阅读说明：本技术 淀粉样蛋白β分解排出促进剂 (Amyloid beta decomposition/excretion promoter ) 是由 山本征辉 三泽幸一 石田惠子 西村瞳 于 2018-05-08 设计创作，主要内容包括：本发明提供一种安全性高且可持续地摄取的淀粉样蛋白β分解排出促进剂。该淀粉样蛋白β分解排出促进剂以绿原酸类或其盐为有效成分。(The invention provides an amyloid beta decomposition/excretion promoter which is highly safe and can be ingested continuously. The amyloid beta decomposition/excretion promoter contains chlorogenic acids or salts thereof as an active ingredient.)

1. An amyloid β decomposition/excretion promoter characterized by:

which comprises chlorogenic acids or salts thereof as an active ingredient.

2. An agent for preventing, treating or ameliorating Alzheimer's disease, which comprises:

which comprises chlorogenic acids or salts thereof as an active ingredient.

3. A food for promoting amyloid-beta decomposition/excretion, which is characterized in that:

which comprises chlorogenic acids or salts thereof as an active ingredient.

4. A food for preventing or ameliorating Alzheimer's disease, which comprises:

which comprises chlorogenic acids or salts thereof as an active ingredient.

5. The amyloid β degradation/excretion promoter according to claim 1, the agent for preventing, treating or ameliorating alzheimer's disease according to claim 2, the food for promoting amyloid β degradation/excretion according to claim 3, or the food for preventing or ameliorating alzheimer's disease according to claim 4, wherein:

the chlorogenic acids contain at least 5-caffeoylquinic acid.

6. Use of chlorogenic acids or salts thereof for producing an agent for promoting amyloid β decomposition/excretion.

7. Use of a chlorogenic acid compound or a salt thereof for producing a prophylactic, therapeutic, or ameliorating agent for alzheimer's disease.

8. Use of chlorogenic acids or salts thereof for producing foods for promoting amyloid β degradation excretion.

9. Use of a chlorogenic acid or a salt thereof for producing a food for preventing or improving Alzheimer's disease.

10. Use according to claim 6 or 7, characterized in that:

the agent is an orally administered formulation.

11. A chlorogenic acid or its salt for promoting decomposition and excretion of amyloid beta.

12. A chlorogenic acid or its salt for preventing, treating or improving diseases is provided.

13. Chlorogenic acids or salts thereof according to claim 11 or 12, characterized in that:

it is administered orally.

14. Non-therapeutic use of chlorogenic acids or salts thereof in the dissociation of excretion-promoting amyloid β.

15. A non-therapeutic use of a chlorogenic acid or a salt thereof in preventing or ameliorating alzheimer's disease.

16. The non-therapeutic use according to claim 14 or 15, wherein:

the chlorogenic acid or salt thereof is administered orally.

17. A method for promoting the decomposition and excretion of amyloid β, comprising:

chlorogenic acids or salts thereof are administered or ingested in an effective amount to a subject in need thereof.

18. A method for preventing, treating or ameliorating alzheimer's disease, comprising:

chlorogenic acids or salts thereof are administered or ingested in an effective amount to a subject in need thereof.

19. The method of claim 17 or 18, wherein:

the administration is oral.

Technical Field

The present invention relates to an amyloid β decomposition/excretion promoter that promotes decomposition and excretion of amyloid β.

Background

Alzheimer's disease is a neurodegenerative disease in which impairment of cognitive functions such as memory/learning or understanding/judgment is a main symptom. It has been reported that cognitive impairment caused by alzheimer's disease accounts for about 70% of the cases of elderly people who need care and assistance, and is the second cause of cerebrovascular disease, fracture, and falling, which is the 3 rd cause (national life basic research of the 25 th-year-old labour province), and that the number of patients is expected to increase rapidly in the future with the aging, and therefore, urgent measures are required. However, there is no effective method for preventing and treating alzheimer's disease at present, and development of a new compound or a method for preventing and treating alzheimer's disease is desired.

The pathological features of alzheimer's disease are senile plaque and neurofibrillary changes, and it is known that senile plaque is a plaque formed by aggregation and fibrosis of amyloid β protein and accumulation outside cells, and the amyloid hypothesis has been paid attention as a mechanism forming the core of the onset and progression of the disease. Amyloid Precursor Protein (APP) is cleaved in stages by an enzymatic reaction to produce amyloid β, which is insolubilized, aggregated, and accumulated extracellularly to cause a disorder in nerve functions such as neurotransmission, thereby causing the progression of symptoms and the onset of alzheimer's disease (non-patent document 1).

Although the detailed role of amyloid β is unclear, it is known that the production of amyloid β increases with age even in healthy people. Amyloid β is produced in brain and peripheral tissues, but brain concentrations are less inhibited by the action of homeostatic mechanisms, particularly clearance from the brain to the periphery. Various routes exist for the clearance of amyloid β, but as a representative route, an excretion mechanism via a transporter low-specificity-protein receptor-related protein (LRP1) or the like existing in cerebral blood vessels is known. That is, it is important to maintain a dynamic balance between the production and excretion of amyloid β in the brain properly, and it is considered that this mechanism is broken by any cause, leading to the onset of alzheimer's disease (non-patent document 2).

Most of the methods for preventing and treating alzheimer's disease caused by the generation of amyloid β, which have been developed and developed in the past, are based on the amyloid hypothesis, and research on substances is being conducted mainly on inhibition of cleavage enzyme of APP, neutralization of amyloid β, inhibition of aggregation and promotion of decomposition of amyloid β, and the like. For example, quercetin or kaempferol, which are flavonoids derived from natural products, have been reported to have an aggregation inhibitory effect on amyloid β (patent document 1), and compounds isolated from uncaria plant extracts have a decomposition effect on aggregated amyloid β (patent document 2).

However, it is difficult to remove the accumulated amyloid β only by the inhibition of the production or aggregation of amyloid β, and it is difficult to obtain a therapeutic effect if the accumulated amyloid β cannot be discharged even if the amyloid β is decomposed. In addition, there are also side effects of amyloid β antibody therapy, and the clear efficacy for alzheimer's disease by these methods has not been achieved so far.

On the other hand, chlorogenic acids are found in plants such as coffee beans and potatoes, and have been reported to have an antioxidant effect, a blood pressure lowering effect, and the like (patent document 3). Further, it has been reported that di-O-caffeoylquinic acid obtained by ester-linking 2 caffeic acids has a neuronal protection activity (patent document 4).

However, chlorogenic acids have not been reported to have an effect of promoting the decomposition and excretion of amyloid β.

(patent document 1) Japanese patent laid-open No. 2007-145839

(patent document 2) Japanese Kokai publication Hei-2004-514679

(patent document 3) Japanese patent application laid-open No. 2002-53464

(patent document 4) International publication No. 2007/091613

(non-patent document 1) Hardy JA et al, science.1992; 256: 184

(non-patent document 2) Zlokovic BV et al, Nature review.2011; 12: 723

Disclosure of Invention

The present invention is the following inventions 1) to 14).

1) An amyloid beta decomposition/excretion promoter contains chlorogenic acids or salts thereof as an active ingredient.

2) An agent for preventing, treating or ameliorating Alzheimer's disease, which comprises a chlorogenic acid or a salt thereof as an active ingredient.

3) A food for promoting amyloid beta decomposition/excretion contains chlorogenic acids or salts thereof as an active ingredient.

4) A food for preventing or improving Alzheimer's disease comprises chlorogenic acids or salts thereof as effective components.

5) Use of chlorogenic acids or salts thereof for producing an agent for promoting amyloid β decomposition/excretion.

6) Use of a chlorogenic acid compound or a salt thereof for producing a prophylactic, therapeutic, or ameliorating agent for alzheimer's disease.

7) Use of chlorogenic acids or salts thereof for producing foods for promoting amyloid β degradation excretion.

8) Use of a chlorogenic acid or a salt thereof for producing a food for preventing or improving Alzheimer's disease.

9) A chlorogenic acid or its salt for promoting decomposition and excretion of amyloid beta.

10) A chlorogenic acid or its salt for preventing, treating or improving Alzheimer's disease is provided.

11) Non-therapeutic use of chlorogenic acids or salts thereof in the dissociation of excretion-promoting amyloid β.

12) A non-therapeutic use of a chlorogenic acid or a salt thereof in preventing or ameliorating alzheimer's disease.

13) A method for promoting the excretion of amyloid β, which comprises administering or taking chlorogenic acids or salts thereof to a subject in need thereof in an effective amount.

14) A method for preventing, treating or ameliorating Alzheimer's disease, which comprises administering or taking chlorogenic acids or salts thereof to a subject in need thereof in an effective amount.

Drawings

FIG. 1 is a graph showing the activity of aggregated amyloid protein decomposition using chlorogenic acids.

FIG. 2 is a graph showing an effect of increasing amyloid β efflux transporter (LRP1, p-gp) due to continuous uptake of chlorogenic acids.

Fig. 3 is a view showing the inhibitory effect on the intracerebral accumulation of amyloid β produced by the continuous uptake of chlorogenic acids (observation image of amyloid β).

Fig. 4 is a graph showing the inhibitory effect on accumulation in hippocampus of amyloid β produced by the continuous uptake of chlorogenic acids (accumulation ratio of amyloid β).

FIG. 5 is a graph showing the effect of improving memory and learning ability by the continuous intake of chlorogenic acids (novel object recognition test).

FIG. 6 is a graph showing the effect of improving memory and learning ability by the continuous uptake of chlorogenic acids (Morris watermaze test).

Detailed Description

The present invention relates to an agent for promoting the release of amyloid beta decomposition, which is highly safe and can be ingested continuously.

The present inventors have conducted various studies on highly safe components that can be taken or ingested over a long period of time, and as a result, have found that: chlorogenic acids have both excellent decomposition promoting action and discharge promoting action of amyloid β; in addition, in the alzheimer model animals, it is effective not only for prevention of alzheimer disease but also for improvement.

The present invention can provide a pharmaceutical and a food which promote the decomposition and excretion of amyloid β and are useful for the prevention, treatment, or amelioration of alzheimer's disease.

The term "chlorogenic acids" as used herein refers to the generic names of monocaffeoylquinic acids of 3-caffeoylquinic acid (3-CQA), 4-caffeoylquinic acid (4-CQA) and 5-caffeoylquinic acid (5-CQA), and monocaffeoylquinic acids of 3-feruloylquinic acid (3-FQA), 4-feruloylquinic acid (4-FQA) and 5-feruloylquinic acid (5-FQA). The content of chlorogenic acids is defined based on the total amount of 6 kinds described above.

The "chlorogenic acids" of the present invention may contain at least 1 of the 6 chlorogenic acids described above, and preferably contains monocaffeoylquinic acid, and more preferably contains at least 5-caffeoylquinic acid, from the viewpoint of the action of promoting the release of amyloid β from decomposition. The content of 5-caffeoylquinic acid in chlorogenic acids is preferably 10% by mass or more, more preferably 20% by mass or more, still more preferably 30% by mass or more, and still more preferably 40% by mass or more.

The chlorogenic acids may be in the form of salts, and examples of the salts include pharmaceutically acceptable salts, for example, alkali metal salts such as sodium and potassium, alkaline earth metal salts such as magnesium and calcium, organic amine salts such as monoethanolamine, diethanolamine and triethanolamine, and basic amino acid salts such as arginine, lysine, histidine and ornithine.

The chlorogenic acids or salts thereof of the present invention may be used in the form of plant extracts containing them, concentrates thereof, or purified products thereof. Examples of such plant extracts include those extracted from sunflower seeds, immature fruits of apples, coffee beans, sweet potato leaves, cones of Pinaceae, seed shells of Pinaceae, potatoes, sweet potatoes, sugar cane, wheat, leaves of Nandina domestica, burdock, carrots, cabbage, lettuce, artichoke, tomato, Taiwan jute (Mulukhiyya), eggplant peel, pears, plums, peaches, apricots, cherries, fruits of plum, coltsfoot, and Vitaceae. Among these, the coffee bean extract is preferably a deep-roasted coffee bean (L value: 16.8 or less), more preferably a medium-roasted coffee bean (L value: more than 16.8 and 24.2 or less), a light-roasted coffee bean (L value: more than 24.2 and 30.2 or less), a slightly-roasted coffee bean (L value: more than 30.2) or a green coffee bean, and further preferably a green coffee bean, from the viewpoint of the content of chlorogenic acids and the like. Here, the "L value" is a value obtained by measuring the brightness of roasted coffee beans with a color difference meter, taking black as the L value 0 and white as the L value 100. The kind of the tree of coffee may be any of arabica species, apocynum species, liberiaca species, and arabibara species (arabiusta).

The coffee bean extract is preferably a substance from which caffeine has been removed, but from the viewpoint of flavor, the mass ratio of caffeine to chlorogenic acids (caffeine/chlorogenic acids) is preferably 0.05 or less, more preferably 0.03 or less, even more preferably 0.02 or less, even more preferably 0.005 or less, even more preferably 0.003 or less, and even more preferably 0.001 or less. The lower limit of the caffeine/chlorogenic acid ratio is not particularly limited, and may be 0.

In the coffee bean extract, the mass ratio [ (K + Na)/chlorogenic acids ] of the sum of potassium (K) and sodium (Na) to chlorogenic acids is preferably 0.18 or less, more preferably 0.14 or less, even more preferably 0.1 or less, and particularly preferably 0.06 or less, from the viewpoint of flavor. The lower limit of the mass ratio [ (K + Na)/chlorogenic acids ] is not particularly limited, and may be 0, but is preferably 0.0001, and more preferably 0.001 from the viewpoint of production efficiency.

As a preferred example of the coffee bean extract used in the present invention, there is a green coffee bean extract in which the mass ratio of caffeine to chlorogenic acids (caffeine/chlorogenic acids) is 0.02 or less and the content of 5-caffeoylquinic acid (5-CQA/perchloroacetic acids) in the total amount of chlorogenic acids is 40 mass% or more. A more preferable example is a green coffee bean extract having a content of (caffeine/chlorogenic acids) of 0.001 or less and a content of (5-CQA/perchloroacetic acids) of 40 mass% or more.

The method and conditions for extraction, concentration and purification of chlorogenic acids or salts thereof of the present invention are not particularly limited, and known methods and conditions can be used. Among them, the extraction is preferably performed with an aqueous ascorbic acid solution, an aqueous citric acid solution, or hot water.

Further, commercially available chlorogenic acid-containing preparations can be used as the raw material of chlorogenic acids or salts thereof, and examples thereof include Flavor holder (フ レ ー バ ー ホ ル ダ ー) RC (kadsura Flavor), green coffee bean extract P (produced by Oryza oil corporation), SVETOL (produced by Nurex inc.), OXCH100 (produced by eastern fermentation corporation), and the like.

As shown in examples described later, chlorogenic acids have a decomposition action of aggregated amyloid β, and in hippocampus, the expression of amyloid β efflux transporter gene (LRP1 gene and p-gp gene) is enhanced, and the intracerebral accumulation of amyloid β is suppressed. Further, it was confirmed that chlorogenic acids exert memory and learning ability improving effects in alzheimer disease model animals.

Therefore, the chlorogenic acids or salts thereof can be used as an amyloid β decomposition/excretion promoter or an agent for preventing, treating or ameliorating alzheimer's disease, can be used for promoting the decomposition and excretion of amyloid β, can be used for preventing, treating or ameliorating alzheimer's disease, and can be used for producing an amyloid β decomposition/excretion promoter or an agent for preventing, treating or ameliorating alzheimer's disease.

Here, "use" may be administration or ingestion to a human or non-human animal, and may be therapeutic use or non-therapeutic use. In addition, "non-therapeutic" is a concept that does not include medical action, that is, a concept that does not include a method of performing surgery, treatment, or diagnosis on a human, and more specifically, a concept that does not include a method of performing surgery, treatment, or diagnosis on a human by a physician or a person instructed by a physician.

In the present invention, "promotion of the catabolic excretion of amyloid β" means: promotes the decomposition of aggregated amyloid β protein accumulated in the brain, and promotes the excretion of amyloid β protein from the brain to inhibit the accumulation in the brain.

In addition, in the present invention, "alzheimer disease" means: dementia diseases which are caused by cognitive disorders (memory disorders, disorganization disorders, learning disorders, attention disorders, spatial cognitive functions, etc.) and personality changes due to the increase/accumulation of amyloid β in the brain and which also exhibit symptoms such as social inadaptation.

In the present specification, "prevention" means: preventing or delaying onset of a disease or condition in a subject, or reducing the risk of onset of a disease or condition in a subject.

In addition, "improve" means: amelioration of a disease, symptom, or condition, prevention or delay of worsening of a disease, symptom, or condition, or reversal, prevention, or delay of progression of a disease or symptom.

In addition, in the "treatment", improvement of symptoms is included in addition to complete cure of the disease.

The amyloid β decomposition/excretion promoter and the agent for preventing, ameliorating or treating alzheimer's disease according to the present invention may be themselves, a pharmaceutical, quasi-pharmaceutical, supplement or food for promoting the decomposition/excretion of amyloid β or preventing, ameliorating or treating alzheimer's disease, or may be a raw material or a preparation used by being incorporated into the pharmaceutical, quasi-pharmaceutical or food.

The food includes foods, functional foods, foods for patients, foods for specified health use, and supplements which are conceptualized as promoting the decomposition and excretion of amyloid β and preventing or ameliorating alzheimer's disease and which show the substance as required. These foods are food products that permit a functional display, and therefore can be distinguished from general foods.

Examples of administration forms of the above-mentioned pharmaceutical products (including quasi-drugs) include: oral administration such as tablets, capsules, granules, powders and syrups, or parenteral administration such as injections, suppositories and inhalants. These formulations can be prepared by using the chlorogenic acids or salts thereof of the present invention alone or in combination with other pharmaceutically acceptable excipients, binders, extenders, disintegrants, surfactants, lubricants, dispersants, buffers, preservatives, flavors, fragrances, coating agents, carriers, diluents, and other pharmaceutically effective components other than the chlorogenic acids or salts thereof of the present invention. Of these administration forms, the preferred form is oral administration.

As forms of the above-mentioned food, in addition to various foods such as drinks and foods such as refreshing and refreshing beverage, tea-based beverage, coffee beverage, fruit juice beverage, carbonated beverage, jelly, biscuit, bread, noodle, sausage, and nutritional foods, a nutritional supplement composition in the same form (tablet, capsule, syrup, and the like) as the above-mentioned orally administrable preparation can be cited.

The foods of various forms can be prepared by using the chlorogenic acids or salts thereof of the present invention alone, or in combination with other food materials as appropriate, or a solvent, softener, oil, emulsifier, preservative, sour agent, sweetener, bitter agent, flavor, stabilizer, colorant, antioxidant, humectant, thickener, active ingredient other than chlorogenic acids or salts thereof, and the like.

The content of the chlorogenic acids or salts thereof of the present invention in the above-mentioned drugs (including quasi drugs) or foods varies depending on the form of use thereof, and is usually preferably 0.001 mass% or more, more preferably 0.01 mass% or more, further preferably 0.1 mass% or more, and further preferably 90 mass% or less, more preferably 60 mass% or less, and further preferably 30 mass% or less of the total amount of chlorogenic acids. The amount of the organic solvent is preferably 0.001 to 90% by mass, more preferably 0.01 to 60% by mass, and still more preferably 0.1 to 30% by mass.

The dose or intake amount of the above-mentioned drugs (including quasi drugs) and foods can be determined as appropriate, and is usually preferably 100mg or more, more preferably 300mg or more, and further preferably 3000mg or less, more preferably 1000mg or less per 1 day for an adult (60 kg). In the present invention, the amount is preferably administered or ingested 1 time.

The above-mentioned preparation is administered or ingested on an arbitrary schedule, and the administration or ingestion period is not particularly limited, but preferably repeated and continuous administration or ingestion, more preferably administration or ingestion for 7 or more days, and still more preferably administration or ingestion for 28 or more days.

The administration or intake target is not particularly limited as long as it is a human or non-human animal whose cognitive function is required or desired to be prevented or improved from being deteriorated, and administration or intake to a human is effective. The reduction of cognitive function as referred to herein means a symptom seen in cognitive dysfunction represented by alzheimer's disease, and means a state in which work or daily activities are impaired or the ability to complete work is reduced, for example, judgment about impairment or lack of ability accompanying memory/learning impairment (impairment of ability to acquire new information and to stay in memory), inference, operation of complicated work, visual space cognitive impairment, language impairment, personality, behavior, or behavior. The persons who need or want to prevent such a decrease in cognitive function include, for example, 27 to 30 points of healthy persons in a simple mental state examination (MMSE) which is the most widely used internationally in cognitive function tests, and the persons who need or want to improve the decrease in cognitive function include 22 to 26 points of persons suspected of having mild cognitive impairment and persons with a high possibility of having cognitive impairment such as cognitive impairment of 21 points or less in the above-mentioned examination.

The present invention discloses the following embodiments with respect to the above-described embodiments.

< 1 > an amyloid β decomposition/excretion promoter comprising chlorogenic acids or salts thereof, or plant extracts containing the same as an active ingredient.

< 2 > an agent for preventing, treating or ameliorating Alzheimer's disease, which comprises a chlorogenic acid compound or a salt thereof, or a plant extract containing the same as an active ingredient.

< 3 > a food for promoting amyloid β decomposition/excretion, which contains chlorogenic acids or salts thereof, or plant extracts containing the same as an active ingredient.

< 4 > a food for preventing or improving Alzheimer's disease, which comprises chlorogenic acids or salts thereof, or plant extracts containing the same as an active ingredient.

Use of < 5 > chlorogenic acids or salts thereof, or plant extracts containing the same, for producing an agent for promoting amyloid β decomposition/excretion.

Use of < 6 > chlorogenic acids or salts thereof, or plant extracts containing the same, for producing a prophylactic, therapeutic, or ameliorating agent for Alzheimer's disease.

Use of < 7 > chlorogenic acids or salts thereof, or plant extracts containing the same, for producing foods for promoting amyloid β degradation excretion.

Use of < 8 > chlorogenic acids or salts thereof, or plant extracts containing the same, for producing a food for preventing or improving Alzheimer's disease.

Use as described in < 9 > such as < 5 > or < 6 > wherein the agent is an orally administered formulation.

< 10 > a chlorogenic acid or a salt thereof, or a plant extract containing the same, for promoting the decomposition and excretion of amyloid β.

< 11 > a chlorogenic acid compound or a salt thereof, or a plant extract containing the same, for preventing, treating or ameliorating Alzheimer's disease.

Chlorogenic acids or salts thereof < 12 > such as < 10 > or < 11 > or plant extracts containing the same, which are administered orally.

< 13 > non-therapeutic use of chlorogenic acids or salts thereof, or plant extracts containing same, for the dissociation of excretion-promoting amyloid beta.

< 14 > a non-therapeutic use of chlorogenic acids or salts thereof, or plant extracts containing the same, for preventing or ameliorating alzheimer's disease.

< 15 > such as < 13 > or < 14 > wherein the chlorogenic acid or salt thereof, or plant extract containing the same is administered orally.

< 16 > a method for promoting the decomposition and excretion of amyloid β, wherein chlorogenic acids or salts thereof, or plant extracts containing the same are administered or ingested in an effective amount to a subject in need thereof.

< 17 > a method for preventing, treating or ameliorating alzheimer's disease, wherein chlorogenic acids or salts thereof, or plant extracts containing the same are administered or ingested in an effective amount to a subject in need thereof.

The method of < 18 > as < 16 > or < 17 > wherein the administration is oral.

< 19 > in < 1 > -18 >, the chlorogenic acids contain at least 5-caffeoylquinic acid.

< 20 > in < 1 > -19 >, the plant extract containing chlorogenic acids or salts thereof is a coffee bean extract, preferably a green coffee bean extract.

< 21 > in < 20 >, the green coffee bean extract preferably has a caffeine to chlorogenic acids mass ratio (caffeine/chlorogenic acids) of 0.02 or less, and the content of 5-caffeoylquinic acid (5-CQA/perchloroacetic acids) in the total chlorogenic acids amount of 40% by mass or more, more preferably has a (caffeine/chlorogenic acids) of 0.001 or less, and has a (5-CQA/perchloroacetic acids) of 40% by mass or more.

The amyloid beta decomposition/excretion promoter described in < 22 > in < 1 > and < 5 >, the Alzheimer's disease preventive, therapeutic, or ameliorating agent described in < 2 > and < 6 >, the amyloid beta decomposition/excretion promoter described in < 3 > and < 7 >, and the Alzheimer's disease preventive or ameliorating food described in < 4 > and < 8 >, wherein the content of the active ingredient as chlorogenic acids in the total amount is preferably 0.001 mass% or more, more preferably 0.01 mass% or more, further preferably 0.1 mass% or more, further preferably 90 mass% or less, more preferably 60 mass% or less, further preferably 30 mass% or less. The amount of the organic solvent is preferably 0.001 to 90% by mass, more preferably 0.01 to 60% by mass, and still more preferably 0.1 to 30% by mass.

< 23 > in < 10 > -18 >, the dose of chlorogenic acids per 1 day for 1 adult is preferably 100mg or more, more preferably 300mg or more, and further preferably 3000mg or less, more preferably 1000mg or less.