JP4812240B2 - Blood fluidity improver - Google Patents

Description

  The present invention relates to a blood fluidity improving agent and / or a blood circulation promoter.

  Blood circulation plays an important role in the supply of oxygen and nutrients to human tissues and the excretion of waste products.

  In recent years, with the introduction of information devices such as computers, the living environment has been increasing in the number of people who maintain the same posture for a long time, and the number of people who have poor circulation in various parts of the body is increasing. Seasonal changes also cause changes in life activity. For example, in winter, blood circulation such as peripheral circulation is often caused. In addition, the decline in physical function due to aging cannot be avoided by anyone, and there is concern about poor blood circulation.

  As described above, poor blood circulation caused by various factors such as living environment, seasonal change or aging often causes troubles in smooth life activities in various parts of the body, and as a result, causes mental and physical problems.

Examples of components that promote conventional blood circulation or blood fluidity that is a factor of blood circulation promotion include collagen peptides (see Patent Document 1), Sendangsa plants, particularly Vidence pillowa or its components (see Patent Document 2), γ- Linolenic acid alone or γ-linolenic acid and a fat-soluble antioxidant (see Patent Document 3), dilazep, its acid addition salt (see Patent Document 4), hydroxymethylfurfural derivative (see Patent Document 5), estrogen agonist (Patent Document) 6), brewed vinegar (see Patent Document 7), materials such as mulberry leaves, plum seeds, plum meat, shiso leaves (see Patent Document 8), plasmin and plasminogen activator (see Patent Document 9), hyaluron Acid (see Patent Document 10), bilobalide (see Patent Document 11), which is a component in ginkgo biloba, and the like are known.
JP 2002-121148 A JP 2002-205954 A JP 2000-302677 A JP-A-11-92382 JP-A-11-228561 Japanese Patent Laid-Open No. 10-7564 Japanese Patent Laid-Open No. 10-28567 JP-A-10-127253 Japanese Patent Laid-Open No. 8-40931 JP-A-8-53356 JP 7-53371 A

  However, currently, there are many drugs for improving blood fluidity and / or promoting blood circulation that are satisfactory in terms of effectiveness, but the burden on patients is large due to side effects such as difficulty in stopping hemostasis. In addition, foods that are said to have improved blood fluidity and / or blood circulation or active ingredients thereof are not necessarily satisfactory, and the effects of blood fluidity improvement and / or blood circulation promotion are manifested. Many things take a long time to complete. Accordingly, the present invention provides a blood fluidity improving agent and / or a blood circulation promoting agent that has a high blood fluidity improving and / or blood circulation promoting action, is excellent in safety, and does not burden daily intake. With the goal.

Therefore, the present inventor has conducted various studies to find a component having a blood fluidity improving effect and / or a blood circulation promoting effect from among highly safe components that can be taken or taken for a long time. It has been found that at least one selected from acids, ferulic acid and pharmaceutically acceptable salts thereof is useful as an excellent blood fluidity improving agent and / or blood circulation promoter. In addition, administration of one or more selected from chlorogenic acids, caffeic acid, ferulic acid and their pharmaceutically acceptable salts to humans with impaired peripheral circulatory function improves peripheral circulation and cools the limbs. It was also found that the body temperature was improved and the decrease in body temperature was improved. Moreover, it has been found that the material of the present invention is useful as a safe health food or pharmaceutical because it has almost no side effects as observed in pharmaceuticals and is easily ingested in daily life.
That is, the present invention relates to a blood flow improver, a blood circulation promoter, a cooling improver, and a body temperature lowering agent comprising at least one selected from chlorogenic acids, caffeic acid, ferulic acid and pharmaceutically acceptable salts thereof. It provides an improving agent.

  The blood fluidity-improving agent and / or blood circulation promoter of the present invention improves blood fluidity and / or blood circulation, and is therefore useful for the prevention and treatment of any poor blood circulation caused by living conditions, seasonal changes or aging. Since these are highly safe and can be taken orally for a long period of time, they are useful not only as pharmaceuticals but also as functional foods and foods for specified health use.

  The chlorogenic acids, caffeic acid, and ferulic acid used in the present invention can be extracted from natural products containing them, particularly plants, and can be industrially produced by chemical synthesis.

The chlorogenic acids, caffeic acid, and ferulic acid in the present invention have stereoisomers, and in the present invention, pure stereoisomers or a mixture thereof can be used. Specific examples of the chlorogenic acids in the present invention include 3-caffeylquinic acid, 4-caffeylquinic acid, 5-caffeylquinic acid, 3,4-dicaffeylquinic acid, 3,5-dicaffeylquinic acid, 4,5- Dicafeylquinic acid, 3-ferrylquinic acid, 4-ferrylquinic acid, 5-ferrylquinic acid and 3-ferryl-4-caffeylquinic acid are included (Nakabayashi et al., Chemistry and Technology of Coffee Roasting, Kogaku Publishing Co., Ltd., p166-167).

  Chlorogenic acids, caffeic acid, and ferulic acid can improve water solubility and increase physiological effectiveness by making them into salts. These salts may be pharmaceutically acceptable salts. Examples of such basic substances for salt formation include hydroxides of alkali metals such as lithium hydroxide, sodium hydroxide and potassium hydroxide; hydroxides of alkaline earth metals such as magnesium hydroxide and calcium hydroxide. Products; inorganic bases such as ammonium hydroxide, basic amino acids such as arginine, lysine, histidine, ornithine; organic bases such as monoethanolamine, diethanolamine, and triethanolamine are used, particularly alkali metals or alkaline earth metals Hydroxides are preferred. In the present invention, these salts may be prepared and then added to a composition comprising other components, or chlorogenic acids and salt-forming components may be separately added to the composition. What formed the salt in it may be used.

Natural product extracts containing chlorogenic acids and caffeic acid, especially plant extracts include, for example, coffee, cabbage, lettuce, arch chalk, tomato, eggplant, potato, carrot, apple, pear, plum, peach, apricot, cherry Those extracted from plants such as sunflower, morroheiya, sweet potato, southern leaves, blueberries and wheat are preferred.
For example, chlorogenic acids are preferably extracted from plants such as green coffee beans, southern leaves, and unripe apples. Furthermore, what was obtained by extracting from the seeds of coffee arabica LINNE with warm ascorbic acid, citric acid acidic aqueous solution or hot water is more preferable.

  Specifically, Hasegawa Fragrance Co., Ltd. “Flavor Folder” as raw coffee bean extract, Nikka Whiskey Co., Ltd. “Applephenon” as apple extract, Dainippon Ink Chemical Co., Ltd. as sunflower seed extract Industrial Co., Ltd. “Heliant” and the like.

  As a natural product extract containing ferulic acid, in particular, a plant extract, for example, coffee, onion, radish, lemon, nematode, toki, pine, auren, agi, sweet potato, corn, barley, wheat, rice and the like are preferable, Rice is particularly preferable. The rice in the present invention means raw or dried products such as seeds of Oryza sativa LINNE.

  As a method for extracting ferulic acid from plants, for example, rice bran oil obtained from rice bran was distributed with hydrous ethanol and hexane under slightly alkaline at room temperature, and then ferulic acid ester obtained in the hydrous ethanol fraction Can be obtained by hydrolyzing and purifying the product with sulfuric acid when heated under pressure. In addition, bacteria (Pseudomonas) are cultured in a culture solution containing clove oil obtained by steam distillation from buds and leaves of Syzygium aromaticum MERRILL et PERRY, or eugenol obtained by purification from clove oil. The culture solution can also be obtained by separation and purification.

  Ferulic acid can also be produced by chemical synthesis, for example, a condensation reaction between vanillin and malonic acid (Journal of American Chemical Society, 74, 5346, 1952).

  Two or more of the above components of the present invention may be used in combination. These components are preferably taken in an amount of 10 mg to 10 g, more preferably 35 mg to 5 g, still more preferably 70 mg to 1 g per day for an adult (body weight 60 kg) from the viewpoint of obtaining a blood fluidity improving effect and / or a blood circulation promoting effect. .

Blood flow characteristics become important as a passive factor in circulation, especially in the microcirculation. For example, in capillaries and small arteries and veins, the mechanical properties of blood cells such as erythrocyte deformability and leukocyte adhesion are the main factors governing blood rheology, and microcirculatory disturbance due to these abnormalities is the cause and pathology of many diseases. It is estimated that it constitutes.
As a method for measuring the effect of improving blood fluidity, the microchannel method (Kikuchi, Y., Sato, K., Ohki H and Kaneko T .: “Optically accessible microchannels formed in a sngle-crystal silicon substrate for studies of blood rheology. "Microvasc. Res. 44, 226-240 (1992)), Laser diffraction (Manno S., Takakuwa Y., Nagao K., Mohandas N.,:" Modulation of erythrocyte membrane mechanical function by beta-spectrin phosphorylation and dephosphorylation . "J. Biol. Chem. 270 (10), 5659-5665 (1995)), filter method (Oonishi T., Sakashita K., Uyesaka N.,:" Regulation of red bloood cell filterability by Ca ²⁺ influx and cAMP-mediated signaling pathways. "Am.J.Physiol.273 (6), C1828-1834 (1997)), micropipette method (Discher DE, Mohandas N.,:" Kinematics of red cell aspiration by fluorescence-imaged microdeformation. "Biophys J.71 (4) 1680-1694 (1996)).
Of these, the microchannel method is the most widely used method.

  The subject of administration of the blood fluidity improving agent of the present invention is preferably a person having a whole blood passage time of 10 seconds to 1000 seconds.

As a method of measuring the blood circulation promoting effect, a laser Doppler blood flow meter (Abbot NC, Ferrell WR, Lockhart JC, and Lowe JG ,: "Laser Doppler perfusion imaging of skin blood flow using red and near-infrared sources." J Invest Dermatol 107 882-886 (1996)); transdermal oxygen partial pressure measurement (Hanna GP, Fujise K., Kjellgren O., Feld S. Fife C., Schroth G., Clanton T., Anderson V., Smalling R., : "Infrapopliteal interventions for limb salvage in diabetic patients." J. Am. Coll. Cardiol 30 664-669 (1997)); Cold water immersion test (Kamimura. J. Clin. Nutr., 27, 1110-1116 (1974)). Of these, the cold water immersion test is a widely used method.

  As an administration target of the blood circulation promoter of the present invention, for example, a hand or fingertip is immersed in cold water (15 ° C., 5 minutes) in a cold water immersion test, and the skin temperature recovery time of the hand or fingertip after removal (time to return to 25 ° C.) ), That is, a person whose finger surface temperature recovery time after loading with cold water is 10 minutes or more is preferable.

  One or more kinds selected from the chlorogenic acids, caffeic acid, ferulic acid and pharmaceutically acceptable salts thereof of the present invention are improved blood circulation as a result of improving the blood fluidity in the periphery, and are improved in cooling and improved in lowering body temperature. It is also useful as an agent. These active ingredients are preferably blended in the blood fluidity improver and / or blood circulation promoter in an amount of 0.01 to 80% by weight, more preferably 0.05 to 60% by weight, and particularly preferably 0.1 to 60% by weight.

When the blood fluidity-improving agent and / or blood circulation promoter of the present invention is used as a pharmaceutical product, a pharmaceutically acceptable carrier can be added to the active ingredient to make an oral or parenteral composition. .
Oral compositions include solid preparations or powders such as tablets, granules, fine granules, pills, powders, capsules (including hard capsules and soft capsules), troches, chewables, and supplements. Formulation etc. are mentioned. These preparations may be used as foods such as supplements.
The content of the component of the present invention in these preparations is preferably 0.1 to 80% by weight, particularly 10 to 60% by weight in consideration of the effective intake per day.

When the blood fluidity-improving agent and / or blood circulation promoter of the present invention is used as a food, the form of the food includes beverages, soy sauce, and milk in addition to the above-mentioned preparations, as well as active ingredients in addition to the active ingredients. , Yogurt, miso and other liquid or milky or pasty foods; jelly, gummy and other semisolid foods; cookies, gums, tofu and the like.
The content of the component of the present invention in the liquid, milky or pasty food or semi-solid food is 0.01 to 50% by weight, particularly 0.05 to 10% by weight in consideration of the effective intake per day. Is preferred.

  Examples of the parenteral composition include intravenous preparations such as injections, suppositories, and external preparations for skin.

  The blood fluidity-improving agent and / or blood circulation promoter of the present invention is excellent in safety, and there is no problem even if a healthy person, a semi-healthy person, a sick person eats or drinks everyday, and forms of supplements such as tablets and granules Alternatively, it may be used in the form of various beverages, various foods, particularly food for specified health use.

Test Example 1 (Blood fluidity evaluation)
i) Experimental materials and methods (a) Animals used 6-week-old stroke-prone hypertensive rats (SHRSP / Izm, male) were acclimated for one week or longer before the test was started. All rats were housed under conditions of a temperature of 20 to 26 ° C., a humidity of 40 to 70%, and a lighting time of 12 hours (6 am to 6 pm).
(B) Administration method and dosage The samples of Examples and Comparative Examples were repeatedly administered once a day from 8 weeks of age for 28 days. The administration method was oral administration, and forced administration was performed using a polypropylene disposable syringe fitted with a metal oral sonde. In the examples, 50 mg / kg / day of chlorogenic acid (Sigma Chemical Co.) was used, and water for injection (Otsuka Pharmaceutical) was used in the comparative example. The medium of the experimental example was water for injection.
The feed is solid feed (CRF-1, Oriental Yeast Co., Ltd.) from arrival to grouping, and solid feed (SP (0.4% salt-containing feed), Oriental Yeast Industry Co., Ltd.) after grouping. ). Drinking water was ingested freely from the arrival to the grouping, and tap water and 1% saline after the grouping.
(c) Test method After repeated administration of the specimen for 28 days, blood was collected into 7 mL of Benogect II vacuum blood collection tube (Terumo) into which 350 μL of heparin as an anticoagulant was added in advance (added 5% to whole blood). After blood collection, it was quickly mixed to obtain a blood measurement sample. As the measuring device, a cell microrheology measuring device (MC-FAN: Hitachi Haramachi Electronics Co., Ltd.) was used. The device incorporates an array of microchannels that model capillaries and measures blood cell flow characteristics under a certain pressure differential. As the capillary model, a silicon single crystal substrate processed with a 7 μm microchannel was used.
The measurement first measured the time for 100 μL of physiological saline to pass through the capillary model under a pressure difference of 20 cm water column (measured values are used for correction). Next, the passage time (seconds) of 100 μL of the blood measurement sample was measured. The measurement was performed every 10 μL. The passage of the blood measurement sample through the capillary model was observed with a microscope. Using the passage time as an indicator of blood fluidity, it was determined that the shorter the passage time, the better the fluidity.

ii) Results As is clear from Table 1, since the passage time was shorter in the experimental example (chlorogenic acid administration group) than in the comparative example (water injection administration group), improvement in blood fluidity was observed.

Test example 2 (peripheral circulation function evaluation by Cooling-rewarming test)
i) Experimental Materials and Methods Five healthy women with reduced peripheral circulation function were treated with 125 mL of raw coffee bean extract mixed vegetable fruit juice (140 mg (chloroformic acids) (0.1 wt%)) as an example per day. One bottle was drunk for 6 weeks. Three weeks after drinking for 6 weeks, the same subject as a comparative example, 125 mL of vegetable fruit juice drink containing no raw coffee bean extract (containing 6 mg of chlorogenic acids (0.005 wt%)) once a day Drunk for 6 weeks. The peripheral circulation function of this test subject was evaluated by a cold water immersion test. In the test, the subject was acclimated for 30 minutes at 20 ° C. (50 RH%), then immersed in cold water at 15 ° C. for 5 minutes until the left wrist, and the temperature at which the left hand third fingertip abdominal skin temperature recovered after removal was measured (Anritsu HPD). -2236 DIGITAL THERMOMETER).

ii) Results Table 2 shows the results obtained. Table 2 shows the recovery temperatures 45 minutes after drinking and after 6 weeks of drinking. As is apparent from Table 2, the body temperature was significantly increased in the Examples, indicating that the peripheral circulation function, that is, the blood circulation was improved by taking chlorogenic acids. In addition, improvement of blood circulation and improvement of body temperature reduction were also observed.

Test Example 3 Effects on symptoms of coldness and decreased body temperature i) Experimental materials and methods Tablets containing ferulic acid 19 mg (2% by weight) as an example for 4 men, Tablets without ferulic acid (0% by weight) as comparative examples , Cooled and evaluated changes in symptoms of hypothermia.
In the test, the symptom in the morning was evaluated, the tablets were taken, and the symptom in the afternoon was evaluated. The degree of symptom was evaluated by the following 5 grades and evaluated by an improvement score.

Score 1 Feeling symptoms 2 Feeling symptoms a little 3 Not being able to say 4 Not feeling symptoms 5 Not feeling symptoms Improvement score = Score after intake-Score before intake

ii) Results Table 3 shows the results of cooling, and Table 4 shows the results of the decrease in body temperature. In the present invention, the improvement score was high for any symptom, and reduction of these symptoms was recognized.

Example 1 (soft capsule)
Gelatin 70.0 (wt%)
Glycerin 22.9
Methyl paraoxybenzoate 0.15
Propyl paraoxybenzoate 0.51
Water 6.44
Soft capsule skins (oval type, weight 150 mg) having the above composition were filled with 400 mg soybean oil, 50 mg caffeic acid and 50 mg ferulic acid by a conventional method to produce soft capsules.

Example 2
Next, the usage example as a drink is shown.
Nonfat dry milk 3.5 (wt%)
Milk casein enzyme degradation product 3.5
Fructose 9.0
Chlorogenic acid 0.3
Sodium ferulate 1.0
Citric acid 0.1
Ascorbic acid 0.1
Fragrance 0.1
Water 82.4
The beverage having the above composition had high storage stability and good flavor.

Claims (1)

An oral blood fluidity improving agent containing 0.01 to 80% by mass of chlorogenic acid and ingesting 10 mg to 10 g per day for an adult .