JP2006206567A - Catecholamine regulator, food, drink, food additive and medicine containing the same - Google Patents

Abstract

<P>PROBLEM TO BE SOLVED: To provide a catecholamine regulator which is safe and effective, even when continuously administered for a long period. <P>SOLUTION: This catecholamine regulator contains an apple extract as an active ingredient. The catecholamine regulator, wherein the apple extract is a polyphenol derived from apples. <P>COPYRIGHT: (C)2006,JPO&NCIPI

Description

  The present invention relates to a catecholamine regulator, a food or drink containing the same, a food additive, and a medicine.

  In vivo, catecholamines act as neurotransmitters in the central nervous system via adrenergic receptors and dopamine receptors, and have a wide range of regulatory actions in the circulatory system, endocrine / metabolic system, digestive system, kidney and urinary system, etc. (Non-patent document 1).

  In addition to β1 adrenergic receptor centering on heart rate increasing action and β2 adrenergic receptor centering on bronchial smooth muscle relaxation, β adrenergic receptor selectively activates heat production in brown adipocyte tissue There is a β3 adrenergic receptor that promotes lipolysis of white adipose tissue.

  Human β3 adrenergic receptors are most abundant in brown adipose tissue, and are also expressed in white adipose tissue, gallbladder, stomach, small intestine, colon, prostate, and brain, and are also found in atrium and striated muscle ing. The main β-adrenergic receptor involved in lipolysis in adipocytes is this β3-adrenergic receptor.

  Free fatty acids and neutral fats play an important role in energy metabolism in the body. Adipose tissue breaks down neutral fat into free fatty acids and glycerol by lipolysis as needed, and supplies it as an energy source. Adipocytes are widely distributed throughout the body, such as subcutaneously and around the viscera, and have white cells that perform energy storage functions and brown adipocytes that control energy production. Both of these functions are mainly controlled by sympathetic nerves. Involved in obesity pathogenesis.

  The raw materials for neutral fat synthesis in adipocytes are glucose and fatty acids. Glucose is taken in via a sugar transport carrier induced by insulin, and when it becomes glycerol 3-phosphate, three molecules of fatty acid are ester-linked to become neutral fat. Adrenaline suppresses lipoprotein lipase activity in white adipocytes and suppresses fatty acid uptake into adipocytes. In white adipose tissue, β3 adrenergic receptors are distributed more in visceral fat than in subcutaneous fat, and are also involved in free fatty acid transport to portal blood.

Brown adipose tissue has an anti-obesity effect that consumes excess energy in addition to storing fat, producing metabolic heat. Noradrenaline binds to β3 adrenergic receptor on brown adipocyte membrane, increases cAMP concentration by activation of adenylate cyclase, PKA (protein kinase A) activation, activates HSL (hormone sensitive lipase), Promotes lipolysis. In addition, catecholamines enhance lipoprotein lipase production in brown adipocytes and promote fatty acid supply from blood lipoproteins. Free fatty acids are oxidatively decomposed and used as a heat-generating substrate, and at the same time, bind directly to UCP (uncoupling protein) to release suppression by purine nucleotides and activate UCP to promote heat production.

  In recent years, fat intake has been increasing in Japan with the diversification of eating habits. According to Non-Patent Document 2, the fat energy ratio exceeds 25%, which is the appropriate ratio for adults aged 20 to 49 years. Excess fat intake is a cause of various lifestyle-related diseases as well as obesity. Research has also reported that the higher the fat intake in the diet, the higher the body fat percentage, and the accumulation of fat causes metabolic syndrome against insulin resistance, resulting in diabetes, hyperlipidemia, hypertension It will lead to the development of arteriosclerosis due to the development of lifestyle-related diseases such as infectious diseases.

In today's society, it is difficult to continuously limit calorie intake and exercise therapy, such as increased energy intake and changes in the working environment due to the westernization of meals. The development of products having an action to prevent obesity is being promoted, and active drug therapy using natural product materials with few side effects is required. However, conventional anti-obesity agents for treating or preventing obesity have been insufficient in their effects or have side effects, and have been taken safely for a long period of time, and sufficient effects have not been obtained.
Atsushi Morimura et al. Obesity-Bioactive substances and clinical studies of obesity-, Nippon Clinic, 2003 Health and Nutrition Information Study Group, 2002 Ministry of Health, Labor and Welfare National Nutrition Survey Results, Daiichi Publishers, 2004

  An object of the present invention is to provide a catecholamine regulator for regulating catecholamines and preventing or improving obesity, which is safe and effective even when continuously taken for a long period of time, foods and drinks containing the same, food additives and pharmaceuticals Is to provide.

  As a result of intensive studies to solve the above problems, the present inventors have found that an apple extract has a catecholamine-modulating action, and have completed the present invention.

That is, the present invention has the following contents.
(1) A catecholamine regulator comprising an apple extract as an active ingredient.
(2) The catecholamine regulator according to (1), wherein the apple extract is an apple-derived polyphenol.
(3) Food / beverage products containing the catecholamine regulator as described in (1) or (2).
(4) A food additive containing the catecholamine regulator according to (1) or (2).
(5) A medicament comprising the catecholamine modulator according to (1) or (2).

  The catecholamine regulator comprising the apple extract of the present invention as an active ingredient can raise catecholamine with very few side effects.

  In addition, foods and drinks, food additives and medicines containing the catecholamine regulator as an active ingredient can raise catecholamines with very few side effects.

  The catecholamine in the present invention refers to adrenaline, noradrenaline and dopamine.

  In vivo, catecholamines act as neurotransmitters in the central nervous system via adrenergic receptors and dopamine receptors, and have a wide range of regulatory actions in the circulatory system, endocrine / metabolic system, digestive system, kidney and urinary system, etc. Therefore, the decrease or deficiency of catecholamine expression causes serious damage to the living body. The catecholamine regulator in the present invention refers to those that normally regulate the blood concentration of catecholamine.

  The apple-derived polyphenol in the present invention contains the derived polyphenol as an active ingredient in the apple extract. The catecholamine regulator in the present invention may be either an apple extract or an apple-derived polyphenol, but is preferably an apple-derived polyphenol. Apple-derived polyphenols with a high degree of purification have high processing applicability, such as being less likely to cause turbidity and turbidity when added to foods and drinks, and also capable of suppressing the influence of flavor on foods and drinks themselves.

  The apple extract containing apple-derived polyphenol used in the present invention is extracted by known extraction means from fruits of the family Rosaceae, for example, cultivars such as Fuji, Mutsu, Tsugaru, Starking Delicious, and original apples Is obtained.

  Although both mature and immature fruits can be used as fruits, immature fruits are particularly preferred because they contain more polyphenol compounds and contain a large amount of various active ingredients having a wide range of physiological effects.

  The apple-derived polyphenol contained in the apple extract of the present invention is composed of a polyphenol fraction purified from apple fruit or squeezed fruit juice or extract of an immature fruit. It is carried out by treating the juice juice and the extract with an adsorbent, and polyphenol is contained in a fraction adsorbed on the adsorbent (hereinafter referred to as an adsorbed fraction). The adsorbent is not particularly limited as long as it adsorbs polyphenol. For example, hydrophilic vinyl polymer resin (“Toyopearl HW40” manufactured by Tosoh Corporation), styrene-divinylbenzene resin (“Separbeads SP-850” manufactured by Mitsubishi Chemical Corporation). ) And gel type synthetic resin (“Diaion HP-20” manufactured by Mitsubishi Chemical Corporation).

  The polyphenol fraction is purified by eluting the adsorbed fraction adsorbed on the adsorbent with an alcohol solvent such as water-containing ethanol. The polyphenol fraction can then be concentrated to obtain a liquid formulation, and further, a powder formulation can be obtained by spray drying or freeze-drying the liquid formulation.

As an extraction method of an apple extract that is a raw material for apple-derived polyphenols, for example, the washed raw material is crushed at pH 3.2 to 4.6, preferably pH 3.5 to 4.3, and pectinase is added to the obtained fruit juice. Clarified by adding 10 to 100 ppm, more preferably 20 to 30 ppm at ˜75 ° C., preferably 30 to 60 ° C., and centrifuging at 5 to 75 ° C., preferably 15 to 25 ° C. after centrifugation. Silica 300S "(manufactured by Chuo Silica Co., Ltd.) is further clarified by filtration to obtain a clarified juice. Alternatively, partitioning with an organic solvent such as hexane and chloroform and filtration can be performed to obtain an apple extract as a clarified extract.

  In order to obtain an apple-derived polyphenol from an apple extract, the clarified extract is then 0 to 40 ° C, preferably 15 to 25 ° C, pH 1.5 to 4.2, preferably pH 3.0 to 4.0. Through an adsorption column (trade name “Diaion HP-20”, manufactured by Mitsubishi Chemical Corporation) to adsorb polyphenols. Subsequently, pure water is passed through to remove non-adsorbing substances (saccharides, organic acids, etc.) in the column, and then the adsorbed fraction is eluted with 10 to 90%, preferably 30 to 80% ethanol. Ethanol is distilled off from the obtained adsorbed fraction under reduced pressure at 25 to 100 ° C., preferably 35 to 90 ° C., and the concentrated solution may be used as it is as a liquid apple-derived polyphenol. Or powder auxiliary agents, such as dextrin, may be added, spray-drying or freeze-drying may be carried out, and it may be set as the extraction powder product of an apple origin polyphenol.

The dose per day for an adult to obtain an effect of regulating catecholamines by the catecholamine modulator of the present invention is 100 mg as apple extract or apple polyphenol.
˜2500 mg, preferably 150-1500 mg, more preferably 150-1000 mg, especially 150-750 mg.

  When the catecholamine regulator of the present invention is used, in terms of absorption of polyphenols, the blood concentration of polyphenols increases when the amount of apple extract per day or the amount of polyphenol derived from apples is ingested in a small number of times. It is easy to develop a similar action.

  The catecholamine regulator of the present invention can be used by adding as a food additive to foods in general, including beverages, such as soups, beverages (juice, liquor, mineral water, coffee, tea, non-alcoholic beer, etc.) Suitable for confectionery (gum, candy, chocolate, snacks, jelly, etc.), noodles (soba, udon, ramen, etc.), alcoholic beverages (beer, sparkling liquor, cocktail, Chuhai, shochu, sake, whiskey, brandy, wine, etc.) Used for.

  The pharmaceutical dosage form containing the catecholamine modulator of the present invention is not particularly limited, but for example, solid preparations such as tablets, powders, fine granules, granules, capsules, pills, solutions, suspensions, syrups, Oral administration agents such as liquids such as emulsions can be mentioned. This orally administered agent includes excipients, disintegrants, binders, lubricants, surfactants, alcohols, water, water-soluble polymers, sweeteners, flavoring agents, It can be produced by a commonly used method by adding a sour agent, a pharmaceutical carrier and the like.

  The present invention will be specifically described below with reference to examples and test examples.

  Example

(Production Example 1)
300 kg of apple fruit from Aomori Prefecture was crushed and pressed to obtain 210 kg of fruit juice. The obtained fruit juice was clarified with 30 ppm of pectinase, and after centrifugation, clarification was performed by filtration through diatomaceous earth (silica 300S, manufactured by Chuo Silica Co., Ltd.) to obtain a clarified fruit juice. The clarified fruit juice was passed through an adsorption column (Sepahees HP-20, manufactured by Mitsubishi Chemical Corporation) to adsorb polyphenols. Subsequently, pure water was passed through to remove non-adsorbed substance chambers (saccharides, organic acids, etc.) in the column, and then eluted with 80% alcohol. Alcohol was concentrated under reduced pressure from the obtained fraction to prepare about 2 kg of an extracted powder product. When the extracted powder product was assayed using reversed-phase high performance liquid chromatography, chlorogenic acids (about 20%), fluorethylene glycosides (about 5%), flavonols (about 15%), proanthocyanidins (about 50%) %) And other browning substances (about 10%). Furthermore, as a result of analysis by a matrix-assisted laser ionization-time-of-flight mass spectrometer (MALDI-TOF / MS, manufactured by Applied Biosystems), the protosiadinins are quantified from catechins and shrimp catechins that are flavonols It was confirmed to be an oligomer or polymer from the body to the 15-mer. (M. Ohnishi-kameyama et al. Mass Spectrometry, 11, 31, -36, 1997)

(Example 1) Tablet 150 g of apple-derived polyphenol obtained in Production Example 1, 90 g of lactose and 17 g of corn starch were mixed, and the mixture was granulated with a paste prepared in advance from 70 g of corn starch. 1 g of magnesium stearate was added to the obtained granules and mixed well, and the mixture was tableted with a tableting machine to produce 1000 tablets.

(Test Example 1) Fat accumulation inhibitory action of apple-derived polyphenol (human)
Next, through clinical trials, eight subjects examined the catecholamine-modulating action when 10 apple-derived polyphenol-containing tablets obtained in Example 1 (apple-derived polyphenol: 1500 mg) were ingested for 8 weeks. The test was conducted in accordance with the Declaration of Helsinki, and the following conditions were set as test subjects.

(1) 8 men and women aged 20 to 65 years old (including 5 women)
(2) BMI value is 24 or more and less than 30 (higher BMI ~ mild obesity)
(3) Male: Body fat percentage of 20% or more
(4) Women: Body fat percentage of 22% or more

In addition, the following conditions were set as exclusion criteria for subjects.
(1) Persons using drugs or health supplements that affect body fat reduction
(2) Persons using pharmaceuticals and supplements containing polyphenols with enhanced polyphenols, tea catechins, grape seed extracts, isoflavones, etc.
(3) Persons with serious diseases such as diabetes, liver disease, kidney disease, heart disease
(4) Persons participating in other clinical studies at the start of this study
(5) Those who are pregnant or may be pregnant, those who wish to become pregnant during lactation or during the study period
(6) Those who are judged inappropriate by the investigator in the examination before the start of ingestion

The blood concentrations of adrenaline, noradrenaline and dopamine were measured for the subjects, and the results are shown in Table 1. As is clear from Table 1, in subjects who took apple-derived polyphenols, catecholamine was regulated, and adrenaline, noradrenaline, and dopamine increased significantly at the end compared to before the start (p <0.01, p <0.01, p < 0.05). At the end, the body fat (impedance method) (−1.63), waist (−0.30 cm), hip (−1.96 cm), and waist / height ratio (−0.002) were reduced compared to before the start. Moreover, the significant fall (p <0.05, p <0.01, p <0.01) was confirmed by the 4th week compared with the total cholesterol level and LDL-cholesterol level which are a lipid related item, respectively.

  In addition, the blood pressure of the subject was measured, and the results are shown in FIG. As is clear from the results shown in FIG. 1, the subjects who took apple-derived polyphenols were confirmed to have a tendency to decrease in blood pressure. The reason for the decrease in blood pressure is presumed to be due to the vasodilating action of catecholamines.

  Some significant changes were observed in blood tests (blood biochemistry tests, general blood tests) and urinalysis, but the magnitude of the changes was small, and no clinically significant changes were found. As subjective symptoms, abdominal symptoms such as diarrhea and abdominal pain were observed, but they were transient and not related to the test meal. There was no problem.

  According to the present invention, a catecholamine-modulating agent capable of regulating catecholamine is obtained, so that it can be used for highly safe drugs, foods, medicines and the like that can prevent or improve obesity.

The graph which shows the result of the blood pressure measurement of the test subject of Example 1.

Claims (5)

A catecholamine regulator comprising an apple extract as an active ingredient. The catecholamine regulator according to claim 1, wherein the apple extract is an apple-derived polyphenol. Food-drinks containing the catecholamine regulator of Claim 1 or 2. The food additive containing the catecholamine regulator of Claim 1 or 2. The pharmaceutical containing the catecholamine regulator of Claim 1 or 2.

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