JP2007332336A - Metabolic syndrome therapeutic agent - Google Patents

Abstract

<P>PROBLEM TO BE SOLVED: To provide a method for manufacturing a new metabolic syndrome therapeutic agent with high safety or a β-glucan and compound sugar-containing vegetable chitosan useful as a new neutral fat-lowering food from the hymenocarp or mycelium of food Basidiomycetes. <P>SOLUTION: Disclosed is a method for manufacturing an aqueous solvent-soluble β-glucan and a compound sugar-containing vegetable chitosan that are prepared from the hymenocarp or mycelium of enokidake mushroom. <P>COPYRIGHT: (C)2008,JPO&INPIT

Description

  The present invention relates to a method for producing β-glucan and a complex carbohydrate-containing plant chitosan which are novel therapeutic agents for metabolic syndrome.

  In recent years, various physiological activities of basidiomycetes have attracted attention, and the prevention or treatment of metabolic syndrome, the effect of reducing triglycerides, etc. have been pointed out. In addition, various effective ingredients such as anticancer action, immunostimulatory action, cholesterol lowering action, antithrombosis, blood pressure lowering, and blood sugar lowering are being proved, and they are attracting attention as new drug development and functional food materials. .

  Among such various physiological activities, there are very few reports on the blood cholesterol-lowering effect of basidiomycetous plant chitosan, and the plant has the effect of preventing adult diseases obtained from enokitake mushroom extract so far. There are only patent applications such as sex chitosan and its production method (Patent Document 1). Further, the cholesterol-lowering action of plant chitosan possessed by enoki mushroom (Non-patent Document 1) has been reported in academic societies and the like.

In recent years, metabolic syndrome has attracted attention, and blood cholesterol lowering and neutral fat lowering have become increasingly important. Metabolic syndrome has the following symptoms: Hyperglycemia, hypertension, obesity, HDL cholesterol lowering, triglyceride elevation. Related diseases include fatty liver, polycystic ovary syndrome, hemochromatosis, melanoma, nonalcoholic fatty liver.
Diagnostic criteria for metabolic syndrome The Japanese Society of Hypertension, the Japanese Society of Obesity, etc. have created a “diagnosis criterion” using a new concept of “metabolic syndrome” and presented it at the Japan Society of Internal Medicine. The diagnostic criteria are as follows: waist size (85 centimeters for men, 90 centimeters or more for women) is the first condition, and (1) maximum blood pressure is 130 or higher or minimum blood pressure is 85 or higher. (2) Fasting blood glucose The value is 110 or more. (3) If two or more of the three items of neutral fat are 150 or more or good cholesterol is less than 40, a metabolic syndrome is determined. It is estimated that there are over 10 million people in Japan who fall under this metabolic syndrome.
This is not a US standard, but a standard value for Japanese people proposed by Prof. Kazuaki Shimamoto of Sapporo Medical University.
1. 1. Waist is 85 cm or more; for women, 90 cm or more. 2. Triglyceride rise; 150 mg / dl or more HDL cholesterol reduction 40 mg / dl or less: 50 mg / dl or less for women.
4). Blood pressure is 130/85 or higher.
5). The glucose level is 110 mg / dl or higher.

Pathology of metabolic syndrome The causes of metabolic syndrome are extremely complex. Most patients are old and fat and have problems with insulin resistance. There is a debate about whether obesity and insulin resistance are the cause or consequence of metabolic syndrome. Markers for inflammation are often increasing. For example, CRP, fibrinogen, interleukin 6, TNFα and the like. The normal chain appears to be an increase in visceral fat. At this time, the blood level of TNFα is increased. TNFα is not only involved in the production of inflammatory cytokines, but is linked to the TNFα receptor that results in insulin resistance. In the rat experiment where the amount of food was reduced to 1/3, sucrose has become a model for the development of metabolic syndrome. Sucrose first increased blood triglycerides, increased visceral fat, and eventually caused insulin resistance.
In addition, “saturated fatty acids” from fat cells that have become obese and huge have activated the functions of immune cells, and this time immune cells have activated fat cells, leading to the production of inflammatory proteins from fat cells and visceral fat. There is research that causes the arteriosclerosis to be caused by adiponectin decreasing from fat cells when accumulated.

Treatment:
The main treatment is lifestyle. Calorie restriction and exercise. However, medical treatment is also performed in parallel. For high blood pressure, ACE inhibitors and cholesterol drugs lower LDL cholesterol. Metformin or thiazolidindione is administered to lower insulin resistance.
Japanese Patent Application No. 2004-542850 Hideo Okazaki: About the effect of chitoglucan on lipid absorption suppression, Food Style 21, 9 (2), 28-30 (2005) Nakamura Yasuko, Ooka Tomoe et al .: Effects of mushroom chitosan on body weight and body fat of adult women, Food Style 21, 10 (3), 29-33 (2006) Hideo Okazaki: Examination of diet effect of mushroom chitosan, Food Style 21, 10 (6), 85-90 (2006)

  Lifestyle changes or improvements are the most powerful treatments for metabolic syndrome, but it is often pointed out that this is actually very difficult to achieve. In other words, stop eating or reducing your favorite food to less than half and concentrate on unfamiliar exercises, such as walking down a train in front of one station, walking for 1 hour after dinner, changing your eating habits and lifestyle habits It is an event that overturns the foundation. Is it possible to treat metabolic syndrome without changing lifestyle? The present invention has been made in view of the above circumstances, and produces β-glucan and complex carbohydrate-containing plant chitosan useful for the prevention or treatment of novel metabolic syndrome, which effectively uses edible mushrooms and has very few side effects. A method is provided.

  The present invention relates to a novel method for producing β-glucan and complex carbohydrate-containing plant chitosan useful for treating or preventing metabolic syndrome obtained from enokitake mushroom, shiitake mushroom, mushroom, maitake fruit body or mycelium.

  As a result of earnest search for a novel metabolic syndrome therapeutic agent derived from basidiomycetes and having few side effects in order to solve such problems, the present inventors, among edible basidiomycetes, enokitake, shiitake, mushroom, maitake fruiting body or mycelium It has been found that a novel therapeutic agent for metabolic syndrome can be obtained from the extract, and the present invention has been completed.

The present inventors have already found that plant-derived chitosan obtained from basidiomycetes is useful for improving lifestyle-related diseases, and have applied for a patent for its production method. However, the conventional method is not a production method that can be easily performed at home, such as using high-concentration caustic soda. Even if it is manufactured industrially, there are considerably dangerous work processes such as the use of high-concentration hot caustic soda, and it is difficult to say that it is a simple method. In the present invention, the production method has been further devised and improved, and natural ingredients that are safer and have fewer side effects have been successfully extracted from edible basidiomycetes.
As is clear from the results of Tables 1, 2 and 3, the preventive or therapeutic effect of novel metabolic syndrome from aqueous solvent extracts of enoki mushrooms, shiitake mushrooms, mushrooms, maitake mushrooms and mycelium as edible basidiomycetes Β-glucan and complex carbohydrate-containing plant chitosan having the above were obtained.

Pharmaceuticals or foods using β-glucan and complex carbohydrate-containing plant chitosan β-glucan and complex carbohydrate-containing plant chitosan of the present invention has waist, body weight, blood pressure, blood glucose level, HbA1c, HDL cholesterol level, and neutral fat level. Etc. have a lowering effect. Therefore, the β-glucan and complex carbohydrate-containing plant chitosan of the present invention is highly effective in improving the test values of lifestyle-related diseases such as hypertension and diabetes, and adult diseases, and is suitable for use in the form of pharmaceuticals or foods. It is.
In order to use the β-glucan and complex carbohydrate-containing plant chitosan of the present invention in the form of a solution, β-glucan and complex carbohydrate-containing plant chitosan, sodium benzoate, methyl p-oxybenzoate, sodium dehydroacetate, etc. Preservatives, solubilizing agents such as malic acid, ascorbic acid, citric acid, and acetic acid, as well as coloring agents, flavoring agents, flavoring agents, sweetening agents such as glucose and mannitol, etc. A diluent such as saline is added as necessary to prepare a pharmaceutical product or food.
Drugs containing β-glucan and complex carbohydrate-containing vegetable chitosan as active ingredients are usually prepared in the form of solid preparations such as tablets, pills, powders, granules, capsules, and suppositories. At that time, these pharmaceutical preparations are prepared using diluents or excipients such as fillers, extenders, binders, moisturizers, disintegrants, surfactants, lubricants and the like that are usually used. .
In forming into tablets, conventionally known carriers can be widely used as carriers, such as lactose, mannitol, sucrose, sodium chloride, glucose, starch, calcium carbonate, kaolin, crystalline cellulose and other excipients, Distilled water, physiological saline, simple syrup, glucose solution, starch solution, gelatin solution, carboxymethylcellulose, potassium phosphate, polyvinylpyrrolidone and other binders, dried starch, sodium alginate, agar powder, sodium bicarbonate, calcium carbonate, lauryl Disintegrants such as sodium sulfate, stearic acid monoglyceride, starch, lactose, disintegration inhibitors such as sucrose, stearin, cocoa butter, hydrogenated oil, dissolution absorption accelerators such as acetic acid, ascorbic acid, malic acid, glycerin, starch, lactose , Kaolin, bentonite, colloid Adsorbent such as Jo silicate, purified talc, stearates, such as lubricants such as polyethylene glycol. Furthermore, the tablet can be a sugar-coated tablet, a gelatin-encapsulated tablet, an enteric-coated tablet, a film-coated tablet, a double tablet, or a multilayer tablet as necessary.
In molding into the form of pills, conventionally known carriers can be widely used as carriers, such as glucose, lactose, mannitol, starch, cocoa butter, hydrogenated vegetable oil, kaolin, talc and other excipients, gum arabic Powders, disintegrating agents such as gelatin are listed. In molding into a suppository, a conventionally known carrier can be widely used as the carrier, and examples thereof include cocoa butter, higher alcohol esters, and gelatin.
The content of β-glucan and complex carbohydrate-containing plant chitosan used as active ingredients is not particularly limited and is selected in a wide range. It is good.
The dose is not particularly limited, but may be appropriately selected according to the usage, age, sex, degree of disease, etc., and 0.1 g of β-glucan and complex carbohydrate-containing plant chitosan per 1 kg body weight. The amount of -10 mg, preferably 0.5-5 mg, is orally administered in 1 to 4 divided doses per day. If the content of β-glucan and complex carbohydrate-containing plant chitosan is high, this may cause iron or vitamin deficiency due to absorption and inclusion of iron and vitamins. And because the content of complex carbohydrate-containing plant chitosan is relatively low, there is no need to supplement iron or vitamins.
The food containing the β-glucan of the present invention and the complex carbohydrate-containing plant chitosan is not particularly limited, and examples thereof include soup, miso soup, drink, jelly, gummy and the like. The content of β-glucan and complex carbohydrate-containing plant chitosan in these foods is preferably 0.01 to 5.0% by mass, more preferably 0.02 to 1.0% by mass, and most preferably 0.05. It is -0.5 mass%.

The present invention will be described more specifically with reference to the following examples, but is not limited thereto.

抽出溶媒は、弱い有機酸、弱いアルカリ溶液および純水で行われる。βグルカンおよび複合糖質含有植物性キトサンの回収は、比較的容易である。さらに回収されたβグルカンおよび複合糖質含有植物性キトサンが、純植物性キトサンを含んでいることも証明された。
純植物性キトサンの定量法
βグルカンおよび複合糖質含有植物性キトサン中の純植物性キトサンの含有量は、以下の方法により行う。
βグルカンおよび複合糖質含有植物性キトサン粉末０．５ｇを正確に秤量し、これを５容量％酢酸に溶かして正確に１００ｇとする。この溶液１ｇを２００ｍｌ容の三角フラスコに正確にはかりとり、脱イオン水３０ｍｌを加え、充分攪拌混合する。指示薬として０．１％トルイジンブルー溶液２〜３滴を加え、Ｎ／４００ポリビニル硫酸カリウム溶液［（Ｃ２Ｈ３ＯＳＫ）ｎ、ｎ＝１５００以上］で滴定する。脱アセチル化度（すなわちキトサン含有量＝グルコサミン含有量）は下記の式に従って求める。
脱アセチル化度＝（Ｘ／１６１）／［（Ｘ／１６１）＋（Ｙ／２０３）］×１００（％）
ここに、Ｘ＝（１／４００）×（１／１０００）×ｆ×１６１×ｖ
Ｙ＝０．５×（１／１００）−Ｘ
ｖ＝Ｎ／４００ポリビニル硫酸カリウム溶液滴定値（ｍｌ）
ｆ＝Ｎ／４００ポリビニル硫酸カリウム溶液のファクター
ファクターｆは１．００５である。
式を書き直すと
脱アセチル化度＝［２０３Ｘ／（２０３Ｘ＋１６１Ｙ）］×１００（％）
Ｘ＝１．００５×１６１×ν（滴定値；ｍｌ）
Ｙ＝５−Ｘ
ここで標準として、純植物性キトサンを用いると、試料中の純植物性キトサン含量を、植物性キトサン当量として、計算で求めることができる。
標準の純植物性キトサンの製造方法は、特願２００２−２９５３７９に詳細に記されているが、簡単に再掲しておく。新鮮な担子菌類の子実体１００ｇに等量の固形ＮａＯＨを加えて、１００℃に４時間以上加熱する。これを水洗し、アルカリを除いてから１０％−ＡｃＯＨを５００ｍｌ加えて酢酸酸性となし、布で濾過する。透明な濾液を４０％−ＮａＯＨで中和し、ｐＨを１０以上にすると沈澱が生じ、白濁する。遠心分離でこの沈澱を回収し、中性になるまで水洗でアルカリを除去する。必要に応じて、この操作を数回繰り返す。得られた沈澱を凍結乾燥する。この方法で精製純キトサンが得られる。収率は、２〜３ｇである。Add 250 ml or 500 ml of pure water to 250 g of enoki mushroom and heat with a pressure pan. Cool naturally and filter the extract from the mushrooms. The results shown in Table 1 were obtained by quantifying plant chitosan in the filtrate. The content of plant chitosan was 136 mg or 125 mg. The content of β-glucan soluble in an aqueous solvent and complex carbohydrate-containing mushroom chitosan was 7.70 g or 9.34 g per 250 g of enoki mushroom.

The extraction solvent is a weak organic acid, a weak alkaline solution and pure water. Recovery of β-glucan and complex carbohydrate-containing plant chitosan is relatively easy. Furthermore, it was proved that the recovered β-glucan and complex carbohydrate-containing plant chitosan contained pure plant chitosan.
Quantitative Method for Pure Plant Chitosan The content of pure plant chitosan in β-glucan and complex carbohydrate-containing plant chitosan is determined by the following method.
β-glucan and complex carbohydrate-containing vegetable chitosan powder 0.5 g is accurately weighed and dissolved in 5% by volume acetic acid to make exactly 100 g. 1 g of this solution is accurately weighed into a 200 ml Erlenmeyer flask, added with 30 ml of deionized water, and mixed with sufficient stirring. Add 2-3 drops of 0.1% toluidine blue solution as an indicator and titrate with N / 400 potassium polyvinyl sulfate solution [(C2H3OSK) n, n = 1500 or more]. The degree of deacetylation (ie, chitosan content = glucosamine content) is determined according to the following formula.
Deacetylation degree = (X / 161) / [(X / 161) + (Y / 203)] × 100 (%)
Here, X = (1/400) × (1/1000) × f × 161 × v
Y = 0.5 × (1/100) −X
v = N / 400 potassium polyvinyl sulfate solution titration value (ml)
f = Factor of N / 400 potassium polyvinyl sulfate solution The factor f is 1.005.
When the formula is rewritten, the degree of deacetylation = [203X / (203X + 161Y)] × 100 (%)
X = 1.005 × 161 × ν (Titration value; ml)
Y = 5-X
Here, when pure plant chitosan is used as a standard, the pure plant chitosan content in the sample can be calculated as the plant chitosan equivalent.
The method for producing standard pure plant chitosan is described in detail in Japanese Patent Application No. 2002-295379, but it will be briefly reprinted. An equal amount of solid NaOH is added to 100 g of fresh basidiomycetous fruit bodies and heated to 100 ° C. for at least 4 hours. This is washed with water, and after removing the alkali, 500 ml of 10% AcOH is added to make it acetic acid, and then filtered through a cloth. The clear filtrate is neutralized with 40% -NaOH, and when the pH is increased to 10 or more, precipitation occurs and cloudiness occurs. The precipitate is recovered by centrifugation and the alkali is removed by washing with water until neutral. Repeat this operation several times if necessary. The resulting precipitate is lyophilized. In this way, purified pure chitosan is obtained. The yield is 2-3 g.

熱水抽出したβグルカンおよび複合糖質含有植物性キトサンは、室温の純水に易溶である。しかしリンゴ酸抽出で得られたものは、純水を加えると濁りがでる。βグルカンおよび複合糖質含有植物性キトサンは、熱水に可溶で、エタノール８０％で沈澱するというクライテリアを採用した。100 g of fresh enoki mushrooms, shiitake mushrooms, maitake mushrooms and 80 g of enoki mushrooms + 20 g of shiitake mushrooms, and the yield of vegetable chitosan containing β-glucan and complex carbohydrates by organic acid extraction.

Β-glucan extracted with hot water and complex carbohydrate-containing plant chitosan are readily soluble in pure water at room temperature. However, the product obtained by malic acid extraction becomes turbid when pure water is added. The criteria that β-glucan and complex carbohydrate-containing plant chitosan is soluble in hot water and precipitates with 80% ethanol was adopted.

  Shred 80 g of fresh enoki mushrooms and 20 g of shiitake mushrooms, add about 30 ml of a small amount of pure water, and apply to a food processor. Transfer this to a beaker, add 200 ml of pure water and heat. After boiling, continue heating for 20-30 minutes with a weak heating power. Cool to room temperature and centrifuge at 4000 rpm for 10 minutes. The supernatant is recovered as mushroom chitosan containing β-glucan and complex carbohydrates. Analysis of the pure plant mushroom chitosan contained in the thus produced β-glucan and complex carbohydrate-containing plant chitosan revealed that about 20 mg of pure plant mushroom chitosan was contained. The β-glucan and complex carbohydrate-containing plant chitosan produced in this way can be drunk as it is, but it can be drunk by adding consomme or bouillon or seasoning with citrus juice, lemon or honey. It is also possible to provide.

表３に見られるようにβグルカンおよび複合糖質含有植物性キトサンの長期連続経口投与により、投与前後の検査値に顕著な改善効果が観察された。被験者のライフスタイルすなわち運動量および食習慣は投与前後でほとんど変わっていないので、この改善効果は、純粋にβグルカンおよび複合糖質含有植物性キトサンによるものと推察される。The following table shows the results of oral administration of the basidiomycete extract obtained as described above, 100 ml daily, to 57-year-old male orally for 6 months. Administration may be divided into twice in the morning and evening. The meal during this period maintained normal eating habits. In particular, it does not load exercise.

As can be seen from Table 3, a long-term continuous oral administration of β-glucan and complex carbohydrate-containing plant chitosan showed a remarkable improvement effect on the test values before and after administration. Since the lifestyle, ie, the amount of exercise and the eating habits of the subjects hardly changed before and after administration, this improvement effect is presumed to be purely due to β-glucan and complex carbohydrate-containing plant chitosan.

Industrial application fields

  The present invention relates to a method for producing β-glucan and complex carbohydrate-containing plant chitosan obtained from the fruit body or mycelium of edible basidiomycetes, and particularly useful as a novel therapeutic agent for metabolic syndrome or a food for reducing neutral fat. .

Claims (3)

  A process for producing β-glucan and complex carbohydrate-containing plant chitosan extracted from the fruit body or mycelium of an edible basidiomycete with an aqueous solvent.   A method for producing β-glucan and complex carbohydrate-containing plant chitosan, wherein the edible basidiomycetes are enoki mushroom, mushroom, shiitake and maitake.   A method for producing β-glucan and complex carbohydrate-containing plant chitosan, wherein the aqueous solvent used for extraction is a dilute organic acid or inorganic acid aqueous solution, pure water and mineral water, or a dilute alkaline aqueous solution.