting corresponding to medium roasting. The scent was sweet and soft for 3 to 5 minutes after the start of roasting corresponding to shallow roasting, and the scent was rich and mellow for about 10 minutes roasting corresponding to medium roasting.
So if you blend lightly roasted, medium roasted, deeply roasted coffee, for example, roasted beans for 5 minutes, 10 minutes and 20 minutes, chlorogenic acid, chlorogenic acid lactone, nicotinic acid and Maillard reaction products The amount can be an increased proportion of coffee-like supplements or supplements relative to a certain amount of caffeine in roasted coffee beans.

<4> Liver metabolism of Maillard reaction products Liver metabolism reaction of Maillard reaction products (1)
In order to confirm the liver metabolism of monomethylpyrazine, which is one of the Maillard reaction products, represented by the following formula, the following experiment was conducted.

Monomethylpyrazine (7.5 mg, 50 mg / kg) dissolved in physiological saline was orally administered to Wistar male rats weighing 4 weeks old and weighing 150 g, and urine was collected for 24 hours. 5 μl of that was taken into an injection type microsyringe (trade name EXS-ODS, manufactured by Kusano Kagaku Co., Ltd.) and injected into the HPLC apparatus using 100 μl of acetonitrile / phosphate buffer (7/93) adjusted to pH 2.0 ( Specifications and experimental conditions are the same as above). FIG. 6 is a chromatogram of the obtained urinary metabolite. In FIG. 6, peak P1 is administered monomethylpyrazine, and peak P2 is a metabolite pyrazinecarboxylic acid. When quantified using the calibration curve method, the recovery rate in urine was 22.8%, of which about 90% were metabolites.
That is, monomethylpyrazine, a Maillard reaction product contained in coffee, was converted to a C-type compound having a blood lipid lowering action by liver metabolism.

Liver metabolic reaction of Maillard reaction products (2)
In order to confirm hepatic metabolism of pyrrolaldehyde, which is one of the Maillard reaction products, represented by the following formula, the following experiment was conducted.

Four-week old Wistar male rats weighing 150 g were orally administered with pyrrole-2-aldehyde 7.5 mg (50 mg / kg) dissolved in physiological saline, and urine was collected for 24 hours. 5 μl of the solution was taken into a caster type microsyringe (trade name EXS-ODS, manufactured by Kusano Kagaku Co., Ltd.) and connected to an injector of an HPLC apparatus. Next, 100 μl of acetonitrile / phosphate buffer (7/93) adjusted to pH 2.0 was injected into the HPLC apparatus via an injection type microsyringe. The apparatus and experimental conditions are the same as described above. In FIG. 7, peak 2 is a chromatogram of the obtained urinary metabolite. In FIG. 7, peak 1 is the administered metabolite pyrrole-2-carboxylic acid. The peak of administered pyrrol-2-aldehyde (about 20 minutes) was not detected. The urine recovery rate was almost quantitative, and the total dose was metabolized.
That is, pyrrol-2-aldehyde, a Maillard reaction product contained in coffee, was converted with high efficiency into a C-type compound having a blood lipid lowering action by liver metabolism.

Liver metabolic reaction of Maillard reaction products (3)
In order to confirm the liver metabolism of 2,5-dimethylpyrazine, which is one of the Maillard reaction products, represented by the following formula, the following experiment was conducted.

24-hour urine was collected from rats administered with 50 mg / kg 2,5-dimethylpyrazine, and the amount of metabolite 5-methylpyrazine-2-carboxylic acid excreted was measured. The specifications and experimental conditions of the HPLC apparatus are the same as described above.
FIG. 8 is a chromatograph of urinary metabolites of rats administered with the obtained 2,5-dimethylpyrazine. In FIG. 8, Pl is the administered 2,5-dimethylpyrazine, and P2 is its liver metabolite 5-methylpyrazine-2-carboxylic acid.
As is clear from FIG. 8, in the urine, the peak P2 of the metabolite was observed in addition to the peak P1 of the administered compound. That is, 2,5-dimethylpyrazine, a Maillard reaction product contained in coffee, was converted to a C-type compound having a blood lipid lowering action by liver metabolism.

<5> Blood lipid lowering action by liver metabolites of Maillard reaction products An experiment in which 7.5 mg (50 mg / kg) of 2,5-dimethylpyrazine, a Maillard reaction product, was administered to 150 g Wistar male rats. Illustrate. In order to observe the time course of hepatic metabolism represented by the above formula 4, blood was collected from the tail vein before administration and every hour after administration, and it was 2,5-dimethylpyrazine (2,5-DMP) and metabolites The blood concentration of 5-methylpyrazine-2-carboxylic acid (5-MPCA) was measured.
Specifically, 10 μl was collected at a time, plasma was separated by centrifugation, and 5 μl thereof was injected into an injection type microsyringe (trade name EXS-ODS, manufactured by Kusano Kagaku Co.). The injection type microsyringe was connected to the injector of the HPLC apparatus, and 100 μl of acetonitrile / phosphate buffer (7/93) adjusted to pH 2.0 was injected. The specifications and experimental conditions of the HPLC apparatus are the same as described above.
FIG. 9 shows the time course of blood concentration obtained by quantification using the calibration curve method. In the figure, ♦ is for 2,5-dimethylpyrazine, and ■ is for 5-methylpyrazine-2-carboxylic acid.
As is apparent from FIG. 9, it was found that the peak of the metabolite was observed with a delay following the peak of the administered compound. That is, this delay brings about a slow effect (compared to nicotinic acid) blood lipid concentration lowering effect and complements the immediate effect of nicotinic acid.

Furthermore, the following experiment was conducted using 4-week-old Wistar male rats. Saline was administered to the control group. The test group was administered with 5-methylpyrazine-2-carboxylic acid (5-MPCA) 50 mg / kg dissolved in physiological saline. Six mice were decapitated immediately before the start of administration and 1, 2, 4, and 6 hours after administration, and blood was collected. Plasma was separated according to a conventional method, and the free fatty acid (FFA) blood concentration was measured using a free fatty acid measurement kit. The results are shown in FIG. FIG. 10 is a graph showing the effect of 5-methylpyrazinecarboxylic acid on the blood free fatty acid concentration in rats.
As is clear from FIG. 10, the most important feature is that no rebound phenomenon of blood free fatty acid concentration was observed compared to nicotinic acid. When drinking coffee, 2,5-dimethylpyrazine undergoes hepatic metabolism and becomes effective after becoming 5-MPCA.

<6> Blood lipid lowering action by liver metabolites of Maillard reaction products It has long been known that pyrazine carboxylic acid N-oxides show blood lipid lowering action in the development of nicotinic acid seeds. See, for example, Eur. J. Med. Chem. L5: pp l57-163 (1980)). Acipimox, which showed the strongest action among them, was developed as a therapeutic drug for hyperlipidemia (manufactured by Italian Pharmacia / currently Pfizer). During the development process, the effect of the free base has been considered weak.
In this example, nicotinic acid, acipimox, and pyrazine carboxylic acid and 5-methylpyrazine-2-carboxylic acid, which are liver metabolites of Maillard reaction products, were simultaneously tested and compared in action.

For the above four compounds, 50 mg / kg was administered to 5 Wistar male rats in each group.
One hour after administration, blood was decapitated and blood free fatty acid and blood triglyceride concentrations were measured according to a conventional method. The results are shown in the graph of FIG.
As is clear from FIG. 11, the compound administration group showed a significant decrease in blood lipid compared to the physiological saline administration group, but there was no significant difference in the effect between the compounds. The effect was almost equal, and blood lipids decreased to 50% or less of the control group.

<7> Prevention of rebound phenomenon of nicotinic acid by Maillard reaction products (1)
Each amount of nicotinic acid was orally administered to male Wistar rats weighing 150 g (control, 5, 10, 20, 50 mg / kg) by the same operation as described in <6> above, blood was collected from the tail vein, The time course of medium free fatty acid concentration was measured.
FIG. 12 is a graph showing a dose-dependent rebound phenomenon caused by nicotinic acid obtained from the above operation.
As is clear from FIG. 12, the blood free fatty acid concentration 30 minutes after administration was suppressed to 0.5 mEq / L or less at any dose of 5 mg / kg to 50 mg / kg. Thereafter, the time until the rebound phenomenon was observed varied depending on the dose. It was 1 hour after 5 mg / kg, 2 hours after 10 mg / kg, 2 to 3 hours after 20 mg / kg, and 4 hours after 50 mg / kg. Thus, the onset time of the nicotinic acid rebound phenomenon was dose-dependent, and a positive correlation was established between the dose and time.
This result indicates that the rebound phenomenon of nicotinic acid observed in the free fatty acid concentration in blood is manifested due to the short half-life of nicotinic acid in blood. That is, when nicotinic acid is taken alone, once the blood concentration of nicotinic acid once increased falls, the blood free fatty acid concentration that has been suppressed so far rapidly increases and reverses.

<8> Prevention of the rebound phenomenon of nicotinic acid by Maillard reaction products (2)
The same procedure as described in <6> above, oral administration of nicotinic acid 10 mg / kg alone or in combination with 2,5-DMP 100 mg / kg to Wistar male rats weighing 150 g and blood free fatty acid concentration The time transition of was measured.
FIG. 13 is a graph showing temporal changes in blood free fatty acids when nicotinic acid is 10 mg / kg alone or in combination with 2,5-DMP of 100 mg / kg. In the graph, each point is shown as an average value of six experiments.
As is clear from FIG. 13, in the nicotinic acid single administration group, solids that developed rebound phenomenon in 1 hour and solids that did not appear in 1 hour were mixed, and individual differences were observed, but all after 2 hours. A rebound phenomenon was observed in the solid. On the other hand, in the combination group, the low level of blood free fatty acid was maintained from 30 minutes after administration to 4 hours. That is, the combined use of 2,5-DMP almost completely suppressed the rebound phenomenon, and the pharmacological action of nicotinic acid and 5-MPCA, which is a 2,5-DMP metabolite, continued to be additively expressed.
Therefore, when the supplement of the present invention is ingested, a delayed blood lipid lowering effect derived from the liver metabolite of the Maillard reaction product can be obtained together with a rapid blood lipid lowering effect derived from nicotinic acid without a rebound phenomenon. It is clear.

FIG. 1 shows the action of HM74 ligand and intracellular signal transduction pathway in adipocytes. FIG. 2 is a diagram showing a chromatogram of nicotinic acid contained in roasted coffee beans. FIG. 3 is a graph showing the results of measuring the relationship between the amount of nicotinic acid produced and the roasting time every 10 minutes in the range of 180 to 220 ° C. 4-1 is a figure which shows the NMR spectrum of the coffee aqueous solution used for the quantitative analysis of a Maillard reaction product. 4-2 is a figure which shows the NMR spectrum of the coffee chloroform solution used for the quantitative analysis of the Maillard reaction product. 4-3 is a partially enlarged view of the spectrum of FIG. 4-2 in the range of 2.0 to 2.5 ppm. 4-4 is a figure which shows the NMR spectrum of the coffee aqueous solution used for the quantitative analysis of a Maillard reaction product. 4-5 is a partially enlarged view of the spectrum of FIG. 4-4 near 9 ppm. FIG. 4-6 a) is a partially enlarged view of 2.2 to 3.5 ppm of the NMR spectrum shown in FIG. 4-4. FIG. 4-6 b) is an NMR spectrum (2.2 to 3.5 ppm) of a solution obtained by hot water extraction of a commercially available roasted coffee made from Brazilian coffee beans. FIG. 5-1 is a diagram showing a change over time in the amount of Maillard reaction product produced at a roasting temperature of 200 ° C. FIG. 5-2 is a diagram showing temporal changes of caffeine, trigonelline, chlorogenic acid, chlorogenic acid lactone, nicotinic acid, Maillard reaction product, and sucrose at a roasting temperature of 200 ° C. FIG. 6 is a diagram showing a chromatogram of a rat urinary metabolite administered with monomethylpyrazine. FIG. 7 is a diagram showing a chromatogram of urinary metabolites of rats administered with pyrrol-2-aldehyde. FIG. 8 is a diagram showing a chromatograph of urinary metabolites of rats administered with 2,5-dimethylpyrazine. FIG. 9 is a graph showing blood concentration-time curves of 2,5-dimethylpyrazine and its liver metabolite 5-methylpyrazinecarboxylic acid in rat blood administered with 2,5-dimethylpyrazine. FIG. 10 is a view showing a blood free fatty acid concentration-time curve of a rat administered with 5-methylpyrazinecarboxylic acid. FIG. 11 shows the effect of nicotinic acid and pyrazinecarboxylic acids on lipid metabolism. FIG. 12 is a graph showing a dose-dependent rebound phenomenon caused by nicotinic acid obtained from the above operation. FIG. 13 is a graph showing temporal changes in blood free fatty acids when nicotinic acid is 10 mg / kg alone or in combination with 2,5-DMP of 100 mg / kg.

Claims (13)

3 mg or more of at least one nicotinic acid compound represented by the following general formula A per 10 g of coffee-like supplement, and at least the Maillard reaction product represented by any one of the following general formulas B1 to B3 or a metabolite of the Maillard reaction product A coffee-like supplement containing 30 mg or more of one kind.
(In general formula A, X represents a hydroxyl group, an amino group or a methoxy group.)
(In the general formulas B1 to B3, R ^{11 to} R ¹³ , R ^{21 to} R ²⁴ and R ^{31 to} R ³⁴ each represent a hydrogen atom or a methyl group, provided that R ²¹ may be an aldehyde group.) The supplement according to claim 1, wherein the metabolite of the Maillard reaction product is a compound represented by any one of the following general formulas C1 to C3.
(In the Formula ^{C1~C3, R 41 ~R 43, R} 51 ~R 53 and ^R 61 ^{to R 64} each represent a hydrogen atom or a methyl group.)   The supplement according to claim 1 or 2, which is derived from roasted coffee.   The content of the nicotinic acid compound, the Maillard reaction product and / or the metabolite of the Maillard reaction product is an increased ratio with respect to the standard amount of caffeine from roasted coffee beans, respectively. The supplement according to any one of claims 1 to 3. A coffee-like supplement containing 30 mg or more of chlorogenic acid, 3 mg or more of nicotinic acid compound and 10 mg or more of Maillard reaction product per 10 g of the total amount of roasted coffee bean-derived components, wherein the nicotinic acid compound is represented by the following general formula A A coffee-like supplement, wherein the Maillard reaction product is a compound represented by any one of the following general formulas B1 to B3.
(In general formula A, X represents a hydroxyl group, an amino group or a methoxy group.)
(In the general formulas B1 to B3, R ^{11 to} R ¹³ , R ^{21 to} R ²⁴ and R ^{31 to} R ³⁴ each represent a hydrogen atom or a methyl group, provided that R ²¹ may be an aldehyde group.) Further claim 5 Symbol placing coffee-like supplement containing chlorogenic acid lactones least 1 mg. 3 mg or more of at least one nicotinic acid compound represented by the following general formula A per 10 g of coffee-like supplement and the Maillard reaction product represented by any one of the following general formulas B1 to B3 or a metabolite of the Maillard reaction product A coffee-like supplement containing 30 mg or more of at least one kind.
(In general formula A, X represents a hydroxyl group, an amino group or a methoxy group.)
(In the general formulas B1 to B3, R ^{11 to} R ¹³ , R ^{21 to} R ²⁴ and R ^{31 to} R ³⁴ each represent a hydrogen atom or a methyl group, provided that R ²¹ may be an aldehyde group.) The food supplement according to claim 7, wherein the metabolite of the Maillard reaction product is a compound represented by any one of the following general formulas C1 to C3.
(In the Formula ^{C1~C3, R 41 ~R 43, R} 51 ~R 53 and ^R 61 ^{to R 64} each represent a hydrogen atom or a methyl group.) The supplement according to claim 7 or 8 , which is derived from roasted coffee. The content of the nicotinic acid compound, the Maillard reaction product and / or the metabolite of the Maillard reaction product is an increased ratio with respect to the standard amount of caffeine from roasted coffee beans, respectively. The supplement according to any one of claims 7 to 9 . A coffee-like supplement containing 30 mg or more of chlorogenic acid, 3 mg or more of nicotinic acid compound and 10 mg or more of Maillard reaction product per 10 g of the total amount of roasted coffee bean-derived components, wherein the nicotinic acid compound is represented by the following general formula A A coffee-like supplement, wherein the Maillard reaction product is a compound represented by any one of the following general formulas B1 to B3.
(In general formula A, X represents a hydroxyl group, an amino group or a methoxy group.)
(In the general formulas B1 to B3, R ^{11 to} R ¹³ , R ^{21 to} R ²⁴ and R ^{31 to} R ³⁴ each represent a hydrogen atom or a methyl group, provided that R ²¹ may be an aldehyde group.) The coffee-like supplement according to claim 11, further comprising 1 mg or more of chlorogenic acid lactone. Mixing at least one nicotinic acid compound represented by the following general formula A with at least one of the Maillard reaction product represented by any of the following general formulas B1 to B3 or a metabolite of the Maillard reaction product, Production of coffee-like supplement or coffee-like supplement, wherein the content of the nicotinic acid compound is 3 mg or more and the content of the Maillard reaction product or the metabolite of the Maillard reaction product is 30 mg or more per 10 g of supplement or coffee-like supplement Method.
(In general formula A, X represents a hydroxyl group, an amino group or a methoxy group.)
(In the general formulas B1 to B3, R ^{11 to} R ¹³ , R ^{21 to} R ²⁴ and R ^{31 to} R ³⁴ each represent a hydrogen atom or a methyl group, provided that R ²¹ may be an aldehyde group.)