JP5991617B2 - Method for producing pancreatic lipase inhibitor - Google Patents
Method for producing pancreatic lipase inhibitor Download PDFInfo
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- JP5991617B2 JP5991617B2 JP2012195737A JP2012195737A JP5991617B2 JP 5991617 B2 JP5991617 B2 JP 5991617B2 JP 2012195737 A JP2012195737 A JP 2012195737A JP 2012195737 A JP2012195737 A JP 2012195737A JP 5991617 B2 JP5991617 B2 JP 5991617B2
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- Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
- Y02—TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
- Y02P—CLIMATE CHANGE MITIGATION TECHNOLOGIES IN THE PRODUCTION OR PROCESSING OF GOODS
- Y02P20/00—Technologies relating to chemical industry
- Y02P20/50—Improvements relating to the production of bulk chemicals
- Y02P20/52—Improvements relating to the production of bulk chemicals using catalysts, e.g. selective catalysts
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- Medicines Containing Plant Substances (AREA)
- Preparation Of Compounds By Using Micro-Organisms (AREA)
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Description
本発明は、食後の中性脂肪の吸収を効果的に抑制する膵リパーゼ阻害剤の製造方法に関する。 The present invention relates to a method for producing a pancreatic lipase inhibitor that effectively suppresses absorption of neutral fat after a meal.
脂肪の過剰摂取は肥満および高脂血症の原因となる。また、肥満ではインスリン抵抗性が惹起され、糖尿病、高血圧症、動脈硬化の発症率が高いことが知られている。このことから、食物中の脂肪の吸収を抑制する薬剤は、肥満や高脂血症の予防または改善に有効であるのみでなく、肥満に起因する糖尿病、高血圧症、動脈硬化などの発症を予防し、生活の質の向上に寄与すると考えられている。 Fat overdose causes obesity and hyperlipidemia. In addition, it is known that obesity induces insulin resistance and has a high incidence of diabetes, hypertension and arteriosclerosis. Therefore, drugs that suppress the absorption of fat in food not only are effective in preventing or improving obesity and hyperlipidemia, but also prevent the onset of diabetes, hypertension, arteriosclerosis, etc. caused by obesity. It is thought to contribute to improving the quality of life.
膵臓から分泌される膵リパーゼは腸管における中性脂肪の消化酵素であり、食事により摂取された中性脂肪は膵リパーゼによって脂肪酸とモノグリセライドに分解されて小腸から吸収される。従って、膵リパーゼの活性を抑制する組成物は、腸管からの脂肪吸収を阻害して、高脂血症及び肥満の予防または改善に有効であると考えられている。 Pancreatic lipase secreted from the pancreas is a digestive enzyme of neutral fat in the intestinal tract, and the neutral fat ingested by the meal is broken down into fatty acids and monoglycerides by the pancreatic lipase and absorbed from the small intestine. Therefore, a composition that suppresses the activity of pancreatic lipase is considered to be effective in preventing or improving hyperlipidemia and obesity by inhibiting fat absorption from the intestinal tract.
実際、欧米において発売されている医療用医薬品の膵リパーゼ阻害剤オルリスタットは食事中の脂肪吸収を抑制し、抗肥満作用および高脂血症改善作用を示すことが知られている。しかしながら胃腸障害や脂肪便等の副作用の報告も多いことから、作用が穏やかで、長期間にわたって摂取しても安全性の高い脂肪吸収抑制剤が求められている。 In fact, orlistat, a pancreatic lipase inhibitor that is marketed in Europe and the United States, is known to suppress fat absorption during meals and exhibit anti-obesity and hyperlipidemia-improving effects. However, since there are many reports of side effects such as gastrointestinal disorders and fatty stool, there is a need for a fat absorption inhibitor that has a mild effect and is highly safe even when ingested over a long period of time.
安全性の高いリパーゼ阻害剤として、これまで各種植物抽出物、例えば各種香辛料の抽出物、ヤーコン抽出物、マテ葉抽出物などがリパーゼ阻害剤として開示されている。具体的には、例えば、以下の(1)〜(11)に示す技術が知られている。
(1)特願平11−237307号公報(特許文献1)
As a highly safe lipase inhibitor, various plant extracts, for example, various spice extracts, yacon extracts, mate leaf extracts, and the like have been disclosed as lipase inhibitors. Specifically, for example, techniques shown in the following (1) to (11) are known.
(1) Japanese Patent Application No. 11-237307 (Patent Document 1)
本公報には高脂血症の治療剤としてエリンギを利用することが記載されており、エリンギ乾燥粉末を90℃の熱水で2時間抽出した抽出液または乾燥粉末をラードおよびコレステロールを添加した高脂肪食とともにラットに3週間与えることによって、体重増加の割合が高脂肪食のみを与えた群と比較して有意に抑制されること、血中のコレステロール、中性脂肪、GOT値およびGPT値も高脂肪食のみを与えた群と比較して低下することが記載されている。
(2)日本食品科学工学会誌53巻、p612−618、2006年(非特許文献1)
This publication describes the use of eringi as a therapeutic agent for hyperlipidemia. An extract obtained by extracting eringi dry powder with hot water at 90 ° C. for 2 hours or a dry powder added with lard and cholesterol. By giving rats with fat diet for 3 weeks, the rate of weight gain is significantly suppressed compared to the group given only high fat diet, blood cholesterol, triglycerides, GOT values and GPT values also It is described that it decreases compared to the group given only a high fat diet.
(2) Journal of Japan Society for Food Science and Technology, Volume 53, p612-618, 2006 (Non-Patent Document 1)
本文献には、ラットに各キノコ乾燥粉末と、ラードおよびコレステロールを添加した高脂肪食を3週間与えると、いずれも体重増加の割合が高脂肪食のみを与えた群と比較して有意に抑制されたこと、いずれも血中のコレステロールは低下していたが中性脂肪は同程度であること、肝臓の中性脂肪はエリンギ、ヒラタケ、ハタケシメジ投与で有意に低下したことが記載されている。
(3)特願2004−158463号公報(特許文献2)
本公報には、ウーロン茶中に含まれるポリフェノールから、膵リパーゼ阻害活性を有する成分を単離している。
(4)特願2005−114294号公報(特許文献3)
In this document, when each rat was given a dry powder of mushrooms and a high-fat diet supplemented with lard and cholesterol for 3 weeks, the rate of weight gain was significantly suppressed compared to the group that received only the high-fat diet. In both cases, it was described that cholesterol in blood was decreased but neutral fat was comparable, and that neutral liver liver was significantly decreased by administration of eringi, oyster mushroom, and bamboo shimeji.
(3) Japanese Patent Application No. 2004-158463 (Patent Document 2)
In this publication, a component having pancreatic lipase inhibitory activity is isolated from polyphenol contained in oolong tea.
(4) Japanese Patent Application No. 2005-114294 (Patent Document 3)
本公報には、ネジレフサマメノキの熱水抽出物には膵リパーゼ阻害活性があり、ラットに中性脂肪とともに経口投与すると、血中の中性脂肪の上昇が抑制されたことが記載されている。
(5)特願2003−412188号公報(特許文献4)
This publication describes that the hot water extract of Nephirama cypress has pancreatic lipase inhibitory activity, and when administered orally with neutral fat to rats, the rise of neutral fat in the blood was suppressed. Yes.
(5) Japanese Patent Application No. 2003-41188 (Patent Document 4)
本公報には、アスコフィラムノドサムの抽出物には膵リパーゼ阻害活性があり、マウスに中性脂肪とともに経口投与すると、血中の中性脂肪の上昇が抑制されたことが記載されている。
(6)特願平11−299329号公報(特許文献5)
This publication describes that the extract of Ascofilum nodosum has pancreatic lipase inhibitory activity, and when administered to mice orally with neutral fat, the increase in blood neutral fat was suppressed. .
(6) Japanese Patent Application No. 11-299329 (Patent Document 5)
本公報には、レモングラス、オールスパイス、シナモン、クローブの少なくとも1種類以上の抽出物にリパーゼ阻害活性のあることが記載されている。
(7)特願2000−126043号公報(特許文献6)
This publication describes that at least one extract of lemongrass, allspice, cinnamon, and clove has lipase inhibitory activity.
(7) Japanese Patent Application No. 2000-126043 (Patent Document 6)
本公報には、ヤーコンの熱水抽出物にリパーゼ阻害活性のあることが記載されている。(8)特願2002−327865号公報(特許文献7) This publication describes that the hot water extract of yacon has lipase inhibitory activity. (8) Japanese Patent Application No. 2002-327865 (Patent Document 7)
マテ茶抽出物にリパーゼ阻害活性があり、ラットに中性脂肪とともに経口投与すると、血中の中性脂肪の上昇が抑制されたこと、高脂肪食とともに抽出物を与えて4週間飼育すると、体重増加および血中中性脂肪の上昇が抑制されたことが記載されている。
(9)Int. J. Obes.、1999年、No.23、98頁〜105頁(非特許文献2)
Mate tea extract has lipase inhibitory activity, and when administered orally with neutral fat to rats, the rise in blood neutral fat was suppressed, and when fed with a high fat diet and fed for 4 weeks, It is described that the increase and the increase of blood neutral fat were suppressed.
(9) Int. J. Obes., 1999, No. 23, pp. 98-105 (Non-patent Document 2)
本文献には、乾燥ウーロン茶葉(Thea sinensis L)を高脂肪食とともにマウスに与えると、高脂肪食のみの群と比較して、体重増加および肝臓への中性脂肪蓄積が抑制されたこと、乾燥ウーロン茶葉を10倍量の沸騰水で1時間抽出した後、濃縮した抽出物を用いて、トリオレイン(中性脂肪)、レシチンおよびタウロコール酸を混合し、超音波処理して調整したエマルジョンを基質として、豚膵リパーゼ阻害活性を測定した結果が報告されている。また、ラットより単離した脂肪細胞にノルアドレナリンを添加し、さらに抽出物を添加すると、中性脂肪の分解がさらに促進され、その活性成分としてカフェインが単離されたことが記載されている。
(10)Int. J. Obes.、1999年、No.23、174頁〜179頁(非特許文献3)
In this document, when dried oolong tea leaves (Thea sinensis L) were given to mice with a high fat diet, weight gain and accumulation of neutral fat in the liver were suppressed compared to the group with only a high fat diet, Extract the dried oolong tea leaves with 10 times the amount of boiling water for 1 hour, then use the concentrated extract to mix triolein (neutral fat), lecithin and taurocholic acid, and sonicate the prepared emulsion. The results of measuring porcine pancreatic lipase inhibitory activity as a substrate have been reported. Further, it is described that when noradrenaline is added to an adipocyte isolated from a rat and an extract is further added, the degradation of neutral fat is further promoted and caffeine is isolated as an active ingredient thereof.
(10) Int. J. Obes., 1999, No. 23, pp. 174-179 (Non-patent Document 3)
本文献には、キチン(20%)とキトサン(80%)の混合物を用いて膵リパーゼ阻害活性を測定した結果が報告されている。また、エマルジョン調製において、界面活性剤としてレシチンの代わりに、Triton X-100またはアラビアゴムを用いて同様に測定すると、いずれも阻害活性は見られず、膵リパーゼ阻害は直接には酵素活性を阻害するのではなく、酵素-基質の相互作用を阻害することが示唆されている。また、キチンキトサン混合物を高脂肪食とともにマウスに与えると、高脂肪食のみ与えた群と比較して、体重増加、肝臓重量増加、肝臓への中性脂肪蓄積、血清中性脂肪等が抑制されたことが報告されている。
(11)J. Nutr. Sci. Vitaminol.、2003年、No.49、340頁〜345頁(非特許文献4)
This document reports the results of measuring pancreatic lipase inhibitory activity using a mixture of chitin (20%) and chitosan (80%). In addition, when preparing in the same manner using Triton X-100 or gum arabic instead of lecithin as a surfactant in emulsion preparation, no inhibitory activity was observed, and pancreatic lipase inhibition directly inhibited enzyme activity. Instead, it has been suggested to inhibit enzyme-substrate interactions. In addition, when chitin chitosan mixture was given to mice with a high fat diet, weight gain, liver weight increase, neutral fat accumulation in the liver, serum neutral fat, etc. were suppressed compared to the group fed only with a high fat diet. It has been reported.
(11) J. Nutr. Sci. Vitaminol., 2003, No. 49, pages 340-345 (non-patent document 4)
本報告には、柑橘類のペクチンを用いて膵リパーゼ阻害活性を測定した結果が報告されている。また、ラットにコーン油(2.5 ml/kg)およびペクチン(250 mg/kg)を経口投与すると、2時間後の血中中性脂肪の上昇が、コントロール群と比較して抑制されたことが記載されている。さらに、エマルジョンにペクチンを添加し、再び油層と水層に分離し、各層の膵リパーゼ量を測定すると、ペクチン添加により、油層に接触する膵リパーゼ量が低下し、ペクチンは酵素と基質の相互作用を阻害することが示唆されている。 In this report, the result of measuring pancreatic lipase inhibitory activity using citrus pectin is reported. In addition, when corn oil (2.5 ml / kg) and pectin (250 mg / kg) were orally administered to rats, the increase in blood triglycerides after 2 hours was suppressed compared to the control group. Has been. Furthermore, when pectin is added to the emulsion and separated into an oil layer and an aqueous layer, and the amount of pancreatic lipase in each layer is measured, the amount of pancreatic lipase in contact with the oil layer decreases due to the addition of pectin, and pectin interacts with the enzyme and substrate. Has been suggested to inhibit.
上記従来技術(1)の治療剤は、多量の中性脂肪を与えたときの、血中の中性脂肪量の上昇を抑制するものであるが、3週間与えた後の比較的長期間経過した場合について、血中の中性脂肪上昇の抑制に関するものであり、食後の中性脂肪上昇を抑制するかは不明である。また、中性脂肪の吸収を抑制しているかも不明である。中性脂肪の消費が早くなっている可能性もあれば、肝臓での合成が少なくなっている可能性などもあり、治療剤を与えた際の数時間後(食後)の中性脂肪上昇については不明であり、膵リパーゼ阻害活性についても明らかではない。 The therapeutic agent of the above prior art (1) suppresses an increase in the amount of neutral fat in the blood when a large amount of neutral fat is given. In this case, it is related to the suppression of the increase in neutral fat in the blood, and it is unclear whether the increase in neutral fat after meal is suppressed. It is also unclear whether the absorption of neutral fat is suppressed. There is a possibility that consumption of triglycerides is accelerated, there is a possibility that synthesis in the liver is reduced, etc. About an increase in triglycerides after several hours (after meal) when giving a therapeutic agent Is unknown, and the pancreatic lipase inhibitory activity is not clear.
上記従来技術(2)では肝臓の中性脂肪蓄積が抑制されたことによって中性脂肪の吸収を抑制しているかは不明であり、また食後の血中の中性脂肪上昇を抑制するかどうかも不明である。また、上記従来技術 (9)では膵リパーゼ阻害活性を測定しているが用いた酵素濃度が記載されておらず、上記従来技術(10)では膵リパーゼ阻害活性測定に用いた酵素濃度が違うために比較することができない。また、上記従来技術 (11)は膵リパーゼ阻害活性測定において、膵リパーゼとしてラット膵臓より調製したものを用いているので比較できない。一方、上記従来技術(3)〜 (8)に記載されている抽出物は何れも効果が低く、また一部のものは原料が入手し難く高価であり、あるいは呈味性の問題などから、日常的に継続摂取することは困難である。
本発明は、従来の治療剤ないし治療方法における上記問題を解決したものであり、治
In the above prior art (2), it is unclear whether the neutral fat accumulation is suppressed by suppressing the neutral fat accumulation in the liver, and whether the increase in neutral fat in the blood after meals is also suppressed. It is unknown. In addition, although the conventional technique (9) measures pancreatic lipase inhibitory activity, the enzyme concentration used is not described, and in the conventional technique (10), the enzyme concentration used for measuring pancreatic lipase inhibitory activity is different. Can not be compared. Moreover, since the said prior art (11) uses what was prepared from the rat pancreas as pancreatic lipase in measurement of pancreatic lipase inhibitory activity, it cannot compare. On the other hand, the extracts described in the above prior arts (3) to (8) are all less effective, and some of them are difficult to obtain raw materials, are expensive, or have a taste problem. It is difficult to take continuously on a daily basis.
The present invention solves the above-mentioned problems in conventional therapeutic agents or treatment methods, and
療剤を与えた際の数時間後(食後)の中性脂肪吸収を効果的に抑制することができる膵リ
パーゼ阻害剤およびその製造方法を提供する。
A pancreatic lipase inhibitor capable of effectively suppressing neutral fat absorption after several hours (after a meal) when a therapeutic agent is given, and a method for producing the same.
本発明に係る発明は、請求項1〜2に示す構成によって従来の上記問題を解決したものであり、請求項1に記載の発明の特徴は、90℃以下で低温乾燥させた後、粉末にしたエリンギ子実体から30℃〜40℃の温度で水抽出し、得られた抽出物から分子量300k以上の抽出画分を分画することを特徴とする膵リパーゼ阻害剤の製造方法にある。
The invention according to the present invention solves the above-mentioned conventional problems by the constitution shown in
請求項2に記載の発明の特徴は、生のエリンギ子実体を乾燥の初期の温度を60℃以下とし、エリンギ子実体が過熱されることによって水分がきのこから垂れるようにでていかない状態まで乾燥が進んだ後に、90℃以下の温度に上昇させることにより低温乾燥させた後、粉末にしたエリンギ子実体から30℃〜40℃の温度で水抽出し、該抽出物から分子量300k以上の抽出画分を分画することを特徴とする膵リパーゼ阻害剤の製造方法にある。
The feature of the invention described in
本発明に係る90℃以下で低温乾燥させた後、粉末にしたエリンギ子実体から30℃〜40℃の温度で水抽出し、得られた抽出物から分子量300k以上の抽出画分を分画する方法によって製造された膵リパーゼ阻害剤は、食後の中性脂肪吸収を効果的に抑制することができ、食事の際に摂取することで、過剰な脂肪の吸収を抑制することができる。そのため、高脂血症、肥満の予防及び改善、さらには肥満に起因する糖尿病、高血圧症、動脈硬化の発症の予防効果が期待できる。 After low-temperature drying at 90 ° C. or less according to the present invention, water extraction is performed from powdered eringi fruit bodies at a temperature of 30 ° C. to 40 ° C., and an extract fraction having a molecular weight of 300 k or more is fractionated from the obtained extract. The pancreatic lipase inhibitor produced by the method can effectively suppress neutral fat absorption after a meal, and can suppress absorption of excess fat by ingesting it during a meal. Therefore, prevention and improvement of hyperlipidemia and obesity, as well as prevention of the onset of diabetes, hypertension and arteriosclerosis caused by obesity can be expected.
また、本発明に係る上記エリンギ低温抽出物の膵リパーゼ阻害効果は熱によっては損なわれないため、他の食品に添加して調理したものもその効果を発揮できる。食品の形態としては特に制限はなく、飲料をはじめ、パンや菓子類、その他の加工食品の原料として用いることができる。さらには、ペットフードなどとして利用することも可能である。 Moreover, since the pancreatic lipase inhibitory effect of the above-mentioned Eringi low-temperature extract according to the present invention is not impaired by heat, it can also be exerted by cooking it by adding it to other foods. There is no restriction | limiting in particular as a form of foodstuff, It can use as a raw material of bread, confectionery, and other processed foods including a drink. Furthermore, it can be used as pet food.
さらに食品以外にも経口投与される薬剤として用いることができる。例えば、ドリンク剤、錠剤、カプセル剤、顆粒剤、散剤、ドロップ剤などの形態で使用することができる。 Furthermore, it can be used as an orally administered drug other than food. For example, it can be used in the form of drinks, tablets, capsules, granules, powders, drops and the like.
本発明に係るエリンギ低温抽出物を主成分とする膵リパーゼ阻害剤は、エリンギが持つビタミン類やトレハロース等の水溶性物質を含むため、それらの持つ薬理的効果も同時に働くことが期待できるが、本抽出物中の分子量が300k以上の分画で膵リパーゼの阻害効果が高いため、より発明の効果を高めるために分子量300k以上の抽出画分を上記食品等に使用することができる。この場合には、膵リパーゼ阻害活性の高い分画のみを使用するため各食品への本抽出物の添加量が少なくて済み、各食品の味や風味への影響が押さえられるという効果も生じる。 Pancreatic lipase inhibitor based on the low temperature extract of eringi according to the present invention contains water-soluble substances such as vitamins and trehalose possessed by eringi, so it can be expected that their pharmacological effects will also work simultaneously. Since the fraction having a molecular weight of 300 k or more in the present extract has a high inhibitory effect on pancreatic lipase, the extract fraction having a molecular weight of 300 k or more can be used for the above food or the like in order to further enhance the effects of the invention. In this case, since only a fraction with high pancreatic lipase inhibitory activity is used, the amount of the extract to be added to each food can be reduced, and the effect on the taste and flavor of each food can be suppressed.
以下、本発明を実施例と共に具体的に説明する。 Hereinafter, the present invention will be specifically described together with examples.
本発明の製造方法により得られる膵リパーゼ阻害剤はエリンギの低温抽出物を主成分とするものである。高脂血症、肥満等を予防するためには、作用が穏やかで、長期間にわたって摂取できる安価で安全性の高い膵リパーゼ阻害剤が求められている。このような膵リパーゼ阻害剤を得るためには、その原料として、安価で日常的に摂取されている食品の利用が考えられ、その一つとして食用キノコが挙げられる。食用キノコは日常的に摂取されているので、安全性も高い。 The pancreatic lipase inhibitor obtained by the production method of the present invention is mainly composed of a low temperature extract of eringi. In order to prevent hyperlipidemia, obesity, etc., there is a need for an inexpensive and highly safe pancreatic lipase inhibitor that has a mild action and can be taken for a long period of time. In order to obtain such a pancreatic lipase inhibitor, it is conceivable to use a cheap and daily ingested food as a raw material, and one of them is an edible mushroom. Edible mushrooms are taken on a daily basis, so they are safe.
本発明の膵リパーゼ阻害剤は食用キノコの一種であるエリンギを利用し、その低温抽出物を主成分としたものであり、優れたリパーゼ阻害活性を有し、以下に示すように食後の血中中性脂肪の上昇を効果的に抑制することができる。 The pancreatic lipase inhibitor of the present invention uses eringi, which is a kind of edible mushroom, and has a low-temperature extract as a main component, has excellent lipase inhibitory activity, and is present in the blood after meal as shown below. An increase in neutral fat can be effectively suppressed.
本発明のエリンギ低温抽出物を主成分とする膵リパーゼ阻害剤は、例えば、90℃以下で低温乾燥させたエリンギ子実体を粉末にし、水を加えて低温で水抽出することにより製造することができる。また、生のエリンギ子実体を低温で水抽出することによっても製造することができる。このエリンギの場合には、これを細断又は擂り潰したものに、水を加えて低温で水抽出してもよい。 The pancreatic lipase inhibitor comprising the low-temperature extract of eringi of the present invention as a main component can be produced, for example, by powdering eringi fruit bodies dried at a low temperature of 90 ° C. or lower and adding water to extract the water at a low temperature. it can. It can also be produced by water extraction of raw eringi fruit bodies at a low temperature. In the case of this eringi, water may be added to the chopped or crushed material and extracted with water at a low temperature.
低温抽出温度は、実験によれば30℃〜40℃において好ましいリパーゼ阻害活性が得られた。抽出時間は、短ければ抽出量が少ないが、10分以上であればよく、30分以上が好ましい。
子実体の低温乾燥は、60℃以下であれば、天日干し、真空凍結乾燥等乾燥方法は問わない。
According to the experiment, a preferable lipase inhibitory activity was obtained at a low extraction temperature of 30 ° C. to 40 ° C. If the extraction time is short, the extraction amount is small, but it may be 10 minutes or more, and preferably 30 minutes or more.
As long as the fruit body is dried at a low temperature of 60 ° C. or lower, any drying method such as sun drying or vacuum freeze drying may be used.
しかし、加熱を伴う乾燥方法による場合は、まず乾燥の初期は、60℃以下とする。これは乾燥工程の初期から70℃以上に温度を上げると、エリンギ子実体が煮えたような状態になりまた、水分がきのこから垂れるようにでていくため、ロスが多くなることに起因する。更に90℃を越えて100℃になれば沸騰する。従って、40℃位から乾燥を始め、乾燥度が進むにつれて徐々に温度を上げて最終的に60℃位までとすることが好ましい。この乾燥工程は12時間程度で完了する。また、ある程度乾燥が進めば、即ち、エリンギ子実体が過熱されることによって水分がきのこから垂れるようにでていかない状態まで乾燥が進んだ後は、90℃程度まで上昇させてもよい。一方100℃を越えると焦げが生じる場合があり好ましくない。 However, in the case of a drying method involving heating, first, the initial stage of drying is set to 60 ° C. or lower. This is because when the temperature is raised to 70 ° C. or more from the initial stage of the drying process, the eringi fruit body is boiled and water is dripped from the mushroom, resulting in an increase in loss. If it exceeds 90 ° C and reaches 100 ° C, it boils. Therefore, it is preferable to start drying at about 40 ° C. and gradually increase the temperature to about 60 ° C. as the degree of drying progresses. This drying process is completed in about 12 hours. Further, if the drying proceeds to some extent, that is, after the drying has progressed to a state where moisture does not come out of the mushroom due to overheating of the eringi fruit body, the temperature may be raised to about 90 ° C. On the other hand, if it exceeds 100 ° C., it may cause scorching, which is not preferable.
実施例に示すように、30℃付近で抽出したものは最も阻害活性が強く、抽出温度が30℃より高いと抽出効率が低下する。また、30℃付近で抽出したものは、沸騰水中で一定時間加熱しても、その阻害活性は失活しない。このことからエリンギに含まれる膵リパーゼ阻害物質は高温では抽出できず、50℃以下、特に30℃付近で抽出された阻害物質自身は熱に安定であることが分かる。 As shown in the Examples, those extracted at around 30 ° C. have the strongest inhibitory activity, and when the extraction temperature is higher than 30 ° C., the extraction efficiency decreases. Moreover, what was extracted at about 30 degreeC does not deactivate the inhibitory activity, even if it heats for a fixed time in boiling water. This indicates that the pancreatic lipase inhibitor contained in eringi cannot be extracted at high temperatures, and the inhibitor itself extracted at 50 ° C. or less, particularly around 30 ° C., is stable to heat.
本発明の膵リパーゼ阻害剤は、上記抽出液の状態で用いることができ、あるいは上記抽出液を凍結乾燥などによって乾燥し、固形の抽出物として用いることもできる。 The pancreatic lipase inhibitor of the present invention can be used in the state of the above extract, or the extract can be dried by freeze drying or the like and used as a solid extract.
エリンギ子実体の乾燥粉末を低温で水抽出した抽出物からなる本発明の膵リパーゼ阻害剤は、これを有効量投与することによって、食後の中性脂肪の吸収を抑制する治療方法に用いることができる。有効投与量は例えば1回あたり0.1〜1000mg/kg程度が妥当である。 The pancreatic lipase inhibitor of the present invention comprising an extract obtained by water extraction of a dry powder of ering fruiting body at low temperature can be used in a therapeutic method for suppressing absorption of neutral fat after meal by administering an effective amount thereof. it can. An effective dose is, for example, about 0.1 to 1000 mg / kg per dose.
本発明の膵リパーゼ阻害剤は、食後の脂肪吸収を抑制する。また、食前、食後、食間の何時でも酵素活性阻害は起こるので、本発明の膵リパーゼ阻害剤による効果は得られる。例えば、食前に本発明の膵リパーゼ阻害剤を摂取して酵素活性を抑止しておき、その後に食物(脂質)を摂取した場合でも膵リパーゼ阻害効果が期待できる。なお本発明の膵リパーゼ阻害剤の最も効果的な摂取方法は食事と同時に摂取することであり、飲料や加工食品に配合して摂取することがより効果的である。 The pancreatic lipase inhibitor of the present invention suppresses postprandial fat absorption. In addition, since enzyme activity inhibition occurs at any time before, after, and between meals, the effect of the pancreatic lipase inhibitor of the present invention can be obtained. For example, the pancreatic lipase inhibitory effect can be expected even when the enzyme activity is suppressed by ingesting the pancreatic lipase inhibitor of the present invention before eating and then food (lipid) is ingested thereafter. The most effective method of taking the pancreatic lipase inhibitor of the present invention is to take it at the same time as eating, and it is more effective to mix it with beverages and processed foods.
本発明のエリンギ低温抽出物を主成分とする膵リパーゼ阻害剤の調製及び該膵リパーゼ阻害剤を用いた膵リパーゼ活性の測定、および脂肪負荷試験の実施例を以下に示す。
〔膵リパーゼ阻害剤の調製〕
Examples of preparation of a pancreatic lipase inhibitor mainly composed of the low-temperature extract of eringi of the present invention, measurement of pancreatic lipase activity using the pancreatic lipase inhibitor, and fat load test are shown below.
[Preparation of pancreatic lipase inhibitor]
60℃で一晩乾燥させたエリンギ子実体を粉末化し、15倍量の水を加えて室温で4時間抽出し、凍結乾燥して本発明に係る膵リパーゼ阻害剤であるエリンギ抽出物(以下、単に「エリンギ抽出物」と記す)を得た。
〔実施例1:膵リパーゼ活性の測定〕
Elingi fruiting bodies dried at 60 ° C. overnight were pulverized, extracted with 15 times the amount of water, extracted at room temperature for 4 hours, freeze-dried, and eringi extract (hereinafter referred to as the pancreatic lipase inhibitor according to the present invention) Simply referred to as “Eringi extract”).
[Example 1: Measurement of pancreatic lipase activity]
(1) 4-methylumbelliferyl oleateを、13 mM Tris-HCl、150 mM NaCl、1.3 mM CaCl2(pH 8)溶液で0.1mMに調製した溶液250μlに、エリンギ抽出物溶液を加えたもの、及びコントロールとしてエリンギ抽出物の代わりに水を125μl加えたものを調製し、それらに125μlのリパーゼ(Lipase:0.15mg/ml)を加え、25℃で30分反応させた。 (1) 4-methylumbelliferyl oleate was added to 250 μl of a solution prepared with 0.1 mM of 13 mM Tris-HCl, 150 mM NaCl, 1.3 mM CaCl 2 (pH 8) solution, and an eringi extract solution was added, and as a control What added 125 microliters of water instead of the eringi extract was prepared, 125 microliters of lipase (Lipase: 0.15 mg / ml) was added to them, and it was made to react at 25 degreeC for 30 minutes.
次いで、500μlの0.1M Sodium citrate(pH 4.2)を加えて反応を停止した後、Excitationを355nm、Emissionを460nmで蛍光を測定し、コントロールとして水を加えた際の活性を100%として、相対的活性を求めた。 Subsequently, 500 μl of 0.1 M sodium citrate (pH 4.2) was added to stop the reaction, fluorescence was measured at 355 nm for Excitation and 460 nm for Emission, and the activity when water was added as a control was defined as 100%. Activity was sought.
エリンギ抽出物量を変えたときの相対活性の変化を図1に示し、抽出温度を変えたときの相対活性の変化を図2示し、加熱時間を変えたときの相対活性の変化を図3示した。 The change in relative activity when the amount of eringi extract is changed is shown in FIG. 1, the change in relative activity when the extraction temperature is changed is shown in FIG. 2, and the change in relative activity when the heating time is changed is shown in FIG. .
また、前記膵リパーゼ阻害剤の調製で得られたエリンギ抽出物を限外ろ過デバイス(PALL製品)を用いて、分子量3K以下、3〜30K、30〜300K、300K以上に分画し、各画分の相対活性を上記と同様の方法で相対活性を求めた結果を図4に示した。
〔実施例2:膵リパーゼ活性の測定〕
In addition, the eringi extract obtained by the preparation of the pancreatic lipase inhibitor is fractionated to a molecular weight of 3K or less, 3 to 30K, 30 to 300K, 300K or more using an ultrafiltration device (PALL product). FIG. 4 shows the result of determining the relative activity of the minute relative activity by the same method as described above.
[Example 2: Measurement of pancreatic lipase activity]
(2) 9mlの0.1M NaClを含む0.1M TES buffer(pH 7)に、トリオレイン80mg、レシチン10mg、タウロコール酸5mgを超音波処理にて懸濁して基質とした。この基質100μlに50μlのリパーゼ(50μg/ml)および100μlのSample(上記エリンギ抽出物溶液)又は水を加えて、37℃で30分反応させた。次いで、3mlのヘプタン:クロロホルム:MeOH(49:49:2)で脂肪酸を抽出し、1mlの銅試薬を加えた。激しく混和後、遠心(2000×g, 10 min)して上層を200μl分取した。これに200μlの発色液(0.1%Bathcuproine, 0.05%3-t-butyl-4-hydroxyanisole in chloroform)を加え、波長480nmにおける吸光度を測定した。さらに、レシチンの代わりに、Triton X-100またはアラビアゴムを用いて同様に測定した。コントロールとして水を加えた際の活性を100%として、相対的活性を求めた。
レシチン、Triton X-100、アラビアゴムを用いたときの各々の相対活性の変化を図5に示した。
(2) In 0.1 M TES buffer (pH 7) containing 9 ml of 0.1 M NaCl, triolein 80 mg, lecithin 10 mg, and
FIG. 5 shows changes in relative activities of lecithin, Triton X-100, and gum arabic.
図1に示すように、エリンギ抽出物は用量依存的に膵リパーゼを阻害した(図1、方法(1))。また、図2に示すように、各温度で抽出したところ、30℃および40℃の抽出物にリパーゼ阻害活性が認められた。特に30℃の抽出物に強いリパーゼ阻害活性が認められた。一方、50℃以上の抽出物にはほとんどリパーゼ阻害活性が認められず、30℃付近が最適抽出温度であることが判明した。 As shown in FIG. 1, eringi extract inhibited pancreatic lipase in a dose-dependent manner (FIG. 1, method (1)). Moreover, as shown in FIG. 2, when extracted at each temperature, the lipase inhibitory activity was recognized by the extract of 30 degreeC and 40 degreeC. In particular, a strong lipase inhibitory activity was observed in the extract at 30 ° C. On the other hand, the lipase inhibitory activity was hardly observed in the extract at 50 ° C. or higher, and it was found that the optimum extraction temperature was around 30 ° C.
また、30℃の抽出物は沸騰水中で一定時間加熱してもその阻害活性は失活しないことにより(図3)、エリンギに含まれる膵リパーゼ阻害物質は、50℃以上の高温では抽出されないが、30℃付近の低温で抽出されたリパーゼ阻害物質自身は熱に安定であることが判明した。さらに、エリンギ抽出物中に含まれるリパーゼ阻害活性物質は300K以上の高分子域にあることが判明した(図4)。 In addition, when the extract at 30 ° C. is heated in boiling water for a certain period of time, its inhibitory activity is not inactivated (FIG. 3), but the pancreatic lipase inhibitor contained in eringi is not extracted at a high temperature of 50 ° C. or higher. The lipase inhibitor itself extracted at a low temperature around 30 ° C. was found to be stable to heat. Furthermore, the lipase inhibitory active substance contained in the eringi extract was found to be in the high molecular range of 300K or more (FIG. 4).
さらに、方法(2)において、阻害活性を測定すると、エマルジョンを調製する界面活性剤の違いにより、阻害活性に違いが見られたことより、エリンギ抽出物は、膵リパーゼを直接阻害するのではなく、酵素と基質の相互作用を阻害することが示唆された。ちなみに、従来から医薬品として欧米では利用されているオルリスタットは、酵素の活性中心に結合して直接に阻害するので、エリンギ抽出物の作用とは異なる。なお、エリンギ抽出物と類似の作用で阻害するものには、キチンキトサン混合物、ペクチンなどがある。ここで、一般にペクチンの抽出は高温酸性条件下で行われ、また、キチンキトサンは水に不溶である。よって、低温で水抽出した本発明の膵リパーゼ阻害物質はこれらとは異なるものであることは明らかであることを付記しておく。
〔実施例3:脂肪負荷試験〕
Furthermore, in the method (2), when the inhibitory activity was measured, the difference was found in the inhibitory activity due to the difference in the surfactant for preparing the emulsion, so that the eringi extract does not directly inhibit pancreatic lipase. It was suggested to inhibit the enzyme-substrate interaction. Incidentally, orlistat, which has been conventionally used as a pharmaceutical in Europe and the United States, binds to the active center of the enzyme and directly inhibits it, which is different from the action of eringi extract. In addition, what inhibits by the effect | action similar to an eringi extract includes a chitin chitosan mixture, pectin, etc. Here, extraction of pectin is generally performed under high temperature acidic conditions, and chitin chitosan is insoluble in water. Therefore, it should be noted that it is clear that the pancreatic lipase inhibitor of the present invention extracted with water at a low temperature is different from these.
[Example 3: Fat tolerance test]
ICRマウス(雄、7週齢)を1週間馴らし飼育した後に実験に供した。20時間絶食させた後、コントロール群には水(2.5ml/kg)とコーン油(2.5ml/kg)を経口投与し、投与群には抽出物溶液(2.5ml/kg、抽出物250mg/kg)とコーン油(2.5ml/kg)を経口投与した。コーン油投与前、投与後1.5時間後、3時間後、4.5時間後、6時間後に尾静脈より採血し、血漿中の中性脂肪量を測定した(和光純薬のトリグリセライド−E−テストワコーを使用)。1週間回復期間を設けた後、投与物を交換して同様の試験を行った。 ICR mice (male, 7 weeks old) were acclimated for one week and then subjected to experiments. After fasting for 20 hours, water (2.5 ml / kg) and corn oil (2.5 ml / kg) were orally administered to the control group, and the extract solution (2.5 ml / kg, extract 250 mg / kg) was administered to the administration group. ) And corn oil (2.5 ml / kg) were orally administered. Before administration of corn oil, 1.5 hours, 3 hours, 4.5 hours, and 6 hours after administration, blood was collected from the tail vein and the amount of triglyceride in plasma was measured (Triglyceride-E of Wako Pure Chemicals). -Use test Wako). After providing a recovery period of 1 week, the same test was conducted with the dose changed.
食事由来の中性脂肪はタンパク質などと複合体を形成し、カイロミクロンとして血中を運搬される。そこで、上記と同様にして1.5時間後、3時間後に採血し、カイロミクロン中性脂肪量を、血漿1μlをタイタンジェルリポ蛋白(ヘレナ研究所製品)で分離後、コレトリコンボTG(ヘレナ研究所製品)で染色し、カイロミクロン画分をScion Imageによるデンシトメトリーによって定量した。
また、カイロミクロン中の中性脂肪はlipoprotein lipase(LPL)によって分解される。
Dietary neutral fat forms a complex with proteins and is transported through the blood as chylomicrons. Therefore, blood was collected after 1.5 hours in the same manner as described above, and chylomicron triglyceride was separated from 1 μl of plasma with Titangel lipoprotein (product of Helena Laboratories), and then Choletricombo TG (Helena Research Center) Product) and the chylomicron fraction was quantified by densitometry with Scion Image.
Neutral fat in chylomicron is broken down by lipoprotein lipase (LPL).
そこで、前述したICRマウスに対するコーン油投与と同様の脂肪負荷後、採血10分前にヘパリン(1 unit/g)を尾静脈投与し、脂肪負荷1.5時間後、3時間後に採血した。 Therefore, heparin (1 unit / g) was administered to the tail vein 10 minutes before blood collection after fat loading similar to the corn oil administration to ICR mice described above, and blood was collected 1.5 hours after fat loading and 3 hours later.
得られた血漿3μlに25 mM SDS(0.2 M Tris-HCl, pH 8.2)3μlを加え、26℃で1時間処理した。これに0.5μCi 3H-triolein、0.4 mg/ml triolein、20 mg/ml BSA、0.1% Triton X-100、20% FBS、0.1 M Tris−HCl(pH 8.6)を含む基質溶液100μlを加え、37℃で1時間反応させた。1.625 mlのクロロホルム:ヘプタン:MeOH(1:1.37:1.28)及び0.5 mlの0.1M K2CO3/H3BO3(pH 10.5)を加え混合し、3000 rpm、4℃、20分間遠心した。上清0.5 mlに5 mlのACS2を加え、液体シンチレーションカウンターにて測定し、活性を求めた。 3 μl of 25 mM SDS (0.2 M Tris-HCl, pH 8.2) was added to 3 μl of the obtained plasma and treated at 26 ° C. for 1 hour. To this was added 100 μl of a substrate solution containing 0.5 μCi 3H-triolein, 0.4 mg / ml triolein, 20 mg / ml BSA, 0.1% Triton X-100, 20% FBS, 0.1 M Tris-HCl (pH 8.6), and 37 ° C. For 1 hour. 1.625 ml of chloroform: heptane: MeOH (1: 1.37: 1.28) and 0.5 ml of 0.1M K2CO3 / H3BO3 (pH 10.5) were added, mixed, and centrifuged at 3000 rpm, 4 ° C. for 20 minutes. The activity was determined by adding 5 ml of ACS2 to 0.5 ml of the supernatant and measuring with a liquid scintillation counter.
血漿中の中性脂肪量の経時的変化を図6に示し、カイロミクロン中の中性脂肪量を図7に示し、LPL活性を図8に示した。これらから抽出物投与によって血漿中の中性脂肪量増加の抑制は、吸収後の分解促進ではなく、腸管からの吸収が抑制される作用による効果であることが明らかとなった。
[実施例4:臨床試験]
The time-dependent change in the amount of neutral fat in plasma is shown in FIG. 6, the amount of neutral fat in chylomicron is shown in FIG. 7, and the LPL activity is shown in FIG. From these results, it was clarified that the suppression of the increase in the amount of neutral fat in plasma by administration of the extract is not the promotion of decomposition after absorption but the effect by the action of suppressing absorption from the intestinal tract.
[Example 4: Clinical trial]
年齢が35歳以上59歳以下で、中性脂肪が110〜275 mg/dlの範囲、総コレステロールが300 mg/dl以下、空腹時血糖が125 mg/dl以下、HbA1cが6.4%以下、GOTが60IU/l以下、GPTが60IU/l以下、γ-GTPが105IU/l以下の全てに該当する25名(男性20名、女性5名)を対象に、臨床試験を行った。
Age 35 to 59 years old, neutral fat in the range of 110-275 mg / dl,
高脂肪食として、コーンスープ150 mlに無塩バター25 gとラード18 gを加えた飲料(脂肪含有量40 g,426 kcal )を調製した。試験食品には,さらにエリンギ抽出物を5 g を加えたものを調製した。 As a high fat diet, a beverage (fat content 40 g, 426 kcal) prepared by adding 25 g of unsalted butter and 18 g of lard to 150 ml of corn soup was prepared. The test food was prepared by adding 5 g of eringi extract.
被験者には,試験前夜の午後9時以降は絶食させ、翌朝空腹時に初回採血を行い、ただちにコントロール飲料あるいは試験飲料を摂取させた。試験開始から試験終了までは、少量の水以外は絶食とした。 Subjects were fasted after 9 pm the night before the test, the first blood was collected the next morning on an empty stomach, and immediately received a control or test beverage. From the start of the test to the end of the test, all but a small amount of water was fasted.
採血は脂肪負荷飲料の摂取直前ならびに摂取後5時間後までは1時間おきに計6回行い、血中の中性脂肪量測定を標準的な検査法で行った。また、曲線下面積(AUC:area under the curves)を、空腹時の値を基準として摂取後0〜5時間までの血中濃度から台形法により算出した。 Blood samples were collected 6 times every hour just before intake of fat-loaded beverages and up to 5 hours after intake, and the amount of triglyceride in the blood was measured by a standard test method. In addition, the area under the curves (AUC) was calculated by the trapezoidal method from the blood concentration from 0 to 5 hours after ingestion based on the fasting value.
中性脂肪量の経時的変化を図9に示した。脂肪負荷後3時間および4時間後では、抽出物投与により、中性脂肪の上昇が抑制されていた(t検定、p<0.05)。また、曲線下面積においてもコントロールが286.2±25.3 mg・h/dl(平均値±SE)、抽出物投与が234.4±16.8 mg・h/dlであり、抽出物投与により有意に低下していた(t検定、p<0.05)。 The change in the amount of neutral fat over time is shown in FIG. At 3 and 4 hours after fat loading, the increase in neutral fat was suppressed by the extract administration (t test, p <0.05). Moreover, in the area under the curve, the control was 286.2 ± 25.3 mg · h / dl (mean value ± SE) and the extract administration was 234.4 ± 16.8 mg · h / dl, which were significantly decreased by the extract administration ( t test, p <0.05).
これらの結果から、ICRマウスでの効果と同様に、人間においても食後の血漿中の中性脂肪量の増加を有意に抑制することが判明した。 From these results, it was clarified that the increase in the amount of neutral fat in plasma after meal was significantly suppressed in humans as well as the effect in ICR mice.
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KR20160141027A (en) * | 2015-05-27 | 2016-12-08 | 경상북도 | Phamaceutical composition or healthy food comprising water extracts from Pleurotus eryngii var. ferulea (Pf.). for treating or preventing metabolic disorder |
CN105168981A (en) * | 2015-10-22 | 2015-12-23 | 河南金贵元生物科技有限公司 | Medicinal-edible homologous composition for treating three-highs (hypertension, hyperglycemia and hyperlipidaemia) and anhypnia and preparation method thereof |
KR102429280B1 (en) * | 2020-06-29 | 2022-08-05 | (주)노바셀테크놀로지 | Phamaceutical composition and health functional food for preventing or treating obesity comprising powder of a novel hydridized mushroomstrain |
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2008
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