JP5689055B2 - Antihyperglycemic and / or antihyperlipidemic agent comprising chicken skin-derived sphingomyelin-containing substance as an active ingredient - Google Patents
Antihyperglycemic and / or antihyperlipidemic agent comprising chicken skin-derived sphingomyelin-containing substance as an active ingredient Download PDFInfo
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- JP5689055B2 JP5689055B2 JP2011513379A JP2011513379A JP5689055B2 JP 5689055 B2 JP5689055 B2 JP 5689055B2 JP 2011513379 A JP2011513379 A JP 2011513379A JP 2011513379 A JP2011513379 A JP 2011513379A JP 5689055 B2 JP5689055 B2 JP 5689055B2
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- Prior art keywords
- chicken skin
- sphingomyelin
- deoiled
- antihyperglycemic
- mass
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Images
Classifications
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/66—Phosphorus compounds
- A61K31/683—Diesters of a phosphorus acid with two hydroxy compounds, e.g. phosphatidylinositols
- A61K31/688—Diesters of a phosphorus acid with two hydroxy compounds, e.g. phosphatidylinositols both hydroxy compounds having nitrogen atoms, e.g. sphingomyelins
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P3/00—Drugs for disorders of the metabolism
- A61P3/06—Antihyperlipidemics
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P3/00—Drugs for disorders of the metabolism
- A61P3/08—Drugs for disorders of the metabolism for glucose homeostasis
- A61P3/10—Drugs for disorders of the metabolism for glucose homeostasis for hyperglycaemia, e.g. antidiabetics
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- Health & Medical Sciences (AREA)
- Diabetes (AREA)
- Medicinal Chemistry (AREA)
- Veterinary Medicine (AREA)
- Public Health (AREA)
- General Health & Medical Sciences (AREA)
- Animal Behavior & Ethology (AREA)
- Life Sciences & Earth Sciences (AREA)
- Chemical & Material Sciences (AREA)
- Pharmacology & Pharmacy (AREA)
- Bioinformatics & Cheminformatics (AREA)
- General Chemical & Material Sciences (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Organic Chemistry (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Obesity (AREA)
- Hematology (AREA)
- Engineering & Computer Science (AREA)
- Endocrinology (AREA)
- Emergency Medicine (AREA)
- Epidemiology (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Medicines Containing Material From Animals Or Micro-Organisms (AREA)
Description
本発明は、鳥皮由来スフィンゴミエリン含有物を有効成分とする抗高血糖及び／又は抗高脂血症剤に関する。 The present invention relates to an antihyperglycemic and / or antihyperlipidemic agent comprising a chicken skin-derived sphingomyelin-containing substance as an active ingredient.
スフィンゴミエリンは、細胞膜上の脂質ミクロドメインであるラフトの主要構成成分として、また脂質シグナリングの起点として、現在の生物科学において注目を集めているリン脂質の一つである。特にラフトは、免疫応答を始め、さまざまなシグナリングの場として、また特定の物質輸送の場として機能していることから、スフィンゴミエリンが、生体膜の構造維持とともに細胞内情報伝達系への関与など細胞の機能発現にも大きく関わる物質である可能性も考えられている。 Sphingomyelin is one of the phospholipids attracting attention in the current biological science as a major component of raft, a lipid microdomain on the cell membrane, and as a starting point for lipid signaling. In particular, rafts function as a field of various signaling and specific substance transport, including immune responses, so that sphingomyelin is involved in the intracellular signal transduction system as well as maintaining the structure of biological membranes. It is also considered that it may be a substance that greatly contributes to cell function expression.
例えば、特許文献１に記載されるように、近年、高脂血症・動脈硬化のメカニズム解析が進むにつれ、これらの発症に深く関与すると考えられている低比重リポタンパク質ＬＤＬ中にスフィンゴミエリンが多く含まれること、高脂血症患者の血漿中のスフィンゴミエリン量が有意に増加していること、またＬＤＬの変性にスフィンゴミエリン分解酵素が関与していることなどが報告され、スフィンゴミエリンの増加が高脂血症の発症に関与している可能性が指摘されている。 For example, as described in Patent Document 1, as the mechanism analysis of hyperlipidemia and arteriosclerosis progresses in recent years, there are many sphingomyelin in low density lipoprotein LDL which is considered to be deeply involved in the onset of these. It is reported that the amount of sphingomyelin in the plasma of patients with hyperlipidemia is significantly increased, and that sphingomyelinase is involved in the degeneration of LDL. It has been pointed out that it may be involved in the development of hyperlipidemia.
また、特許文献２に記載されるように、スフィンゴミエリンがシアロムチンの分泌促進効果、悪酔い予防効果、抗アレルギー効果、抗酸化効果、感染防御効果、養毛効果、脱髄疾患治療効果、抗色素沈着効果または抗炎症効果を有することも示唆されている。
In addition, as described in
さらに、上述のようにスフィンゴミエリンの重要性が認識されるにつれ、スフィンゴミエリンを大量にかつ安価に製造する方法についても関心が高まっている。 Furthermore, as the importance of sphingomyelin is recognized as described above, there is a growing interest in methods for producing sphingomyelin in large quantities and at low cost.
通常、スフィンゴミエリンは牛乳（ホエーやバター等牛乳由来製品も含む）や卵黄を原材料として製造されている。特許文献２において実験に使用されたスフィンゴミエリンも、ホエータンパク質から抽出されたものである。
Usually, sphingomyelin is produced from milk (including milk-derived products such as whey and butter) and egg yolk. The sphingomyelin used in the experiment in
ただ、牛乳や卵黄はそれ自体商品価値があり、原材料として使用するにはコストがかかるという問題があった。当該問題についても検討がなされており、例えば特許文献３には、加工食品製造過程で通常廃棄される鶏の表皮を原材料として純度約７０質量％以上のスフィンゴミエリンを製造する方法が記載されている。 However, milk and egg yolk themselves have commercial value, and there is a problem that it is expensive to use as raw materials. For example, Patent Document 3 discloses a method for producing sphingomyelin having a purity of about 70% by mass or more using chicken skin that is usually discarded in the process of manufacturing processed food as a raw material. .
本発明は、大量にかつ安価にスフィンゴミエリン含有物を得ること、及びスフィンゴミエリン含有物の有用用途を見出すことを課題とする。 An object of the present invention is to obtain a sphingomyelin-containing material in a large amount and at a low cost and to find a useful use of the sphingomyelin-containing material.
本発明者らは、驚くべき事に、９０質量％以上のスフィンゴミエリンを含有する鳥皮抽出物を製造する方法（抽出方法）を見出し、また、当該抽出物及び当該抽出物の粗抽出物や原材料（特に脱油鳥皮）が優れた抗高血糖作用及び抗高脂血症作用を有することをも見出し、さらに改良を重ねて本発明を完成させるに至った。 The present inventors have surprisingly found a method (extraction method) for producing a chicken skin extract containing 90% by mass or more of sphingomyelin, and the extract and a crude extract of the extract, The inventors have also found that raw materials (particularly deoiled chicken skin) have excellent antihyperglycemic action and antihyperlipidemic action, and have made further improvements to complete the present invention.
本発明は例えば以下の項に記載の剤及び方法等を包含する。
項Ａ−１．
鳥皮由来スフィンゴミエリン含有物を有効成分とする、抗高血糖及び／又は抗高脂血症剤。
項Ａ−２．
脱油鳥皮を有効成分とする、項Ａ−１に記載の抗高血糖及び／又は抗高脂血症剤。
項Ａ−３．
乾燥質量換算で、１００ｇあたり８０〜４００ｍｇのスフィンゴミエリンが含まれる脱油鳥皮を有効成分とする、項Ａ−２に記載の抗高血糖及び／又は抗高脂血症剤。
項Ａ−４．
内部圧力が０．０５〜０．３ＭＰａ、内部温度が１０５±１０℃、内部酸素濃度が０．２％以下であるチャンバ内で、鳥皮に１２０〜１３５℃の水蒸気を吹き付ける工程を経て脱油された脱油鳥皮を有効成分とする、項Ａ−２又はＡ−３に記載の抗高血糖及び／又は抗高脂血症剤。
項Ａ−５．
鳥皮由来スフィンゴミエリン含有物の中性脂肪含有量が３０質量％以下である、項Ａ−１〜Ａ−４のいずれかに記載の抗高血糖及び／又は抗高脂血症剤。
項Ａ−６．
スフィンゴミエリンを９０質量％以上含有する鳥皮抽出物を有効成分とする、項Ａ−１に記載の抗高血糖及び／又は抗高脂血症剤。
項Ａ−７．
鳥皮が鶏皮である、項Ａ−１〜Ａ−６のいずれかに記載の抗高血糖及び／又は抗高脂血症剤。
項Ｂ−１．
予防又は治療有効量の鳥皮由来スフィンゴミエリン含有物を経口投与することにより、高血糖及び／又は高脂血症を予防又は治療する方法。
項Ｂ−２．
鳥皮由来スフィンゴミエリン含有物が脱油鳥皮である、項Ｂ−１に記載の方法。
項Ｂ−３．
鳥皮由来スフィンゴミエリン含有物が、乾燥質量換算で１００ｇあたり８０〜４００ｍｇのスフィンゴミエリンが含まれる脱油鳥皮である、項Ｂ−１に記載の方法。
項Ｂ−４．
鳥皮由来スフィンゴミエリン含有物がスフィンゴミエリンを９０質量％以上含有する鳥皮抽出物である、項Ｂ−１に記載の方法。
項Ｃ−１．
高血糖及び／又は高脂血症の予防又は治療における使用のための、鳥皮由来スフィンゴミエリン含有物。
項Ｃ−２．
脱油鳥皮である、項Ｃ−１に記載の鳥皮由来スフィンゴミエリン含有物。
項Ｃ−３．
乾燥質量換算で１００ｇあたり８０〜４００ｍｇのスフィンゴミエリンが含まれる脱油鳥皮である、項Ｃ−１に記載の鳥皮由来スフィンゴミエリン含有物。
項Ｃ−４．
スフィンゴミエリンを９０質量％以上含有する鳥皮抽出物である、項Ｃ−１に記載の鳥皮由来スフィンゴミエリン含有物。
項Ｄ−１．
高血糖及び／又は高脂血症の治療又は予防のための医薬の製造における鳥皮由来スフィンゴミエリン含有物の使用。
項Ｄ−２．
鳥皮由来スフィンゴミエリン含有物が脱油鳥皮である、項Ｄ−１に記載の使用。
項Ｄ−３．
鳥皮由来スフィンゴミエリン含有物が、乾燥質量換算で１００ｇあたり８０〜４００ｍｇのスフィンゴミエリンが含まれる脱油鳥皮である、項Ｄ−１に記載の使用。
項Ｄ−４．
鳥皮由来スフィンゴミエリン含有物がスフィンゴミエリンを９０質量％以上含有する鳥皮抽出物である、項Ｄ−１に記載の使用。The present invention includes, for example, the agents and methods described in the following sections.
Term A-1.
An antihyperglycemic and / or antihyperlipidemic agent comprising a chicken skin-derived sphingomyelin-containing substance as an active ingredient.
Term A-2.
The antihyperglycemic and / or antihyperlipidemic agent according to Item A-1, comprising deoiled chicken skin as an active ingredient.
Term A-3.
The antihyperglycemic and / or antihyperlipidemic agent according to Item A-2, comprising, as an active ingredient, deoiled chicken skin containing 80 to 400 mg of sphingomyelin per 100 g in terms of dry mass.
Term A-4.
Oil is removed through a process of spraying water vapor of 120 to 135 ° C. on chicken skin in a chamber having an internal pressure of 0.05 to 0.3 MPa, an internal temperature of 105 ± 10 ° C., and an internal oxygen concentration of 0.2% or less.
Term A-5.
The antihyperglycemic and / or antihyperlipidemic agent according to any one of Items A-1 to A-4, wherein the neutral fat content of the chicken skin-derived sphingomyelin-containing product is 30% by mass or less.
Term A-6.
The antihyperglycemic and / or antihyperlipidemic agent according to Item A-1, comprising a chicken skin extract containing 90% by mass or more of sphingomyelin as an active ingredient.
Term A-7.
The antihyperglycemic and / or antihyperlipidemic agent according to any one of Items A-1 to A-6, wherein the chicken skin is chicken skin.
Term B-1.
A method for preventing or treating hyperglycemia and / or hyperlipidemia by orally administering a chicken skin-derived sphingomyelin-containing amount of a prophylactic or therapeutic effective amount.
Term B-2.
The method according to Item B-1, wherein the chicken skin-derived sphingomyelin-containing material is deoiled chicken skin.
Term B-3.
The method according to Item B-1, wherein the chicken skin-derived sphingomyelin-containing material is a deoiled chicken skin containing 80 to 400 mg of sphingomyelin per 100 g in terms of dry mass.
Term B-4.
The method according to Item B-1, wherein the chicken skin-derived sphingomyelin-containing material is a chicken skin extract containing 90% by mass or more of sphingomyelin.
Term C-1.
A chicken skin-derived sphingomyelin-containing product for use in the prevention or treatment of hyperglycemia and / or hyperlipidemia.
Term C-2.
The chicken skin-derived sphingomyelin-containing material according to Item C-1, which is a deoiled chicken skin.
Term C-3.
The chicken skin-derived sphingomyelin-containing material according to Item C-1, which is a deoiled chicken skin containing 80 to 400 mg of sphingomyelin per 100 g in terms of dry mass.
Term C-4.
The chicken skin-derived sphingomyelin-containing product according to Item C-1, which is a chicken skin extract containing 90% by mass or more of sphingomyelin.
Term D-1.
Use of a chicken skin-derived sphingomyelin-containing material in the manufacture of a medicament for the treatment or prevention of hyperglycemia and / or hyperlipidemia.
Term D-2.
The use according to Item D-1, wherein the chicken skin-derived sphingomyelin-containing material is deoiled chicken skin.
Term D-3.
The use according to Item D-1, wherein the chicken skin-derived sphingomyelin-containing material is deoiled chicken skin containing 80 to 400 mg of sphingomyelin per 100 g in terms of dry mass.
Term D-4.
The use according to Item D-1, wherein the chicken skin-derived sphingomyelin-containing material is a chicken skin extract containing 90% by mass or more of sphingomyelin.
本発明により、鳥皮由来スフィンゴミエリン含有物を有効成分とする抗高血糖組成物及び／又は抗高脂血症剤が提供される。また、鳥皮由来スフィンゴミエリン含有物を経口投与することにより、高血糖及び／又は高脂血症を予防又は治療する方法が提供される。 ADVANTAGE OF THE INVENTION By this invention, the antihyperglycemic composition and / or antihyperlipidemic agent which use a chicken skin origin sphingomyelin containing material as an active ingredient are provided. Moreover, the method of preventing or treating hyperglycemia and / or hyperlipidemia is provided by orally administering a chicken skin origin sphingomyelin containing material.
鳥皮は従来から食物として摂取されていることから、安全性が高いことが経験的に確認されている。よって、本発明により、副作用の心配をほとんどすることなく、高血糖及び／又は高脂血症の予防及び治療を行うことができる。 Since chicken skin has been ingested as food, it has been empirically confirmed that it is highly safe. Therefore, according to the present invention, it is possible to prevent and treat hyperglycemia and / or hyperlipidemia with almost no worry about side effects.
またさらに、鳥皮は非常に安く入手することが可能な素材であるため、本発明により、医薬等を用いる場合に比べて格段にコストを抑えて高血糖及び／又は高脂血症の予防及び治療を行うことができる。 Furthermore, since chicken skin is a material that can be obtained very cheaply, according to the present invention, it is possible to prevent hyperglycemia and / or hyperlipidemia at a much lower cost than when using pharmaceuticals and the like. Can be treated.
以下、本発明について、さらに詳細に説明する。 Hereinafter, the present invention will be described in more detail.
本発明は、鳥皮由来スフィンゴミエリン含有物を有効成分とする抗高血糖及び／又は抗高脂血症剤に係る。 The present invention relates to an antihyperglycemic and / or antihyperlipidemic agent comprising a chicken skin-derived sphingomyelin-containing substance as an active ingredient.
本発明において、鳥皮由来スフィンゴミエリン含有物とは鳥皮から得られるスフィンゴミエリンを含有する組成物であって、鳥皮から製造されるものをいう。ただし、鳥皮から得られるスフィンゴミエリンそのものを意味するものではない。例えば、スフィンゴミエリンを含有する鳥皮抽出物や、鳥皮に脱油処理を施した脱油鳥皮などの、鳥皮分画画分が、本発明の鳥皮由来スフィンゴミエリン含有物に含まれる。 In the present invention, the chicken skin-derived sphingomyelin-containing material is a composition containing sphingomyelin obtained from chicken skin, which is produced from chicken skin. However, it does not mean sphingomyelin itself obtained from chicken skin. For example, chicken skin fractions such as chicken skin extract containing sphingomyelin and deoiled chicken skin obtained by deoiling chicken skin are included in the chicken skin-derived sphingomyelin-containing product of the present invention. .
本発明において、鳥皮抽出物は、鳥皮から抽出された組成物であって、スフィンゴミエリンを含有する組成物をいう。当該組成物は、スフィンゴミエリン以外に鳥皮由来成分（例えばプラズマローゲン等）を含む。抽出方法は特に制限されないが、後に詳述するように水又は有機溶媒（例えばメタノール、エタノール、プロパノール、ブタノール、イソプロパノール等）による抽出を行うことが好ましい。また、抽出に供される鳥皮は、脱油処理された脱油鳥皮（乾燥脱油鳥皮を含む）であることが好ましい。 In the present invention, the chicken skin extract refers to a composition extracted from chicken skin and containing sphingomyelin. In addition to sphingomyelin, the composition contains a chicken skin-derived component (for example, plasmalogen). The extraction method is not particularly limited, but it is preferable to perform extraction with water or an organic solvent (for example, methanol, ethanol, propanol, butanol, isopropanol, etc.) as described in detail later. Moreover, it is preferable that the chicken skin provided for extraction is deoiled chicken skin (including dried deoiled chicken skin) that has been deoiled.
用いる鳥皮は、いずれの鳥の皮であってもよいが、通常食用とされる鳥（食鳥）の皮であることが好ましい。例えば、鶏、アヒル、ウズラ、カモ、キジ、ダチョウ、ホロホロ鳥又は七面鳥等の皮が例示できるが、これらに限定されない。日本においては、食鳥として最も流通しているのは鶏であることから、入手のし易さやコストの面から考えて鶏皮が特に好ましい。なお、複数種の鳥の皮を２種以上組み合わせて用いてもよい。 The bird skin to be used may be any bird skin, but is preferably the skin of a bird (food bird) that is normally eaten. For example, skins of chickens, ducks, quails, ducks, pheasants, ostriches, guinea fowls or turkeys can be exemplified, but not limited to these. In Japan, chickens are the most widely distributed food birds, and chicken skin is particularly preferred in view of availability and cost. Two or more kinds of bird skins may be used in combination.
鳥皮抽出物におけるスフィンゴミエリン含有量は、特に制限はされないが、５０質量％以上が好ましく、６０質量％以上がより好ましく、７０質量％以上がさらに好ましく、８０質量％以上がよりさらに好ましく、９０質量％以上が特に好ましい。なお、スフィンゴミエリン含有量は、当該抽出物を高速液体クロマトグラフィー（検出にはELSD蒸発光散乱検出器を用いる）で解析して得られるクロマトグラムにおいて、スフィンゴミエリンを示すピーク面積が全ピークの合計面積の何％にあたるかを算出することで求めることができる。 The sphingomyelin content in the chicken skin extract is not particularly limited, but is preferably 50% by mass or more, more preferably 60% by mass or more, still more preferably 70% by mass or more, and even more preferably 80% by mass or more, 90 A mass% or more is particularly preferred. The sphingomyelin content is the sum of all peaks in the peak area showing sphingomyelin in the chromatogram obtained by analyzing the extract by high performance liquid chromatography (ELSD evaporative light scattering detector is used for detection). It can be obtained by calculating what percentage of the area.
また、本発明において鳥皮抽出物は、他の複合脂質（例えばホスファチジルコリン、ホスファチジルエタノールアミン等）の含有量が通常５０質量％以下、好ましくは４０質量％以下、より好ましくは３０質量％以下、さらに好ましくは２０質量％以下、特に好ましくは１０質量％以下である。 In the present invention, the chicken skin extract has a content of other complex lipids (for example, phosphatidylcholine, phosphatidylethanolamine, etc.) usually 50% by mass or less, preferably 40% by mass or less, more preferably 30% by mass or less, Preferably it is 20 mass% or less, Most preferably, it is 10 mass% or less.
なお、鳥皮抽出物は、鳥皮からスフィンゴミエリンを抽出及び精製する工程の途中で得られるもの（粗抽出物）であってもよい。 Note that the chicken skin extract may be one (crude extract) obtained during the process of extracting and purifying sphingomyelin from chicken skin.
また、本発明において、脱油鳥皮は、鳥（例えば先に例示した各鳥）の皮を脱油処理して得ることができる。脱油鳥皮を得るための脱油処理方法は特に制限されるものではなく、通常食品業界において食肉を脱油する際に用いられる方法を用いることができる。例えば、圧搾方法、機械的方法、温水浸漬加熱方法、直接加熱方法、脂肪族炭化水素溶媒による方法等を採用することができる。 In the present invention, the deoiled chicken skin can be obtained by deoiling the skin of a bird (for example, each bird exemplified above). The deoiling treatment method for obtaining the deoiled chicken skin is not particularly limited, and a method usually used for deoiling meat in the food industry can be used. For example, a pressing method, a mechanical method, a hot water immersion heating method, a direct heating method, a method using an aliphatic hydrocarbon solvent, or the like can be employed.
特に、高温熱水噴射方式低温過熱蒸気で鳥皮を処理できる高温熱水噴射方式低温過熱水蒸気装置により効率的かつ非侵襲的な脱油が可能であり、好ましい。また、当該脱油工程では鳥皮の水分減少がほとんど起こらない。このため、鳥皮を乾燥させずに脱油可能であり、鳥皮含有物が酸化され減耗するのを防ぐことができる。このような脱油方法としては、例えば脱油が行われる加熱チャンバの内部圧力を０．０５〜０．３ＭＰａ、内部温度を１０５±１０℃、内部酸素濃度を０．２％以下に制御し、チャンバ内の鳥皮ミンチに１２０〜１３５℃の水蒸気をノズルから高速噴射して吹き付けることで行うことができる。なお、ノズルの内部圧力は０．１５〜０．３ＭＰａとすることが好ましい。このような特定の条件で水蒸気を高速噴射することにより、結果として鳥皮には、１００±５℃熱水（微細熱水滴）、飽和蒸気、及び１１７±５℃水蒸気（過熱蒸気）の混合媒体が吹き付けられることとなり、上述した効果（鳥皮の水分減少がほとんど起こらず、鳥皮含有物が酸化され減耗するのを防ぐ効果）が奏される。飽和蒸気のみでは乾燥が効率よく行えず、過熱蒸気のみでは乾燥が進んで鳥皮含有物が酸化され減耗するおそれがあるところ、当該脱油方法によれば鳥皮含有物が非酸化の非乾燥脱油鳥皮を得ることができるのである。当該脱油方法は、例えばhi-LOHS-R連続製造装置（株式会社タイヨー製作所）を用いて行うことができる。 In particular, a high temperature hot water injection type low temperature superheated steam apparatus capable of treating chicken skin with high temperature hot water injection type low temperature superheated steam is preferable because it can be efficiently and non-invasively deoiled. Further, the water removal of the chicken skin hardly occurs in the deoiling process. For this reason, it is possible to deoil without drying the chicken skin, and it is possible to prevent the chicken skin-containing material from being oxidized and depleted. As such a deoiling method, for example, the internal pressure of the heating chamber where deoiling is performed is controlled to 0.05 to 0.3 MPa, the internal temperature is 105 ± 10 ° C., and the internal oxygen concentration is controlled to 0.2% or less, This can be performed by spraying water vapor of 120 to 135 ° C. at high speed from a nozzle onto chicken skin mince in the chamber. The internal pressure of the nozzle is preferably 0.15 to 0.3 MPa. By spraying water vapor at a high speed under such specific conditions, as a result, a mixed medium of 100 ± 5 ° C. hot water (fine hot water droplets), saturated steam, and 117 ± 5 ° C. water vapor (superheated steam) As a result, the effects described above (the effect of preventing the chicken skin content from being oxidized and depleted with little decrease in the moisture content of the chicken skin) are exhibited. When saturated steam alone is used, drying cannot be performed efficiently, and with only superheated steam, drying may proceed and the chicken skin content may be oxidized and depleted. Deoiled chicken skin can be obtained. The deoiling method can be performed using, for example, a hi-LOHS-R continuous production apparatus (Taiyo Manufacturing Co., Ltd.).
なお、脱油は、これらの手法を２種以上組み合わせて行ってもよい。 Note that deoiling may be performed by combining two or more of these techniques.
本願でいう「脱油」とは、具体的には中性脂肪を除くことであり（すなわち「脱中性脂肪」ともいえる）、より具体的にはトリアシルグリセロール、ジアシルグリセロール、遊離脂肪酸を除くことである。上記例示のいずれの方法でも効率的に中性脂肪を除去でき、またスフィンゴ脂質やプラズマローゲンの流出はほとんどない。例えば、生鶏皮中の全脂質含量は約３０〜５０質量％であって、高温熱水噴射方式低温過熱蒸気による脱油鶏皮の全脂質含有量は通常３０質量％以下、好ましくは２０質量％以下、より好ましくは１５質量％以下、さらに好ましくは１０質量％以下となるが、この減少分の大半が中性脂肪である。 The term “deoiling” as used in the present application is specifically removal of neutral fat (that is, it can also be referred to as “de-neutral fat”), and more specifically, triacylglycerol, diacylglycerol and free fatty acids are excluded. That is. Neutral fat can be efficiently removed by any of the above-exemplified methods, and sphingolipids and plasmalogens are hardly discharged. For example, the total lipid content in raw chicken skin is about 30-50% by mass, and the total lipid content of deoiled chicken skin by high-temperature hot water injection system low-temperature superheated steam is usually 30% by mass or less, preferably 20% by mass. % Or less, more preferably 15% by mass or less, and even more preferably 10% by mass or less. Most of the decrease is neutral fat.
なお、上述のように、脱油鳥皮は生鳥皮から中性脂肪を除去したものであり、スフィンゴミエリン含有量は比較的多くはない。例えば、脱油鶏皮のスフィンゴミエリン含有量は通常０．０８質量％以上、好ましくは０．１質量％以上、より好ましくは０．１５質量％以上、さらに好ましくは０．２質量％以上である。 As described above, deoiled chicken skin is obtained by removing neutral fat from raw chicken skin, and the sphingomyelin content is not relatively high. For example, the sphingomyelin content of the deoiled chicken skin is usually 0.08% by mass or more, preferably 0.1% by mass or more, more preferably 0.15% by mass or more, and further preferably 0.2% by mass or more. .
また、特に制限するものではないが、脱油鳥皮は、中性脂肪含有量が３０質量％以下であることが好ましく、２０質量％以下であることがより好ましく、１５質量％以下であることがさらに好ましく、１０質量％以下であることがよりさらに好ましい。 Although not particularly limited, the deoiled chicken skin preferably has a neutral fat content of 30% by mass or less, more preferably 20% by mass or less, and 15% by mass or less. Is more preferable, and it is still more preferable that it is 10 mass% or less.
脱油鳥皮は、乾燥させて水分を蒸発させて用いてもよい。すなわち、乾燥脱油鳥皮を用いてもよい。乾燥方法は特に制限されず、適当な方法を選択して用いることができる。 The deoiled chicken skin may be used after drying to evaporate water. That is, dry deoiled chicken skin may be used. The drying method is not particularly limited, and an appropriate method can be selected and used.
なお、脱油鳥皮は、乾燥する前又は乾燥した後に常法に従って粉砕化、粉末化されてもよい。 The deoiled chicken skin may be pulverized or powdered according to a conventional method before drying or after drying.
本発明の鳥皮由来スフィンゴミエリン含有物の製造方法は、スフィンゴミエリンを含有する組成物（好ましくは中性脂肪含有量が３０質量％以下、好ましくは２０質量％以下、より好ましくは１５質量％以下、さらに好ましくは１０質量％以下）が得られるものであれば特に制限されない。上述の通り、脱油工程を経た脱油鳥皮を鳥皮由来スフィンゴミエリン含有物として用いることができる。また、鳥皮（脱油鳥皮でもよい）を例えば有機溶媒抽出工程に供し、スフィンゴミエリン含有量を高めた鳥皮抽出物を鳥皮由来スフィンゴミエリン含有物としてもよい。 The method for producing a chicken skin-derived sphingomyelin-containing material of the present invention comprises a composition containing sphingomyelin (preferably a neutral fat content of 30% by mass or less, preferably 20% by mass or less, more preferably 15% by mass or less. And more preferably 10% by mass or less) is not particularly limited. As above-mentioned, the deoiled chicken skin which passed through the deoiling process can be used as a chicken skin origin sphingomyelin containing material. Alternatively, the chicken skin extract (which may be deoiled chicken skin) is subjected to, for example, an organic solvent extraction step, and the chicken skin extract having an increased sphingomyelin content may be used as the chicken skin-derived sphingomyelin containing material.
脱油鳥皮（好ましくは乾燥脱油鳥皮）を用いて、スフィンゴミエリン含有量を高めるため、例えば水又は有機溶媒抽出及び精製を行うことができる。有機溶媒抽出及び精製を行う場合、特に制限されないが、例えば以下の工程（１）を含む方法、工程（１）及び（２）を含む方法、又は工程（１）〜（３）を含む方法が例示できる。
（１）脱油鳥皮のアルコール抽出物を濃縮乾固して濃縮乾固抽出物を得る工程
（２）前記濃縮乾固抽出物をアセトン−水混合溶媒及び／又はアセトンで洗浄した後、さらにヘキサン−アセトン混合溶媒で洗浄してスフィンゴ脂質含有沈殿を得る工程
（３）前記スフィンゴ脂質含有沈殿を溶解したNaOH水溶液を遠心して得られる沈殿を、アセトン−水混合溶媒及び／又はアセトンで洗浄して高純度スフィンゴ脂質含有沈殿を得る工程In order to increase the sphingomyelin content using deoiled chicken skin (preferably dry deoiled chicken skin), for example, water or organic solvent extraction and purification can be performed. When performing organic solvent extraction and purification, although not particularly limited, for example, a method including the following step (1), a method including steps (1) and (2), or a method including steps (1) to (3) It can be illustrated.
(1) A step of concentrating and drying an alcohol extract of deoiled chicken skin to obtain a concentrated dry solid extract (2) After washing the concentrated dry solid extract with an acetone-water mixed solvent and / or acetone, A step of obtaining a sphingolipid-containing precipitate by washing with a hexane-acetone mixed solvent (3) A precipitate obtained by centrifuging a NaOH aqueous solution in which the sphingolipid-containing precipitate is dissolved is washed with an acetone-water mixed solvent and / or acetone. Process for obtaining a high-purity sphingolipid-containing precipitate
工程（１）におけるアルコール抽出物を得るために用いるアルコールは特に制限されず、例えばメタノール、エタノール、プロパノール、ブタノール、イソブタノール、イソプロパノール等の炭素数１〜５のアルコールが例示でき、中でもエタノールが好ましい。また、含水アルコールを用いることもできる。含水アルコールを用いる場合、水分含量は例えば０．１〜４０質量％、好ましくは１〜２０質量％である。 The alcohol used for obtaining the alcohol extract in the step (1) is not particularly limited, and examples thereof include alcohols having 1 to 5 carbon atoms such as methanol, ethanol, propanol, butanol, isobutanol, isopropanol, etc. Among them, ethanol is preferable. . A hydrous alcohol can also be used. When using a hydrous alcohol, a water content is 0.1-40 mass%, for example, Preferably it is 1-20 mass%.
当該アルコール抽出には、乾燥質量換算で脱油鳥皮１ｋｇあたり、例えば１〜１０L、好ましくは１〜６L、さらに好ましくは２〜４Lのアルコール又は含水アルコールを用いることができる。 For the alcohol extraction, for example, 1 to 10 L, preferably 1 to 6 L, more preferably 2 to 4 L of alcohol or hydrous alcohol can be used per 1 kg of deoiled chicken skin in terms of dry mass.
当該アルコール抽出の条件としては、特に制限されないが、冷浸、温浸等の浸漬法、パーコレーション法等により行うことができる。好適な一例として、脱油鳥皮にアルコールを加え、常温で５時間以上、好ましくは常温で５〜４８時間、静置又は撹拌を行う方法が例示できる。 The conditions for the alcohol extraction are not particularly limited, but can be performed by an immersion method such as cold immersion or digestion, a percolation method, or the like. A preferred example is a method in which alcohol is added to deoiled chicken skin and allowed to stand or stir for 5 hours or more at room temperature, preferably 5 to 48 hours at room temperature.
このようにして得られるアルコール抽出物を濃縮乾固する。濃縮乾固する方法は特に制限されないが、例えば減圧乾燥法が例示できる。これにより濃縮乾固抽出物を得られる。 The alcohol extract thus obtained is concentrated to dryness. The method for concentrating and drying is not particularly limited, and for example, a vacuum drying method can be exemplified. Thereby, a concentrated dry solid extract can be obtained.
工程（２）においては、工程（１）で得られた濃縮乾固抽出物を洗浄する。詳細には、当該濃縮乾固抽出物をアセトン−水混合溶媒及び／又はアセトンで洗浄した後、さらにヘキサン−アセトン混合溶媒で洗浄する。なお、「洗浄」は、例えば、沈殿に溶媒を加えて撹拌した後遠心して再度沈殿させて当該沈殿を回収することで行うことができる。当該洗浄における洗浄溶媒の容量、遠心の温度・遠心速度等は、適宜設定することができる。 In step (2), the concentrated dry-solid extract obtained in step (1) is washed. Specifically, the concentrated dry-solid extract is washed with an acetone-water mixed solvent and / or acetone, and then further washed with a hexane-acetone mixed solvent. The “washing” can be performed, for example, by adding a solvent to the precipitate and stirring, then centrifuging to precipitate again and collecting the precipitate. The volume of the washing solvent in the washing, the temperature of centrifugation, the centrifugation speed, and the like can be set as appropriate.
具体的には、例えば、（i）当該濃縮乾固抽出物をアセトン／水（２：１）の混合溶媒で洗浄し、（ii）さらにアセトン／水（１：１）の混合溶媒で洗浄し、（iii）さらにアセトンで洗浄し、（iv）さらにヘキサン／アセトン（７：３）の混合溶媒で洗浄する方法が挙げられる。この場合においては、（iv）の洗浄後の沈殿がスフィンゴ脂質含有沈殿である。当該（i）〜（iv）の洗浄は室温で行ってもよいが、４℃で行うことが好ましい。 Specifically, for example, (i) the concentrated dry-solid extract is washed with a mixed solvent of acetone / water (2: 1), and (ii) further washed with a mixed solvent of acetone / water (1: 1). (Iii) Further washing with acetone, (iv) Washing with a mixed solvent of hexane / acetone (7: 3). In this case, the precipitate after washing in (iv) is a sphingolipid-containing precipitate. The washings (i) to (iv) may be performed at room temperature, but are preferably performed at 4 ° C.
なお、（i）〜（iii）の工程のうち、１又は２以上の工程を省略してもよいが、（i）の洗浄により油脂を除去し、（ii）の洗浄により非脂質成分を除去し、（iii）の洗浄により中性脂質を除去することが期待されることから、これらの工程を全て経ることがより好ましい。 Of the steps (i) to (iii), one or more steps may be omitted, but the fats and oils are removed by washing (i) and non-lipid components are removed by washing (ii). In addition, since it is expected that the neutral lipid is removed by washing (iii), it is more preferable to go through all these steps.
工程（３）においては、工程（２）で得たスフィンゴ脂質含有沈殿をNaOHに溶解させて残存するPC（ホスファチジルコリン）を分解した後、アセトン−水混合溶媒及び／又はアセトンで洗浄してアルカリを除去する。 In step (3), the sphingolipid-containing precipitate obtained in step (2) is dissolved in NaOH to decompose the remaining PC (phosphatidylcholine), and then washed with an acetone-water mixed solvent and / or acetone to remove alkali. Remove.
具体的には、例えば、（I）０．１〜０．４M（好ましくは０．２M） NaOH水溶液にスフィンゴ脂質含有沈殿を分散させて１５〜４５℃（好ましくは３７℃）で０．５〜６時間（好ましくは２時間）静置又は撹拌し、（II）さらにNaOH水溶液の２〜４倍（好ましくは２倍）容量のアセトンで洗浄し、（III）さらにアセトンで洗浄する方法が挙げられる。（II）は省略することもできる。（III）で得られる沈殿は、９０質量％以上のスフィンゴミエリンを有する高純度スフィンゴ脂質含有沈殿であり、当該沈殿を例えば乾固させるなどして鳥皮抽出物として用いることができる。当該沈殿のスフィンゴミエリン以外の大部分は、グルコシルセラミドや遊離セラミドなどのスフィンゴ脂質からなる。 Specifically, for example, (I) 0.1 to 0.4 M (preferably 0.2 M), a sphingolipid-containing precipitate is dispersed in an aqueous NaOH solution at 15 to 45 ° C. (preferably 37 ° C.) and 0.5 to Examples include a method of standing or stirring for 6 hours (preferably 2 hours), (II) further washing with 2 to 4 times (preferably 2 times) the volume of NaOH aqueous solution, and (III) further washing with acetone. . (II) can be omitted. The precipitate obtained in (III) is a high-purity sphingolipid-containing precipitate having 90% by mass or more of sphingomyelin, and can be used as a chicken skin extract, for example, by drying the precipitate. Most of the precipitate other than sphingomyelin consists of sphingolipids such as glucosylceramide and free ceramide.
なお、工程（３）で得られる高純度スフィンゴ脂質含有沈殿のみならず、工程（１）で得られる濃縮乾固抽出物、工程（２）で得られるスフィンゴ脂質含有沈殿（すなわち、粗抽出物）も、鳥皮抽出物として用いることができる。さらに、工程（１）、（２）又は（３）の途中で得られる沈殿も鳥皮抽出物として用いることができる。例えば、工程（１）のアルコール抽出物や、上述の（i）、（ii）、（iii）又は（iv）で得られる各沈殿を鳥皮抽出物として用いることもできるし、（II）又は（III）で得られる沈殿を鳥皮抽出物として用いることもできる。これら工程（１）〜（３）の途中で得られる各沈殿は、工程を多く経たものほどスフィンゴミエリンの含有率が通常増加している。 In addition to the high-purity sphingolipid-containing precipitate obtained in step (3), the concentrated dry-solid extract obtained in step (1) and the sphingolipid-containing precipitate obtained in step (2) (ie, crude extract) Can also be used as a chicken skin extract. Furthermore, the precipitate obtained during the step (1), (2) or (3) can also be used as a chicken skin extract. For example, the alcohol extract of the step (1) and each precipitate obtained in the above (i), (ii), (iii) or (iv) can be used as a chicken skin extract, (II) or The precipitate obtained in (III) can also be used as a chicken skin extract. As for each precipitation obtained in the middle of these steps (1) to (3), the content of sphingomyelin usually increases as the number of steps increases.
例えば上述のようにして得られる鳥皮由来スフィンゴミエリン含有物（脱油鳥皮や鳥皮抽出物）は、本発明の抗高血糖及び／又は抗高脂血症剤の有効成分として好ましく用いることができる。 For example, a chicken skin-derived sphingomyelin-containing material (deoiled chicken skin or chicken skin extract) obtained as described above is preferably used as an active ingredient of the antihyperglycemic and / or antihyperlipidemic agent of the present invention. Can do.
なお、本発明の鳥皮由来スフィンゴミエリン含有物は、例えば上述のようにして鳥皮から抽出又は粗抽出したスフィンゴミエリンを含有する沈殿、これを乾固したもの、又は脱油鳥皮等を２種以上混合したものであってもよい。
In addition, the chicken skin-derived sphingomyelin-containing material of the present invention includes, for example, a precipitate containing sphingomyelin extracted or roughly extracted from chicken skin as described above, a dried product of this, or
本発明の抗高血糖及び／又は抗高脂血症剤は、高血糖値を低下させ、また、血中の高コレステロール値（特に高LDLコレステロール値）を低下させる効果を有する。 The antihyperglycemic and / or antihyperlipidemic agent of the present invention has an effect of lowering a high blood glucose level and lowering a high cholesterol level (particularly, a high LDL cholesterol level) in blood.
当該抗高血糖及び／又は抗高脂血症剤を投与する対象としては、高血糖患者及び高脂血症患者はもちろんのこと、血糖値が高めの人やコレステロール値（特にLDLコレステロール値）が高めの人、血糖値検査において糖尿病型又は境界型と診断された人、メタボリックシンドロームである人など、高血糖又は高脂血症を将来患う可能性の高い人も含まれる。また、人のみならず、これらの病気又は症状を呈する動物（特にペット及び家畜）も対象に含まれ、例えばイヌ、ネコ、牛、馬、豚、羊等が例示できる。 The subject to which the antihyperglycemia and / or antihyperlipidemic agent is administered includes not only hyperglycemic patients and hyperlipidemic patients but also people with high blood sugar levels and cholesterol levels (particularly LDL cholesterol levels). Also included are those who are likely to suffer from hyperglycemia or hyperlipidemia in the future, such as those who are higher, those who have been diagnosed with diabetes or borderline in blood glucose testing, and those who have metabolic syndrome. Further, not only humans but also animals (especially pets and livestock) exhibiting these diseases or symptoms are included in the subject, and examples include dogs, cats, cows, horses, pigs, sheep and the like.
なお、高血糖における糖尿病型とは、早朝空腹時血糖値が１２６ｍｇ／ｄＬ以上、又は７５ｇＯＧＴＴ（経口ブドウ糖負荷試験）でブドウ糖負荷から２時間後の血糖値が２００ｍｇ／ｄＬ以上、又は随時血糖値が２００ｍｇ／ｄＬ以上を指す。境界型（血糖値が高めの人）とは、早朝空腹時血糖値が１１０ｍｇ／ｄＬ以上１２６ｍｇ／ｄＬ未満、又は７５ｇＯＧＴＴでブドウ糖負荷から２時間後の血糖値が１４０ｍｇ／ｄＬ以上２００ｍｇ／ｄＬ未満を指す（日本糖尿病学会編、糖尿病治療ガイド2006-2007）。
In addition, the diabetic type in hyperglycemia is an early morning fasting blood glucose level of 126 mg / dL or higher, or a blood glucose level of 2 hours after glucose load in a 75 g OGTT (oral glucose tolerance test) of 200 mg / dL or higher, or an occasional blood glucose level. It refers to 200 mg / dL or more. Boundary type (person with high blood glucose level) means that early morning fasting blood glucose level is 110 mg / dL or more and less than 126 mg / dL, or 75 gOGTT and
また、高脂血症とは、高コレステロール血症として総コレステロールが２２０ｍｇ／ｄＬ以上、又は高ＬＤＬコレステロール血症としてＬＤＬコレステロールが１４０ｍｇ／ｄＬ以上、又は低ＨＤＬコレステロール血症としてＨＤＬコレステロールが４０ｍｇ／ｄＬ未満、又は高トリグリセリド血症としてトリグリセリドが１５０ｍｇ／ｄＬ以上を指す（日本動脈硬化学会、動脈硬化性疾患診療ガイドライン2002年度版）。 In addition, hyperlipidemia means hypercholesterolemia of total cholesterol of 220 mg / dL or more, or hyper-LDL cholesterolemia of LDL cholesterol of 140 mg / dL or more, or low-HDL cholesterolemia of HDL cholesterol of 40 mg / dL. The triglyceride indicates 150 mg / dL or more as hypertriglyceridemia (Japan Arteriosclerosis Society, Arteriosclerotic Disease Clinical Practice Guidelines 2002 Edition).
なお、本明細書では、ＬＤＬコレステロール値１２０ｍｇ／ｄＬ以上１４０ｍｇ／ｄＬ未満の人をコレステロールが高めの人とする。 In the present specification, a person having an LDL cholesterol level of 120 mg / dL or more and less than 140 mg / dL is a person with high cholesterol.
なお、これらコレステロール値は血中の濃度である。 These cholesterol levels are blood concentrations.
本発明の抗高血糖及び／又は抗高脂血症剤の投与時期は特に限定されず、対象となる疾患の治療方法に従って、適宜投与時期を選択することが可能である。また、投与形態は製剤形態、患者の年齢、性別、その他の条件、患者の症状の程度等に応じて決定されることが好ましいが、特に経口投与が好適である。 The administration time of the antihyperglycemia and / or antihyperlipidemic agent of the present invention is not particularly limited, and it is possible to appropriately select the administration time according to the treatment method for the target disease. The dosage form is preferably determined according to the preparation form, the patient's age, sex, other conditions, the patient's symptom level, etc., and oral administration is particularly preferred.
本発明の抗高血糖及び／又は抗高脂血症剤の投与又は摂取量は、患者の年齢、性別、疾患の程度（血糖値及びコレステロール値（特にＬＤＬコレステロール値）の程度）、その他の条件等により適宜選択される。当該剤の摂取量は、通常摂取した当該剤中のスフィンゴミエリンの量が、好ましくは成人一日あたり０．１〜５０ｍｇ、より好ましくは１〜３０ｍｇの範囲となる量を目安とするのが良い。なお、１日１回又は複数回（好ましくは２〜３回）に分けて投与することができる。また、当該剤１個中に含まれるスフィンゴミエリン量も特に制限されず、摂取量を目安として適宜設定できる。例えば、当該剤中、スフィンゴミエリンを０．００１〜９９．９９質量％、好ましくは０．０１〜９８質量％配合してもよい。 The administration or intake of the antihyperglycemia and / or antihyperlipidemic agent of the present invention depends on the age, sex, degree of disease (degree of blood glucose level and cholesterol level (particularly LDL cholesterol level)), and other conditions. It is appropriately selected depending on the above. The intake amount of the agent should be an amount such that the amount of sphingomyelin in the agent normally taken is preferably in the range of 0.1 to 50 mg, more preferably 1 to 30 mg per adult day. . In addition, it can administer once a day or several times (preferably 2-3 times). Further, the amount of sphingomyelin contained in one agent is not particularly limited, and can be appropriately set based on the intake amount. For example, 0.001 to 99.99 mass%, preferably 0.01 to 98 mass% of sphingomyelin may be blended in the agent.
当該剤の有効成分である鳥皮由来スフィンゴミエリン含有物に含まれるスフィンゴミエリンの量は、常法により測定することができる。例えば、鳥皮由来スフィンゴミエリン含有物から脂質を抽出し、さらにこれを単純脂質画分と複合脂質画分とに分画して、当該複合脂質画分をＨＰＬＣにより分析することで、スフィンゴミエリン量を定量することができる。また、鳥皮由来スフィンゴミエリン含有物が脱油鳥皮である場合は、上述した工程（１）により得られるスフィンゴ脂質含有沈殿（エタノール抽出物）を単純脂質画分と複合脂質画分とに分画し、当該複合脂質画分をＨＰＬＣ分析して、脱油鳥皮中のスフィンゴミエリン量とすることができる。例えば、脱油鳥皮中のスフィンゴミエリン量は、工程（１）により得られたエタノール抽出物から複合脂質画分を分画してＨＰＬＣにて測定した際、乾燥質量換算で脱油鳥皮１００ｇあたり８０〜４００ｍｇであることが好ましく、１００〜４００ｍｇであることがより好ましい。なお、複合脂質画分の分画は、分画対象物をクロロホルム/メタノール溶液（2:1、v/v）に溶解し、これをケイ酸カラムクロマトグラフィーに供し、クロロホルムで単純脂質画分を溶出させ、メタノールで複合脂質画分を溶出させて、行うことができる。 The amount of sphingomyelin contained in the chicken skin-derived sphingomyelin-containing material, which is an active ingredient of the agent, can be measured by a conventional method. For example, by extracting lipids from chicken skin-derived sphingomyelin-containing material, and further fractionating it into a simple lipid fraction and a complex lipid fraction, and analyzing the complex lipid fraction by HPLC, the amount of sphingomyelin Can be quantified. In addition, when the chicken skin-derived sphingomyelin-containing material is deoiled chicken skin, the sphingolipid-containing precipitate (ethanol extract) obtained by the step (1) described above is separated into a simple lipid fraction and a complex lipid fraction. And the amount of sphingomyelin in the deoiled chicken skin can be determined by HPLC analysis of the complex lipid fraction. For example, the amount of sphingomyelin in the deoiled chicken skin is 100 g of deoiled chicken skin in terms of dry mass when the complex lipid fraction is fractionated from the ethanol extract obtained in step (1) and measured by HPLC. 80 to 400 mg per unit is preferable, and 100 to 400 mg is more preferable. For fractionation of complex lipid fractions, the fractionation object is dissolved in a chloroform / methanol solution (2: 1, v / v), and this is subjected to silica column chromatography. It can be carried out by eluting and eluting the complex lipid fraction with methanol.
中性脂肪量が３０質量％以下（好ましくは２０質量％以下、より好ましくは１５質量％以下、さらに好ましくは１０質量％以下）の鳥皮由来スフィンゴミエリン含有物（例えば上述の脱油鳥皮や鳥皮抽出物）は、中性脂肪含有量が低いだけではなく、スフィンゴミエリンとともにプラズマローゲン等の鳥皮由来の多種の機能性物質を含むことから、当該鳥皮由来スフィンゴミエリン含有物に含まれるスフィンゴミエリン量に相当するスフィンゴミエリンを単独で投与又は摂取するよりも、さらに優れた抗高血糖及び／又は抗高脂血症作用（具体的には例えば高血糖値低下作用及び／又は高コレステロール値（特に高LDL値）低下作用）を示すことから、好ましい。 A chicken skin-derived sphingomyelin-containing material having a neutral fat amount of 30% by mass or less (preferably 20% by mass or less, more preferably 15% by mass or less, and even more preferably 10% by mass or less) (for example, the aforementioned deoiled chicken skin or The chicken skin extract) is not only low in triglyceride content, but also contains various functional substances derived from chicken skin such as plasmalogen together with sphingomyelin, so it is included in the chicken skin derived sphingomyelin content Anti-hyperglycemia and / or anti-hyperlipidemia action (specifically, for example, hypoglycemia lowering action and / or high cholesterol level) superior to that of administering or ingesting sphingomyelin corresponding to the amount of sphingomyelin alone (Especially high LDL value) lowering action) is preferable.
なお、スフィンゴミエリンは、セラミドの第一級アルコール性ヒドロキシル基とコリンリン酸がリン酸ジエステル結合した脂質である。セラミドはスフィンゴイド塩基と脂肪酸が酸アミド結合して構成される。スフィンゴイド塩基は通常炭素数１６〜２０の長鎖アミノアルコールである。従って、スフィンゴミエリンには、セラミドを構成するスフィンゴイド塩基の炭素数、メチル側鎖の有無、二重結合数やその位置およびヒドロキシル基の数並びに、脂肪酸の炭素数、二重結合数やその位置およびヒドロキシル基の数の違いによって種々の類似体が存在する。これら異なる類似体を総称してスフィンゴミエリンと呼んでいる訳である。スフィンゴミエリンのこれらの類似体の組成は、スフィンゴミエリンが由来する原材料によって異なる。すなわち、スフィンゴミエリンを精製する原材料が異なれば、得られるスフィンゴミエリンの類似体の組成も異なる。このような、原材料の違いに起因するスフィンゴミエリン含有物に含まれるスフィンゴミエリン類似体組成の違いは、例えば高速液体クロマトグラフィー（ＨＰＬＣ）で分析することで確認できる。具体的には、ＨＰＬＣで分析することにより得られるクロマトグラムのピークの位置（保持時間）、大きさ、及び本数等の違いにより、原材料が異なれば、スフィンゴミエリン含有物のスフィンゴミエリン類似体組成が異なることを確認することができる。 Sphingomyelin is a lipid in which a primary alcoholic hydroxyl group of ceramide and choline phosphate are bonded to a phosphodiester. Ceramide is composed of an acid amide bond between a sphingoid base and a fatty acid. The sphingoid base is usually a long chain amino alcohol having 16 to 20 carbon atoms. Therefore, sphingomyelin includes the number of carbons of the sphingoid base constituting ceramide, the presence or absence of methyl side chains, the number of double bonds and their positions and the number of hydroxyl groups, the number of carbon atoms of fatty acids, the number of double bonds and their positions. There are various analogs depending on the number of hydroxyl groups. These different analogs are collectively called sphingomyelin. The composition of these analogs of sphingomyelin depends on the raw material from which the sphingomyelin is derived. That is, if the raw materials for purifying sphingomyelin are different, the composition of the resulting sphingomyelin analog is also different. Such a difference in the sphingomyelin analog composition contained in the sphingomyelin-containing material due to the difference in the raw materials can be confirmed by, for example, analysis by high performance liquid chromatography (HPLC). Specifically, the sphingomyelin analog composition of the sphingomyelin-containing material is different if the raw materials are different due to differences in the position (retention time), size, number, etc. of the chromatogram obtained by HPLC analysis. Can be different.
鳥皮由来のスフィンゴミエリン中にも複数の類似体が含まれている。鳥皮由来スフィンゴミエリンは、他の原料（例えば牛乳や卵黄等）由来のスフィンゴミエリンと比べ、優れた抗高血糖及び／又は抗高脂血症作用（具体的には例えば高血糖値低下作用及び／又は高コレステロール値（特に高LDLコレステロール値）低下作用）を示す。限定的な解釈を望むものではないが、これは、鳥皮由来のスフィンゴミエリンに含まれる類似体の組成が、抗高血糖及び／又は抗高脂血症作用を示すのに特に好適であるためと考えられる。 A plurality of analogs are also contained in sphingomyelin derived from chicken skin. Compared to sphingomyelin derived from other raw materials (such as milk and egg yolk), chicken skin-derived sphingomyelin is superior in antihyperglycemic and / or antihyperlipidemic action (specifically, / Or high cholesterol level (especially high LDL cholesterol level) lowering effect). Although not wishing to be interpreted in a limited manner, this is because the composition of analogs contained in chicken skin-derived sphingomyelin is particularly suitable for exhibiting antihyperglycemic and / or antihyperlipidemic effects. it is conceivable that.
また、限定的な解釈を望むものではないが、脱油鳥皮においては、鳥皮由来スフィンゴミエリンの類似体組成が好ましいことに加え、含有されるスフィンゴミエリン以外の成分（例えばプラズマローゲン等）も抗高血糖及び／又は抗高脂血症作用に寄与していると考えられ、これらの成分と鳥皮由来スフィンゴミエリンとが相まってより優れた抗高血糖及び／又は抗高脂血症作用を奏するものと考えられる。 In addition, although it is not desired to have a limited interpretation, in the deoiled chicken skin, an analog composition of the chicken skin-derived sphingomyelin is preferable, and components other than the sphingomyelin contained (for example, plasmalogen) It is thought that it contributes to antihyperglycemia and / or antihyperlipidemia action, and these components and sphingomyelin derived from chicken skin combine to exhibit superior antihyperglycemia and / or antihyperlipidemia action. It is considered a thing.
本発明の抗高血糖及び／又は抗高脂血症剤は、医薬分野及び食品分野で好ましく用いられる。すなわち、本発明は、鳥皮由来スフィンゴミエリン含有物を有効成分とする医薬剤、鳥皮由来スフィンゴミエリン含有物を有効成分とする食品添加剤、及び、鳥皮由来スフィンゴミエリン含有物を添加した飲食品からなる抗高血糖及び／又は抗高脂血症剤が含まれる。 The antihyperglycemic and / or antihyperlipidemic agent of the present invention is preferably used in the pharmaceutical field and food field. That is, the present invention provides a pharmaceutical agent comprising a chicken skin-derived sphingomyelin-containing material as an active ingredient, a food additive comprising a chicken skin-derived sphingomyelin-containing material as an active ingredient, and a food and drink to which a chicken skin-derived sphingomyelin-containing material is added. Anti-hyperglycemic and / or anti-hyperlipidemic agents comprising the product.
医薬分野にて用いられる本発明の抗高血糖及び／又は抗高脂血症剤（以下「本発明に係る医薬剤」と記載することがある）は、鳥皮由来スフィンゴミエリン含有物そのものであってもよいし、これと他の薬理活性成分、薬学的に許容される基剤、担体、添加剤（例えば溶剤、分散剤、乳化剤、緩衝剤、安定剤、賦形剤、結合剤、崩壊剤、滑沢剤等）等が必要に応じて配合され、錠剤、丸剤、散剤、液剤、懸濁剤、乳剤、顆粒剤、カプセル剤等の医薬製剤に調製されたものでもよい。 The antihyperglycemic and / or antihyperlipidemic agent of the present invention (hereinafter sometimes referred to as “the pharmaceutical agent according to the present invention”) used in the pharmaceutical field is a chicken skin-derived sphingomyelin-containing product itself. Or other pharmacologically active ingredients, pharmaceutically acceptable bases, carriers, additives (eg, solvents, dispersants, emulsifiers, buffers, stabilizers, excipients, binders, disintegrants). , Lubricants, etc.) may be blended as necessary and prepared into pharmaceutical preparations such as tablets, pills, powders, solutions, suspensions, emulsions, granules, capsules and the like.
このような本発明に係る医薬剤は、上述したように、特に経口投与により、高血糖の改善及び高脂血症の改善の用途に好ましく用いることができる。なお、本発明に係る医薬剤の摂取量、摂取対象等は、上で抗高血糖及び／又は抗高脂血症剤について述べた通りである。 As described above, such a pharmaceutical agent according to the present invention can be preferably used for the purpose of improving hyperglycemia and hyperlipidemia, particularly by oral administration. In addition, the intake of the pharmaceutical agent according to the present invention, the intake target, and the like are as described above for the antihyperglycemia and / or antihyperlipidemic agent.
食品添加剤として用いられる本発明の抗高血糖及び／又は抗高脂血症剤（以下「本発明に係る食品添加剤」と記載することがある）は、鳥皮由来スフィンゴミエリン含有物そのものであってもよいし、これらと食品衛生学上許容される基剤、担体、添加剤や、その他食品添加剤として利用され得る成分・材料が適宜配合されたものでもよい。また、このような食品添加剤の形態としては、例えば液状、粉末状、フレーク状、顆粒状、ペースト状のものが挙げられるがこれらに限定されない。具体的には、調味料（醤油、ソース、ケチャップ、ドレッシング等）、フレーク（ふりかけ）、焼き肉のたれ、スパイス、ルーペースト（カレールーペースト等）等が例示できる。このような食品添加剤は、常法に従って適宜調製することができる。 The antihyperglycemia and / or antihyperlipidemic agent of the present invention used as a food additive (hereinafter sometimes referred to as “the food additive according to the present invention”) is a chicken skin-derived sphingomyelin-containing product itself. These may be appropriately mixed with ingredients and materials that can be used as a food hygiene-acceptable base, carrier, additive, and other food additives. Examples of such food additives include, but are not limited to, liquids, powders, flakes, granules, and pastes. Specific examples include seasonings (soy sauce, sauce, ketchup, dressing, etc.), flakes (sprinkles), grilled meat sauce, spices, roux paste (carrille paste, etc.) and the like. Such food additives can be appropriately prepared according to conventional methods.
このような本発明に係る食品添加剤は、該食品添加剤が添加された食品を食べることにより摂取される。なお、当該添加は食品調理中又は製造中に行ってもよいし、調理済みの食品を食べる直前又は食べながら行ってもよい。当該食品添加剤はこのようにして経口摂取することにより、高血糖の改善効果及び高脂血症の改善効果を発揮する。なお、本発明に係る食品添加剤の摂取量、摂取対象等は、上で抗高血糖及び／又は抗高脂血症剤について述べたのと同様である。 Such a food additive according to the present invention is ingested by eating a food to which the food additive is added. In addition, the said addition may be performed during food preparation or manufacture, and may be performed immediately before eating cooked food or while eating. The food additive exhibits the effect of improving hyperglycemia and the effect of improving hyperlipidemia by ingesting in this manner. In addition, the intake of the food additive according to the present invention, the intake target, and the like are the same as those described above for the antihyperglycemic and / or antihyperlipidemic agent.
食品分野にて用いられる本発明の抗高血糖及び／又は抗高脂血症剤（以下「本発明に係る鳥皮由来スフィンゴミエリン含有物を添加した飲食品からなる抗高血糖及び／又は抗高脂血症剤」と記載することがある）は、鳥皮由来スフィンゴミエリン含有物と、食品衛生学上許容される基剤、担体、添加剤や、その他食品として利用され得る成分・材料等が適宜配合されたものである。例えば、鳥皮由来スフィンゴミエリン含有物を含む、抗高血糖及び／又は抗高脂血症用の加工食品、飲料、健康食品（栄養機能食品、特定保健用食品等）、サプリメント、病者用食品等が例示できる。特に、当該剤は鳥皮由来スフィンゴミエリン含有物を添加した飲食品からなるものであることから、ハンバーグ、ミートボール、ウインナー、鳥そぼろ、鳥皮チップス等の加工肉食品及び加工された肉食品からなる健康食品（栄養機能食品、特定保健用食品等）、サプリメント、病者用食品であることが好ましい。また、鳥皮由来スフィンゴミエリン含有物を（乾燥させ）粉末状にして、飲料類（ジュース等）、菓子類（例えばガム、チョコレート、キャンディー、ビスケット、クッキー、おかき、煎餅、プリン、杏仁豆腐等）、パン類、スープ類（粉末スープ等を含む）、加工食品等の各種飲食品に含有させたものであってもよい。このような、鳥皮由来スフィンゴミエリン含有物を添加した飲食品からなる抗高血糖及び／又は抗高脂血症剤は、高血糖の改善及び高脂血症の改善のために好ましく用いることができる。 Antihyperglycemia and / or antihyperlipidemic agent of the present invention used in the food field (hereinafter referred to as “antihyperglycemia and / or antihyperglycemic consisting of food and drink containing the chicken skin-derived sphingomyelin-containing material according to the present invention”) Is sometimes referred to as a “lipidemia agent”, which contains chicken skin-derived sphingomyelin-containing ingredients, food hygiene-acceptable bases, carriers, additives, and other ingredients and materials that can be used as food. It is appropriately blended. For example, processed foods, drinks, health foods (nutrient functional foods, foods for specified health use, etc.), supplements, foods for the sick, containing chicken skin-derived sphingomyelin-containing foods Etc. can be illustrated. In particular, since the agent consists of foods and drinks to which a chicken skin-derived sphingomyelin-containing material is added, from processed meat foods such as hamburger, meatballs, wieners, bird rags, chicken skin chips, and processed meat foods It is preferable to be a health food (nutrient functional food, food for specified health use, etc.), supplement, food for the sick. In addition, chicken skin-derived sphingomyelin-containing material is (dried) in powder form, and beverages (juice, etc.) and confectionery (eg, gum, chocolate, candy, biscuits, cookies, rice cakes, rice crackers, pudding, apricot tofu, etc.) , Breads, soups (including powdered soups), processed foods and other foods and beverages. Such an antihyperglycemic and / or antihyperlipidemic agent comprising a food or drink to which a chicken skin-derived sphingomyelin-containing material is added is preferably used for improving hyperglycemia and hyperlipidemia. it can.
なお、健康食品（栄養機能食品、特定保健用食品等）、サプリメント又は病者用食品として、当該飲食品からなる抗高血糖及び／又は抗高脂血症剤を調製する場合は、継続的な摂取が行いやすいように、例えば顆粒、カプセル、錠剤（チュアブル剤等を含む）、飲料（ドリンク剤）等の形態で調製することが好ましく、なかでもカプセル、タブレット、錠剤の形態が摂取の簡便さの点からは好ましいが、特にこれらに限定されるものではない。顆粒、カプセル、錠剤等の形態の当該飲食品からなる抗高血糖及び／又は抗高脂血症剤は、薬学的及び／又は食品衛生学的に許容される担体等を用いて、常法に従って適宜調製することができる。また、他の形態に調製する場合であっても、従来の方法に従えばよい。 In addition, when preparing antihyperglycemia and / or antihyperlipidemic agents consisting of the food or drink as health foods (nutrient functional foods, foods for specified health use, etc.), supplements or foods for the sick, It is preferable to prepare in the form of granules, capsules, tablets (including chewables, etc.), beverages (drinks), etc., so that ingestion is easy, in particular, capsules, tablets, tablets are easy to ingest. However, the present invention is not particularly limited thereto. Antihyperglycemic and / or antihyperlipidemic agents composed of the food and drink in the form of granules, capsules, tablets, etc. are in accordance with conventional methods using pharmaceutically and / or food hygienically acceptable carriers, etc. It can be prepared appropriately. Moreover, even if it is a case where it prepares in another form, what is necessary is just to follow the conventional method.
なお、本発明に係る当該飲食品からなる抗高血糖及び／又は抗高脂血症剤の摂取量、摂取対象等は、上で抗高血糖及び／又は抗高脂血症剤について述べたのと同様である。 In addition, the intake amount of the antihyperglycemia and / or antihyperlipidemic agent consisting of the food and drink according to the present invention, the intake target, etc. are described above for the antihyperglycemic and / or antihyperlipidemic agent. It is the same.
また、特に制限されるものではないが、例えば上述した抗高血糖及び／又は抗高脂血症剤を投与する対象と同様の対象（中でも血糖値が高めの人やコレステロール値（特にLDLコレステロール値）が高めの人）が、当該飲食品からなる抗高血糖及び／又は抗高脂血症剤を好ましく摂取し得る。 In addition, although not particularly limited, for example, the same subjects as those to which the above-mentioned antihyperglycemia and / or antihyperlipidemic agent is administered (particularly those with high blood sugar levels or cholesterol levels (especially LDL cholesterol levels) ) Can be preferably taken by the antihyperglycemic and / or antihyperlipidemic agent comprising the food or drink.
本発明は、高血糖患者及び高脂血症患者、並びに血糖値が高めの人やコレステロール値（特にLDLコレステロール値）が高めの人に、本発明の抗高血糖及び／又は抗高脂血症剤を経口投与又は摂取することを特徴とする高血糖の予防又は治療方法及び高脂血症の予防又は治療方法も提供する。当該方法は、具体的には、前述の本発明の抗高血糖及び／又は抗高脂血症剤を投与又は摂取することで実施される。なお、当該方法における、経口投与又は摂取量等の各条件は前述の通りである。 The present invention provides antihyperglycemia and / or antihyperlipidemia of the present invention to patients with hyperglycemia and hyperlipidemia, as well as those with high blood glucose levels and those with high cholesterol levels (particularly LDL cholesterol levels). The present invention also provides a method for preventing or treating hyperglycemia and a method for preventing or treating hyperlipidemia, wherein the agent is orally administered or ingested. Specifically, this method is carried out by administering or ingesting the aforementioned antihyperglycemia and / or antihyperlipidemic agent of the present invention. In this method, each condition such as oral administration or intake is as described above.
以下、本発明を具体的に説明するが、本発明は下記の例に限定されるものではない。 Hereinafter, the present invention will be specifically described, but the present invention is not limited to the following examples.
実施例１：鳥皮由来スフィンゴミエリン含有物の製造
鶏皮を常法に従って採取し、脱油工程に供するまでチルド冷凍保存した。これを約８ｍｍのミンチへと常法により加工し、脱油処理に供した。 Example 1: Production of chicken skin-derived sphingomyelin-containing material Chicken skin was collected according to a conventional method and stored frozen in a chilled state until subjected to a deoiling process. This was processed into a mince of about 8 mm by a conventional method and subjected to deoiling treatment.
＜脱油処理工程＞
上述のようにして得た約８ｍｍミンチ鶏皮を、特殊過熱蒸気により脱油した。具体的には、脱油が行われる加熱チャンバ内部の圧力を０．１ＭＰａ、温度を１０５±４℃、酸素濃度を０．２％以下に制御し、鶏皮ミンチに１００℃熱水（微細熱水滴）、飽和蒸気、及び１１７℃水蒸気（過熱蒸気）の混合系を２５分間高速噴射することにより、脱油を行った。なお、当該脱油工程は、高温熱水噴射方式低温過熱水蒸気装置としてhi-LOHS-R連続製造装置（株式会社タイヨー製作所）を用いて行った。得られた脱油鶏皮をさらに圧搾し、乾燥させ、脱油乾燥鶏皮とした。<Deoiling process>
About 8 mm minced chicken skin obtained as described above was deoiled with special superheated steam. Specifically, the pressure inside the heating chamber where deoiling is performed is controlled to 0.1 MPa, the temperature is 105 ± 4 ° C., and the oxygen concentration is 0.2% or less. The oil was removed by spraying a mixed system of water droplets), saturated steam, and 117 ° C. steam (superheated steam) at a high speed for 25 minutes. In addition, the said deoiling process was performed using the hi-LOHS-R continuous manufacturing apparatus (Taiyo Manufacturing Co., Ltd.) as a high temperature hot water injection type low temperature superheated steam apparatus. The obtained deoiled chicken skin was further pressed and dried to obtain a deoiled and dried chicken skin.
なお、当該脱油乾燥鶏皮のエタノール抽出物を下述工程（１）のようにして得、これをクロロホルム/メタノール溶液（2:1、v/v）に溶解し、ケイ酸カラムクロマトグラフィーに供し、クロロホルムで単純脂質画分を溶出させ、メタノールで複合脂質画分を溶出させ、当該複合脂質画分をＨＰＬＣにて測定したところ、スフィンゴミエリンは脱油乾燥鶏皮１００ｇあたり３２６ｍｇ含まれていた。 In addition, an ethanol extract of the deoiled and dried chicken skin was obtained as described in step (1) below, and this was dissolved in a chloroform / methanol solution (2: 1, v / v) and subjected to silicic acid column chromatography. The simple lipid fraction was eluted with chloroform, the complex lipid fraction was eluted with methanol, and the complex lipid fraction was measured by HPLC. As a result, 326 mg of sphingomyelin was contained per 100 g of deoiled and dried chicken skin. .
当該脱油処理により効率的かつ非侵襲的な脱油が可能であり、上記の工程により鶏皮が有するスフィンゴミエリンをほとんど失わない脱油乾燥鶏皮を得ることができたと考えられる。 Efficient and non-invasive deoiling is possible by the deoiling process, and it is considered that deoiled and dried chicken skin that hardly loses sphingomyelin possessed by chicken skin can be obtained by the above process.
＜有機溶媒抽出工程＞
工程（１）
上述のようにして得た脱油乾燥鶏皮1kgにエタノール２Lを加えて１２時間、40℃で撹拌・静置して抽出する工程を2回行い、得られた抽出液を濾紙で濾過後、減圧乾燥して濃縮乾固抽出物を得た。
工程（２）
上述の濃縮乾固物に水30mLとアセトン60ｍL（すなわち67％アセトン）を加えて撹拌、遠心し、沈殿を回収した。この沈殿に水45ｍLとアセトン45ｍL（すなわち50％アセトン）を加えて撹拌、遠心し、沈殿を回収した。さらにこの沈殿にアセトン90ｍLを加えて撹拌、遠心し、沈殿を得、再度アセトン90ｍLを加えて撹拌、遠心し、沈殿を回収した。さらにこの沈殿にヘキサン/アセトン（７：３）混合溶媒１００ｍＬを加えて撹拌、遠心し、沈殿（スフィンゴ脂質含有沈殿）４gを回収した。なお、遠心は3000rpm×10minで行い、アセトン単一及びヘキサン/アセトン混合溶媒を用いたものは4℃、他は15℃で行なった。
工程（３）
上述のようにして得たスフィンゴ脂質含有沈殿４ｇを０．２Ｍ ＮａＯＨ水溶液４０ｍＬに溶解し、３７℃で２時間撹拌した。その後、２倍容量のアセトンを加えて撹拌、遠心し、沈殿を回収した。さらに、当該沈殿にアセトン／水（２：１）混合溶媒を加えて撹拌、遠心し、沈殿を回収した。さらに当該沈殿にアセトン３０ｍＬ加えて撹拌、遠心し、沈殿（高純度スフィンゴ脂質含有沈殿）を回収した。当該沈殿を減圧乾燥して鶏皮由来高純度スフィンゴミエリン含有物を得た。<Organic solvent extraction process>
Process (1)
2 kg of ethanol was added to 1 kg of deoiled and dried chicken skin obtained as described above, and the mixture was extracted twice by stirring and standing at 40 ° C. for 12 hours. The obtained extract was filtered through filter paper, Concentrated to dry extract was obtained by drying under reduced pressure.
Step (2)
30 mL of water and 60 mL of acetone (that is, 67% acetone) were added to the concentrated dried product described above, and the mixture was stirred and centrifuged to collect a precipitate. To this precipitate, 45 mL of water and 45 mL of acetone (that is, 50% acetone) were added, stirred and centrifuged, and the precipitate was collected. Further, 90 mL of acetone was added to the precipitate and stirred and centrifuged to obtain a precipitate, and 90 mL of acetone was added again and stirred and centrifuged to collect the precipitate. Further, 100 mL of a hexane / acetone (7: 3) mixed solvent was added to the precipitate, followed by stirring and centrifugation, and 4 g of a precipitate (sphingolipid-containing precipitate) was recovered. Centrifugation was performed at 3000 rpm × 10 min. Acetone and hexane / acetone mixed solvent were used at 4 ° C., and others at 15 ° C.
Process (3)
4 g of the sphingolipid-containing precipitate obtained as described above was dissolved in 40 mL of 0.2 M NaOH aqueous solution and stirred at 37 ° C. for 2 hours. Thereafter, 2 volumes of acetone was added, stirred and centrifuged, and the precipitate was collected. Further, an acetone / water (2: 1) mixed solvent was added to the precipitate, and the mixture was stirred and centrifuged to collect the precipitate. Further, 30 mL of acetone was added to the precipitate, followed by stirring and centrifugation, and the precipitate (precipitate containing high-purity sphingolipid) was recovered. The said precipitate was dried under reduced pressure and the chicken skin origin high purity sphingomyelin containing material was obtained.
＜鶏皮由来高純度スフィンゴミエリン含有物の純度の検討＞
上述のようにして得た鶏皮由来高純度スフィンゴミエリン含有物を下記条件のＨＰＬＣにて解析し、当該含有物中のスフィンゴミエリン含有率をピーク面積から算出した。
［ＨＰＬＣ解析条件］
機器；Shimadzu LC-10AD
カラム；LiChrospher Diol 100（250-4, Merck社）（プレカラム無し）
溶媒；A液：ヘキサン/2-プロパノール/酢酸（82:17:1. v/v）
B液：2-プロパノール/水/酢酸（85:14:1, v/v）+0.2%トリエチルアミン
グラジエント条件：表１に示す<Examination of purity of chicken skin-derived high-purity sphingomyelin content>
The chicken skin-derived high-purity sphingomyelin-containing material obtained as described above was analyzed by HPLC under the following conditions, and the sphingomyelin content in the content was calculated from the peak area.
[HPLC analysis conditions]
Equipment: Shimadzu LC-10AD
Column: LiChrospher Diol 100 (250-4, Merck) (no precolumn)
Solvent; Liquid A: Hexane / 2-propanol / acetic acid (82: 17: 1. V / v)
Liquid B: 2-propanol / water / acetic acid (85: 14: 1, v / v) + 0.2% triethylamine gradient conditions: as shown in Table 1
検出；ELSD蒸発光散乱検出器 (島津製作所，京都，日本)
Detection; ELSD evaporative light scattering detector (Shimadzu, Kyoto, Japan)
結果を図１ａ及び図１ｂに示す。図１ａには得られたクロマトグラムを、図１ｂにはスフィンゴミエリンのピークの部分を拡大したクロマトグラムを示す。スフィンゴミエリンのピークが複数検出されているのは、鶏皮由来スフィンゴミエリンが複数の類似体からなるものであることを示す。 The results are shown in FIGS. 1a and 1b. FIG. 1a shows the obtained chromatogram, and FIG. 1b shows an enlarged chromatogram of the sphingomyelin peak. A plurality of sphingomyelin peaks detected indicates that chicken skin-derived sphingomyelin is composed of a plurality of analogs.
検出された全ピークの面積を１００％としたとき、スフィンゴミエリンを示すピークが占める面積は約９１％であった。従って、当該高純度スフィンゴ脂質含有物は、スフィンゴミエリンを約９１質量％含有することがわかった。なお、他の主要なピークとしては、セレブロシド（グルコシルセラミド）が約３．３％、遊離セラミドが約１．４％であり、スフィンゴ脂質が総量として９６％を占めた。 When the area of all detected peaks was 100%, the area occupied by the peak showing sphingomyelin was about 91%. Therefore, it was found that the high-purity sphingolipid-containing material contains about 91% by mass of sphingomyelin. As other major peaks, cerebroside (glucosylceramide) was about 3.3%, free ceramide was about 1.4%, and sphingolipid accounted for 96% in total.
実施例２：鶏皮由来高純度スフィンゴミエリン含有物の抗高脂血症作用の検討
実施例１で得た鶏皮由来高純度スフィンゴミエリン含有物（以下「鶏皮高ＳＭ含有物」と表記することがある）の抗高脂血症作用を検討するため、以下の実験を行った。 Example 2: Examination of antihyperlipidemic action of chicken skin-derived high-purity sphingomyelin-containing material Chicken skin-derived high-purity sphingomyelin-containing material obtained in Example 1 (hereinafter referred to as "chicken skin-high SM-containing material") The following experiment was conducted to investigate the antihyperlipidemic effect of
＜試料の調製＞
実験に使用するＺＤＦ（Zucker Diabetic Fatty）ラット（雄）の飼料として、AIN-93Ｍ（米国国立栄養研究所により1993年に発表されたマウス・ラットの栄養研究用標準飼料）を購入した。また、特注により、鶏皮高ＳＭ含有物を０．１質量％含有するAIN-93Ｍ（以下「ＳＭ含有AIN-93Ｍ」と表記することがある）も購入した（いずれもオリエンタル酵母株式会社）。<Preparation of sample>
As a ZDF (Zucker Diabetic Fatty) rat (male) feed used in the experiment, AIN-93M (a standard feed for mouse and rat nutrition research published in 1993 by the National Institute of Nutrition) was purchased. In addition, AIN-93M containing 0.1% by mass of chicken skin high SM content (hereinafter sometimes referred to as “SM-containing AIN-93M”) was also purchased by special order (all are Oriental Yeast Co., Ltd.).
＜抗高脂血症作用の確認実験＞
日本チャールズ・リバー株式会社から７週齢のＺＤＦラット雄（１６匹）を購入し、AIN-93Ｍ及び飲水は自由摂取させ２週間予備飼育した。<Confirmation experiment of antihyperlipidemic effect>
Seven-week-old male ZDF rats (16 rats) were purchased from Japan Charles River Co., Ltd., and AIN-93M and drinking water were freely taken and preliminarily raised for 2 weeks.
その後、平均体重が同等になるように群分けし（被験群：８匹、対照群：８匹）、被験群にはＳＭ含有AIN-93Ｍを、対照群にはAIN-93Ｍを与え、自由飼料摂取下で４週間飼育し、その後麻酔をかけて採血した。なお、採血は腹大動脈から行い、採血前１８時間は絶食とした。 Thereafter, the groups were divided so that the average body weight was equivalent (test group: 8 animals, control group: 8 animals), the test group was given AIN-93M containing SM, the control group was given AIN-93M, and free food The mice were raised for 4 weeks under ingestion, and then anesthetized and blood was collected. Blood was collected from the abdominal aorta and fasted for 18 hours before blood collection.
得られた血液を用いて、血液生化学検査（総コレステロール値、ＬＤＬコレステロール値、ＨＤＬコレステロール値及び赤血球変形能）を行った。当該検査は株式会社シー・アール・シーに依頼した。なお、赤血球変形能は重量式Nickel Mesh Filtration法を用いて測定された（ＲＣＦはred blood cell filterabilityの略であり、Bufferの流れやすさを100%としたときの赤血球の流れやすさを示す）。結果を図２〜図５に示す。 Using the obtained blood, blood biochemical tests (total cholesterol level, LDL cholesterol level, HDL cholesterol level and red blood cell deformability) were performed. The inspection was requested from CRC Corporation. The erythrocyte deformability was measured using the gravimetric Nickel Mesh Filtration method (RCF is an abbreviation for red blood cell filterability and indicates the ease of red blood cell flow when the flowability of buffer is 100%) . The results are shown in FIGS.
総コレステロール値及びＬＤＬコレステロール値は対照群に比べ被験群の方が有意に低かった（図２及び３）。また、いわゆる善玉コレステロールであるＨＤＬコレステロール値は、対照群と被験群との間に差はなかった（図４）。 Total cholesterol levels and LDL cholesterol levels were significantly lower in the test group than in the control group (FIGS. 2 and 3). Moreover, the HDL cholesterol level which is what is called good cholesterol did not have a difference between a control group and a test group (FIG. 4).
また、赤血球変形能は、対照群に比べ被験群の方が高い傾向にあった（図５）。なお、血液の流動性は赤血球変形能に大きく依存し、赤血球変形能力が低下すると血流障害を起こす恐れがあることから、赤血球変形能は高脂血症・動脈硬化症等に大きな影響を与え得る。 In addition, the red blood cell deformability tended to be higher in the test group than in the control group (FIG. 5). In addition, blood fluidity greatly depends on erythrocyte deformability, and if erythrocyte deformability is reduced, blood flow may be impaired, so erythrocyte deformability has a major impact on hyperlipidemia, arteriosclerosis, etc. obtain.
以上のことから、鶏皮高ＳＭ含有物には、抗高脂血症作用があることが確認できた。 From the above, it was confirmed that the chicken skin high SM content has an antihyperlipidemic action.
実施例３：脱油乾燥鶏皮の抗高血糖作用及び抗高脂血症作用の検討１
実施例１で得た脱油乾燥鶏皮の抗高血糖作用を及び抗高脂血症作用検討するため、以下の実験を行った。 Example 3: Examination 1 of antihyperglycemic action and antihyperlipidemic action of deoiled and dried chicken skin
In order to examine the antihyperglycemic action and antihyperlipidemic action of the deoiled and dried chicken skin obtained in Example 1, the following experiment was conducted.
＜試料の調製＞
実験に使用するZuckerラット（雄）の飼料として、固形飼料ＭＦ（オリエンタル酵母株式会社）を購入した。また、特注により、実施例１で得た脱油乾燥鶏皮の粉末を１質量％含有する固形飼料ＭＦ（以下「脱油鶏皮ＭＦ」と表記することがある）も購入した。<Preparation of sample>
Solid feed MF (Oriental Yeast Co., Ltd.) was purchased as a feed for Zucker rats (male) used in the experiment. In addition, a solid feed MF containing 1% by mass of the deoiled and dried chicken skin powder obtained in Example 1 (hereinafter sometimes referred to as “deoiled chicken skin MF”) was also purchased by special order.
＜抗高血糖作用及び抗高脂血症作用の確認実験＞
日本チャールズ・リバー株式会社から９週齢のZuckerラット雄（１６匹）を購入し、ＭＦを与えて自由飼料飲水摂食下で１週間予備飼育した。<Confirmation experiment of antihyperglycemic action and antihyperlipidemic action>
Nine weeks old male Zucker rats (16 rats) were purchased from Charles River Japan Co., Ltd., MF was given, and they were preliminarily raised for 1 week under free feed drinking.
その後、平均体重が同等になるように群分けし（被験群：８匹、対照群：８匹）、被験群には脱油鶏皮ＭＦを、対照群にはＭＦを与え、自由飼料摂取下で４週間飼育し、その後麻酔をかけて採血した。なお、採血は腹大動脈から行い、採血前１８時間は絶食とした。 Thereafter, the groups were divided so that the average body weights would be equivalent (test group: 8 animals, control group: 8 animals), deoiled chicken skin MF was given to the test group, and MF was given to the control group. The animals were reared for 4 weeks, and then blood was collected under anesthesia. Blood was collected from the abdominal aorta and fasted for 18 hours before blood collection.
得られた血液を用いて、血液生化学検査（ＬＤＬコレステロール値、赤血球変形能、血糖値、クレアチニン値、尿酸値）を行った。当該検査は株式会社シー・アール・シーに依頼した。なお、赤血球変形能は重量式Nickel Mesh Filtration法を用いて測定された（ＲＣＦはred blood cell filterabilityを示す）。結果を図６〜図１０に示す。 Using the obtained blood, blood biochemical tests (LDL cholesterol level, red blood cell deformability, blood glucose level, creatinine level, uric acid level) were performed. The inspection was requested from CRC Corporation. The erythrocyte deformability was measured using gravimetric nickel mesh filtration (RCF indicates red blood cell filterability). The results are shown in FIGS.
ＬＤＬコレステロール値は、対照群に比べ被験群の方が有意に低かった（図６）。さらに、赤血球変形能も、対照群に比べ被験群の方が高い傾向にあった（図７）。 The LDL cholesterol level was significantly lower in the test group than in the control group (FIG. 6). Furthermore, the red blood cell deformability also tended to be higher in the test group than in the control group (FIG. 7).
以上のことから、脱油乾燥鶏皮には、抗高脂血症作用があることが確認できた。 From the above, it was confirmed that deoiled and dried chicken skin has an antihyperlipidemic effect.
また、血糖値は対照群に比べ被験群の方が低い傾向にあった（図８）。さらに、クレアチニン値は対照群に比べ被験群の方が有意に低く（図９）、尿酸値も対照群に比べ被験群の方が低い傾向にあった（図１０）。なお、クレアチニン値及び尿酸値は腎機能の指標であるが、糖尿病患者は合併症として腎機能低下（糖尿病性腎症）を起こしやすく、糖尿病の進行度合いの指標ともできる。どちらも糖尿病の進行に伴い高値になり得るからである。 The blood glucose level tended to be lower in the test group than in the control group (FIG. 8). Furthermore, the creatinine value was significantly lower in the test group than in the control group (FIG. 9), and the uric acid value tended to be lower in the test group than in the control group (FIG. 10). The creatinine level and uric acid level are indicators of renal function, but diabetic patients are likely to suffer from decreased renal function (diabetic nephropathy) as a complication and can also be used as an indicator of the degree of progression of diabetes. This is because both can become high as diabetes progresses.
以上のことから、脱油乾燥鶏皮には、抗高血糖作用があり、糖尿病の改善に好ましく使用できることが確認できた。 From the above, it was confirmed that deoiled and dried chicken skin has an anti-hyperglycemic action and can be preferably used to improve diabetes.
実施例４：脱油乾燥鶏皮の抗高血糖作用及び抗高脂血症作用の検討２
実施例１で得た脱油鶏皮（乾燥前のもの）の抗高血糖作用を及び抗高脂血症作用検討するため、以下の試験を行った。 Example 4: Examination of antihyperglycemic action and antihyperlipidemic action of deoiled and dried
In order to examine the antihyperglycemic action and antihyperlipidemic action of the deoiled chicken skin obtained in Example 1 (before drying), the following tests were conducted.
＜試料の調製＞
１個あたりスフィンゴミエリン５ｍｇ相当を含む脱油鶏皮を含有する、鶏肉ミートボール（以下「ＳＭミートボール」と表記することがある）を作製した。また、対照食品として、グルテンを主成分としたスフィンゴミエリンをほとんど含まない疑似ミートボール（以下「対照ミートボール」と表記することがある）を作成した。なお、いずれのミートボールも重量は約１４ｇであった。<Preparation of sample>
A chicken meatball (hereinafter sometimes referred to as “SM meatball”) containing deoiled chicken skin containing 5 mg of sphingomyelin per piece was produced. In addition, as a control food, a pseudo meatball (hereinafter sometimes referred to as “control meatball”) containing almost no sphingomyelin mainly composed of gluten was prepared. Each meatball weighed about 14 g.
＜抗高脂血症作用の確認試験＞
成人糖尿病患者（トリグリセリド値１５０ｍｇ／ｄＬ以上）１２人を対照に、二重盲検並行群間比較試験を行った。試験開始前には４週間の前観察期間を設けた。<Confirmation test of antihyperlipidemic effect>
A double-blind parallel group comparison test was conducted with 12 adult diabetic patients (triglyceride value of 150 mg / dL or more) as controls. Before the start of the test, a 4-week pre-observation period was provided.
被験者を被験食品群（４人）と対照食品群（８人）とに割り付け、一日２個のミートボールを通常の食事とともに継続して４週間摂取させた。被験食品群にはＳＭミートボールを、対照食品群には対照ミートボールを摂取させた。 Subjects were assigned to the test food group (4 people) and the control food group (8 people), and two meatballs were taken daily with a normal meal for 4 weeks. The test food group received SM meatballs, and the control food group received control meatballs.
摂取期間（４週間）前及び終了後に各人の総コレステロール値及びＬＤＬコレステロール値を測定し、平均値を算出した。さらに、摂取期間前平均値と摂取期間終了後平均値の差を算出して変化量とした。結果を表２に示す。 The total cholesterol level and LDL cholesterol level of each person were measured before and after the intake period (4 weeks), and the average value was calculated. Further, the difference between the average value before the intake period and the average value after the intake period was calculated as the amount of change. The results are shown in Table 2.
総コレステロール値・ＬＤＬコレステロール値のどちらにおいても、被験食品群では摂取期間前に比べて摂取期間終了後の値が低下した。一方、総コレステロール値およびＬＤＬコレステロール値のどちらにおいても、対照食品群では摂取期間前に比べて摂取期間終了後の値が増加した。 In both the total cholesterol level and LDL cholesterol level, the value after the end of the intake period was lower in the test food group than before the intake period. On the other hand, both the total cholesterol level and the LDL cholesterol level increased in the control food group after the intake period compared to before the intake period.
さらに、被験食品群での総コレステロール値の変化量と、対照食品群での総コレステロール値の変化量を比べると、有意な差が見られた。ＬＤＬコレステロール値の変化量でも同様であった。 Furthermore, when the amount of change in the total cholesterol value in the test food group was compared with the amount of change in the total cholesterol value in the control food group, a significant difference was observed. The same was true for the amount of change in LDL cholesterol level.
＜抗高血糖作用の確認試験＞
成人糖尿病患者（ＨｂＡ１ｃ値が５．８％〜８．０％）３１人を対照に、二重盲検並行群間比較試験を行った。試験開始前には４週間の前観察期間を設けた。なお、ヘモグロビンAのβ鎖のN末端にグルコースが結合したものをＨｂＡ１ｃと呼び、過去1〜２ケ月の平均血糖値を反映する。正常範囲（基準範囲）は4.3％から5.8％（平均5％）程度である。<Confirmation test of antihyperglycemic action>
A double-blind parallel group comparison study was performed on 31 adult diabetic patients (HbA1c values of 5.8% to 8.0%). Before the start of the test, a 4-week pre-observation period was provided. In addition, the thing which glucose couple | bonded with the N terminal of the beta chain of hemoglobin A is called HbA1c, and the average blood glucose level of the past 1-2 months is reflected. The normal range (reference range) is about 4.3% to 5.8% (average 5%).
被験者を被験食品群（１６人）と対照食品群（１５人）とに割り付け、一日２個のミートボールを通常の食事とともに継続して４週間摂取させた。被験食品群にはＳＭミートボールを、対照食品群には対照ミートボールを摂取させた。 Subjects were assigned to a test food group (16 people) and a control food group (15 people), and two meatballs were taken daily with a normal meal for 4 weeks. The test food group received SM meatballs, and the control food group received control meatballs.
摂取期間（４週間）前及び終了後に各人のグリコアルブミン値（％）を測定し、平均値を算出した。さらに、摂取期間前平均値と摂取期間終了後平均値の差を算出して変化量とした。結果を表３に示す。なお、グリコアルブミンはアルブミンとブドウ糖が結合したものであり、過去1〜２週間の平均血糖値を反映する。アルブミンが糖と接触した時間、糖の濃度に比例してその比率が増加するため、糖尿病における血糖値の指標として用いられる。 Each person's glycoalbumin value (%) was measured before and after the intake period (4 weeks) and the average value was calculated. Further, the difference between the average value before the intake period and the average value after the intake period was calculated as the amount of change. The results are shown in Table 3. Glycoalbumin is a combination of albumin and glucose and reflects the average blood glucose level over the past 1-2 weeks. Since the ratio of albumin contact with sugar increases in proportion to the sugar concentration, it is used as an indicator of blood glucose level in diabetes.
被験食品群では摂取期間前に比べて摂取期間終了後グリコアルブミン値が低下したが、対照食品群では摂取期間前に比べて摂取期間終了後の値が増加した。さらに、被験食品群でのグリコアルブミン値変化量と、対照食品群でのグリコアルブミン値変化量を比べると、有意な差が見られた。 In the test food group, the glycoalbumin value decreased after the intake period compared to before the intake period, whereas in the control food group, the value after the intake period increased compared to before the intake period. Furthermore, when the amount of change in glycoalbumin value in the test food group was compared with the amount of change in glycoalbumin value in the control food group, a significant difference was observed.
以上の結果から、脱油鶏皮入り鶏肉ミートボールに抗高血糖作用及び抗高脂血症作用があることが確認できた。 From the above results, it was confirmed that chicken meatballs with deoiled chicken skin had antihyperglycemic action and antihyperlipidemic action.
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