JP2006193501A - Adiponectin regulating agent and food, drink, food additive and medicine containing the same - Google Patents

Abstract

<P>PROBLEM TO BE SOLVED: To provide an adiponectin regulating preparation derived from natural materials, having high safety and exhibiting adiponectin regulating action. <P>SOLUTION: The adiponectin regulating agent contains a hop bract extract as an active component. Preferably, the hop bract extract is a polyphenol derived from hop bract. <P>COPYRIGHT: (C)2006,JPO&NCIPI

Description

  The present invention relates to an adiponectin regulator obtained from hop koji, a food / beverage product containing the same, a food additive, and a medicine.

  Hops are a perennial plant of the family Asapaceae, and the fruits (mature of unfertilized female flowers) are generally called hops. This lupulin portion of hop (yellow granule formed at the root of the inner pod of strawberry) is the main bitterness and aroma of hop and is an important beer raw material along with yeast and malt in beer brewing. Hops are also used as a sedative and anti-aphrodisiac in folk remedies.

  On the other hand, hop koji is obtained by removing lupulin from hop koji and is not useful for beer brewing. In some cases, hop koji is removed during beer brewing, and is produced as a by-product. At that time, hop koji is not used as a fertilizer for soil improvement, and no particularly useful usage has been found, and development of a usage with higher added value is desired.

  There are an estimated 7 million diabetic and obese Japanese patients, and the number is still increasing. General type II diabetes and obesity, which accounts for the majority of diabetes, is a multifactor disease that develops by combining multiple causative genes and overlapping environmental factors such as lifestyle habits. The greatest cause of increased diabetes and obesity is considered to be the increase in insulin resistance due to lifestyle habits, such as the westernization of dietary habits, particularly high fat diet and decreased physical activity.

  Currently, arteriosclerotic diseases occupy a large position alongside cancer in the Japanese cause of death statistics, and many of them suddenly develop in work, causing extremely large losses both socially and at home. Therefore, the establishment of effective preventive and therapeutic measures is an essential issue (Non-patent Document 1).

Adiponectin was discovered as a secreted protein that is highly expressed specifically in adipocytes. In later studies, anti-arteriosclerosis such as adhesion of monocytes to vascular endothelial cells and suppression of smooth muscle cell proliferation were suppressed. It became clear that it has the effect.

Regarding the relationship with diabetes, adiponectin in blood was correlated with the decrease of adiponectin in the animal model, type II diabetic monkey as insulin resistance progressed, and the glucose uptake index (M value) in the glucose clamp. Has been shown to rise (Non-Patent Document 2). In addition, administration of adiponectin at physiological concentrations to type II diabetic mice (db / db mice, KKA ^y mice) may improve insulin resistance, and may improve insulin resistance in fat-deficient mice. It has been shown that reduced or deficient adiponectin expression is responsible for obesity insulin resistance and thus obesity and type 2 diabetes. (Non-Patent Document 3).

  In addition, it has been reported that coronary artery disease patients and obese patients have lower blood levels of adiponectin than healthy individuals.

  As described above, adiponectin, a protein specific to adipose tissue, has been known to have vascular smooth muscle proliferation, migration inhibitory action, anti-arteriosclerotic action, monocyte and macrophage activation inhibitory action, anti-inflammatory action, etc. Furthermore, recent studies have confirmed that they have an effect of suppressing liver fibrosis and promoting normal hepatocyte proliferation.

Therefore, there is an urgent need to establish a fundamental prevention method and treatment method for such lifestyle-related diseases.
Guidelines for the treatment of arteriosclerotic diseases, Japan Atherosclerosis Society, 2002 DIABETES Vol.50: 1126/1133 (2001) Nature Medecine Vol. 7: 941-946 (2001)

Dissemination of drug treatment is easily dependent on drugs, and there is a possibility that lifestyle improvement will not be sufficiently performed. However, at present, no satisfactory product has been found in that it is derived from natural products, has a wide range of functionalities for lifestyle-related diseases, and has a very low possibility of side effects. An adiponectin regulator that satisfies the properties is highly desired.
The problem to be solved by the present invention is to provide an adiponectin regulator, food / beverage product, food additive, or medicine that has an effect of regulating adiponectin, is naturally derived and highly safe, and has an adiponectin regulating action. .

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

That is, the present invention has the following contents.
(1) An adiponectin regulator comprising hop koji extract as an active ingredient.
(2) The adiponectin regulator according to (1), wherein the hop koji extract is a hop koji-derived polyphenol.
(3) An adiponectin regulator comprising a substance that is a hop koji extract and does not permeate the membrane when treated with an ultrafiltration membrane having a fractional molecular weight of 1,000 or more.
(4) An adiponectin regulator that is a polyphenol-like substance contained in hop koji and does not permeate the membrane when treated with an ultrafiltration membrane having a molecular weight cut off of 1,000 or more. (5) A food or drink containing the adiponectin regulator according to (1) or (2).
(6) A food additive containing the adiponectin regulator according to (1) or (2).
(7) A medicament containing the adiponectin modulating agent according to (1) or (2).

  The adiponectin regulator comprising the hop koji extract of the present invention as an active ingredient can regulate adiponectin with very few side effects.

  In addition, foods and drinks, food additives and medicines containing the above adiponectin regulator as an active ingredient can regulate adiponectin with very few side effects.

  Reduced or deficient adiponectin expression has been shown to be responsible for obesity insulin resistance and thus obesity and type II diabetes. Furthermore, it has been reported that coronary artery disease patients and obese patients have lower blood levels of adiponectin than healthy individuals. Therefore, the adiponectin regulator in the present invention refers to a substance that normally regulates the blood concentration of adiponectin.

  The hop koji-derived polyphenol in the present invention contains the derived polyphenol as an active ingredient in the hop koji extract. The adiponectin regulator in the present invention may be either a hop koji extract or a hop koji-derived polyphenol, but is preferably a hop koji-derived polyphenol. Highly purified hop koji-derived polyphenol has high processing applicability such as being less likely to cause turbidity and turbidity when added to foods and drinks, and can also suppress the influence of flavor on foods and drinks etc. .

  The hop koji extract containing the hop koji-derived polyphenol used in the present invention is obtained by removing the lupulin portion from the hop koji, and in general, after removing the lupurin portion by sieving the hop koji. Get a hop kite by. However, in recent beer brewing, in order to save the trouble of sieving and removing hop cake, the hop fruit is formed into pellets without removing hop cake that is not useful for beer brewing, It tends to be used for brewing. Therefore, the raw material of the present invention is not particularly limited as long as it contains hop straw, and there is no problem even if hop fruit and hop pellets containing hop straw are used as the raw material.

  The extraction method of the hop koji extract is not particularly limited. For example, hop koji or hop pellets containing hop koji or hop koji as a raw material are 4 to 95 ° C, preferably 30 to 60 ° C. And mixed with 0 to 50% ethanol, preferably 10 to 40% ethanol, and extracted. The ratio of a raw material and an extraction solvent is 1: 20-100 (weight ratio), Preferably it is 1-30-90 (weight ratio), It carries out in stirring for 20-60 minutes, Preferably it is 30-50 minutes. Further clarification is performed by filtration at 5 to 75 ° C., preferably 15 to 25 ° C., through diatomaceous earth (trade name “Silica 300S”, manufactured by Chuo Silica Co., Ltd.). Since the hop koji extract has a neutral fat metabolism control action, it is useful as a neutral fat reduction metabolic control agent.

  Since hop koji extract or hop koji-derived polyphenol has an adiponectin regulating action, it is useful as an adiponectin regulating agent.

  In order to obtain hop cocoon-derived polyphenol from hop cocoon extract, for example, hop cocoon extract is adsorbed with an adsorption resin that adsorbs the polyphenol-like substance, and hop cocoon-derived polyphenol-like material is separated and purified from the hop cocoon extract. That's fine. Although the adsorption treatment method is not particularly limited, for example, the hop koji extract may be adsorbed on the adsorption resin at 0 to 40 ° C., preferably 15 to 25 ° C.

  The adsorption resin is not particularly limited as long as it adsorbs a polyphenol-like substance. For example, a hydrophilic vinyl polymer resin (“Toyopearl HW40” manufactured by Tosoh Corporation), a styrene-divinylbenzene resin (“Separbeads SP-825 manufactured by Mitsubishi Chemical Corporation), etc. )), A gel type synthetic resin ("Diaion HP-20" manufactured by Mitsubishi Chemical Corporation). The hop koji extract is passed through an adsorption column packed with these adsorption resins to adsorb polyphenol-like substances. Subsequently, pure water is passed through to remove non-adsorbing substances (saccharides, organic acids, etc.) in the column, and then the polyphenol-like substance is eluted with 10 to 90%, preferably 30 to 80% ethanol. .

  Of the hop koji extract or hop koji-derived polyphenol-like substance, a substance that does not permeate the membrane when treated with an ultrafiltration membrane having a fractional molecular weight of 1,000 or more is preferable in terms of regulating adiponectin.

  Next, a method using an ultrafiltration membrane will be described. The ultrafiltration having a fractional molecular weight of 1,000 or more, preferably 10,000 to 50,000 is applied to the treatment liquid containing the hop koji extract or the hop koji-derived polyphenol-like substance obtained in the extraction step or the adsorption step. Treat with membrane. If necessary, the treatment liquid containing the hop koji-derived polyphenol-like substance can be concentrated under reduced pressure to lower the ethanol concentration. Further, the treatment depends on the concentration of the organic solvent in the extraction solvent and the ratio of the extraction solvent to hops or hops, but the amount of the remaining liquid is approximately 1/10 to 1/100, preferably 1/20 at the start of the treatment. Repeat until 1/100. The pressure at that time is 9.8 kPa to 981 kPa, preferably 98 kPa to 686 kPa. Although it can be used in the liquid state as it is, it can be dried as described below. From the obtained fraction, ethanol is concentrated under reduced pressure at 25 to 100 ° C., preferably 35 to 90 ° C., the concentrated solution is added as it is or a powder auxiliary such as dextrin is added, spray drying or freeze drying is performed, and an extracted powder product is obtained. obtain.

  The method for obtaining a hop koji-derived polyphenol-like substance that does not pass through the membrane when treated with an ultrafiltration membrane having a molecular weight cut-off of 1,000 or more is not limited to the above method. After the koji-derived extract is treated with an ultrafiltration membrane having a fractional molecular weight of 1,000 or more, a treatment liquid that does not permeate the ultrafiltration membrane may be subjected to an adsorption treatment with a gel polymer.

  The daily dose for adults to obtain the effect of regulating adiponectin by the adiponectin modulating agent of the present invention is 100 to 2500 mg, preferably 150 to 1500 mg as hop koji extract or hop koji polyphenol. More preferably, it is 150 to 1000 mg, particularly 150 to 750 mg.

  When using the adiponectin modulating agent of the present invention, in terms of absorption of polyphenols, the blood concentration of polyphenols will be higher if the amount of hop koji extract or hop koji-derived polyphenol per day is taken less. It is easy to develop the action of polyphenols.

  The adiponectin regulating agent 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 adiponectin modulating agent of the present invention is not particularly limited, but for example, solid preparations such as tablets, powders, fine granules, granules, capsules, pills, liquid preparations, 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.

Examples Next, the present invention will be described in more detail with reference to examples. However, the present invention is not limited to these examples.

(Production Example 1) Preparation from hop spikelets with gel-type synthetic resin 20 g of hop spikelets were pulverized in a mortar and extracted at 90 ° C. for 40 minutes with stirring with 2 L of water. After filtration, the mixture was allowed to cool, and the extract was passed through a column packed with 80 mL of hydrophilic vinyl polymer resin (Toyopearl HW40 manufactured by Tosoh Corporation) over 2 hours (SV = 12.5), and then 400 mL of 5% aqueous ethanol solution. Washed with. Further, 400 mL of 80% ethanol aqueous solution was passed through the same column, and the same eluate was collected and freeze-dried to obtain 0.8 g of a pale yellow powder having an odorless faint bitter taste. The yield from hop camellia was 4%.

(Production Example 2) Preparation from hop koji with gel-type synthetic resin 20 g of hop koji was extracted at 80 ° C. for 40 minutes with stirring with 600 mL of a 50% aqueous ethanol solution. After filtration, the solution was concentrated under reduced pressure until the volume reached 300 mL, and the concentrated solution was passed through a column packed with 80 mL of styrene-divinylbenzene resin (Separbeads SP-825, manufactured by Mitsubishi Chemical Corporation) over 1 hour (SV = 3. 75) and then washed with 400 mL of water. Further, 400 mL of an 80% ethanol aqueous solution was passed through the same column, and the same eluate was collected and freeze-dried to obtain 1.6 g of a pale yellow powder having an odorless faint bitter taste. The yield from hop koji was 8%.

(Production Example 3) Preparation from hop spikelets using ultrafiltration membrane 20 g of hop spikelets were pulverized in a mortar and extracted with 95 ℃ for 40 minutes while stirring with 2 L of water. After filtration, the mixture was allowed to cool, and the extract was treated with an ultrafiltration membrane having a molecular weight cut off of 50,000 (XM50 manufactured by Amicon Co., Ltd.) at 98 kPa and room temperature to 20 mL. The obtained upper residual liquid was dried under reduced pressure to obtain 0.2 g of a light yellow powder having an odorless faint bitter taste. The yield from hop camellia was 1%.

(Production Example 4) Preparation from hop cake by ultrafiltration membrane 20 g of hop cake was extracted with 80 mL of 50% ethanol aqueous solution at 600C for 40 minutes. After filtration, the extract was treated with an ultrafiltration membrane having a molecular weight cut-off of 10,000 (YM10 manufactured by Amicon Co., Ltd.) at 294 kPa and room temperature to 60 mL. The obtained upper liquid residue was freeze-dried to obtain 0.8 g of a pale yellow powder having an odorless faint bitter taste. The yield from hop koji was 4%.

(Production Example 5) Further purification of preparation from hop koji with gel-type synthetic resin)
0.8 g of a preparation from hop koji using gel type synthetic resin obtained in Production Example 2 (preparation from hop koji using gel type synthetic resin) was dissolved in 500 mL of 10% ethanol aqueous solution, and the molecular weight cut off was 10, 000 ultrafiltration membrane (Amicon YM10) was treated at 98 kPa at room temperature until 20 mL. The obtained upper liquid residue was freeze-dried to obtain 0.4 g of a pale yellow powder having an odorless faint bitterness.

(Comparative Example 1) Tablet 140 g of lactose and 17 g of corn starch were mixed, and this 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.

(Example 1) Tablet 150 g of hop koji polyphenol obtained in Production Example 1, 90 g of lactose and 17 g of corn starch were mixed, and this 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 hop koji polyphenol (human)
Next, we examined the effect of hop koji polyphenols on fat accumulation by clinical trials.

[Method]
1) Subjects Among the male and female over 20 years old who volunteered to participate in this study among paid volunteers, in a preliminary study conducted 4 weeks before the start of the study, the body mass index showed 22 <BMI ≤ 30 I chose a name. However, those who are taking medicines and health foods that may affect lipid metabolism, those who have a history of food allergies, 200 ml within 1 month of this study, or 400 ml within 3 months Excluded were those who collected blood (such as blood donation) exceeding the limit, or those judged by the investigator to be inappropriate for study participation. Based on the results of preliminary examinations (blood, physical examination) and CT examinations conducted before ingestion by doctors who do not participate directly in the trial, the age, weight, height, body mass index, blood pressure, They were divided into two groups so that backgrounds such as neutral fat, total fat area (TFA), visceral fat area (VFA), and subcutaneous fat area (SFA) waist / hip were aligned. In addition, this study was conducted in accordance with the purpose of the Declaration of Helsinki, with sufficient explanations of research content and methods, etc., with the consent of documents.

2) Test meal This test meal consists of a tablet containing hop koji polyphenol produced in Example 1 (150 mg / 1 tablet) and a control meal (placebo tablet) containing no polyphenol produced in Comparative Example 1. did. In addition, before conducting the test, the investigator confirmed that there was no distinction between the test beverage and the placebo tablet due to sensory aspects such as flavor and aroma and packaging.

3) Intake method and schedule The study was a parallel two-group comparative study that adopted a double-blind method with random assignment. The test period was set to a total of 20 weeks, including a pre-observation period of 4 weeks, an intake period of 12 weeks, and an observation period of 4 weeks after the end of intake. The subjects were divided into two groups and ingested the test tablets as follows.

Group A: Hops polyphenol-containing test tablets (150 mg / 1 tablet) each 4 tablets before dinner (total 4 tablets / day), hops polyphenol test tablets intake group
Group B: 4 placebo tablets (150 mg / tablet) each before dinner (4 tablets / day in total), the following placebo tablet intake group The subjects except for taking test tablets daily, Instruction was given not to change daily life such as eating, smoking and exercising.

4) Blood test All subjects had adiponectin, Na, Ca, Cl, K, GPT (ALT), LDH, total bilirubin, UIBC, Fe, and γ-GTP on the start of intake and 12 weeks after intake (end of intake). Measurement items of total protein, urea nitrogen, blood cell components (white blood cell, red blood cell, hemoglobin content, hematocrit value, MCV, MCH, MCHC, platelet count) were carried out. In order to avoid external effects such as food and exercise, all tests were fasted for 12 hours or longer, maintained at rest for 10 minutes or more after visiting the hospital, and blood was collected in the sitting position.

[result]
The results are shown in Table 1. Regarding adiponectin, a significant decrease was observed 12 weeks after ingestion in the placebo capsule ingestion group (p <0.001). In comparison between groups, a significant difference was observed between the placebo capsule intake group and the hop-polyphenol test capsule intake group (p <0.05). In addition, no abnormality was observed from various blood tests. During the intake period, no complaining complaints were found.

  The present invention is useful because an adiponectin regulator comprising hop koji extract as an active ingredient and adiponectin can be regulated with very few side effects.

  In addition, the present invention is useful because foods and drinks, food additives and medicines containing the above adiponectin regulator as an active ingredient can regulate adiponectin with very few side effects.

Claims (7)

An adiponectin regulator comprising hop koji extract as an active ingredient. The adiponectin regulator according to claim 1, wherein the hop koji extract is a hop koji-derived polyphenol. An adiponectin regulator that is a hop koji extract and is a substance that does not permeate the membrane when treated with an ultrafiltration membrane with a molecular weight cut off of 1,000 or more. An adiponectin regulator, which is a polyphenol-like substance contained in hop koji and is a substance that does not permeate the membrane when treated with an ultrafiltration membrane having a molecular weight cut off of 1,000 or more. Food-drinks containing the adiponectin regulator of Claim 1 or 2. The food additive containing the adiponectin regulator of Claim 1 or 2. The pharmaceutical containing the adiponectin regulator of Claim 1 or 2.