JP2017171594A - Calcium absorption promoter - Google Patents
Calcium absorption promoter Download PDFInfo
- Publication number
- JP2017171594A JP2017171594A JP2016057637A JP2016057637A JP2017171594A JP 2017171594 A JP2017171594 A JP 2017171594A JP 2016057637 A JP2016057637 A JP 2016057637A JP 2016057637 A JP2016057637 A JP 2016057637A JP 2017171594 A JP2017171594 A JP 2017171594A
- Authority
- JP
- Japan
- Prior art keywords
- calcium absorption
- present
- galactose
- hyuga
- processed product
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Granted
Links
- 239000011575 calcium Substances 0.000 title claims abstract description 66
- OYPRJOBELJOOCE-UHFFFAOYSA-N Calcium Chemical compound [Ca] OYPRJOBELJOOCE-UHFFFAOYSA-N 0.000 title claims abstract description 61
- 229910052791 calcium Inorganic materials 0.000 title claims abstract description 61
- 229940124532 absorption promoter Drugs 0.000 title claims abstract description 21
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Abstract
Description
本発明は、日向夏みかんの処理物を含むカルシウム吸収促進剤、及び該カルシウム吸収促進剤を含むカルシウム吸収促進用食品又は医薬品等に関する。 The present invention relates to a calcium absorption enhancer containing a processed product of Hyuga Natsumikan, and a food or medicine for promoting calcium absorption containing the calcium absorption enhancer.
骨粗鬆症とは、骨塩量の減少によって骨微細構造の破綻を来たし骨強度が低下し骨折に対するリスクが高まる全身性疾患である。今後高齢社会を迎えるに当たり、この疾患に対する予防、治療の重要性がますます高くなるものと考えられる。 Osteoporosis is a systemic disease in which bone microstructure is destroyed due to a decrease in bone mineral content, bone strength is reduced, and the risk for fractures is increased. As we enter an aging society in the future, the importance of prevention and treatment for this disease will increase.
骨粗鬆症の治療薬は、主に骨吸収系を抑制する薬剤、骨形成系を刺激する薬剤、及び腸管からのカルシウム吸収を促進する薬剤の3つに大別される。本発明者らはこれまでに、日向夏みかんの抽出物が骨吸収系を抑制し、かつ骨形成系を刺激することによって骨粗鬆症の有効な治療薬になり得ることを報告している(特許文献1)。これに加えて、カルシウム吸収を促進する薬剤を見出すことができれば、異なる作用機構に基づいてより効果的に骨粗鬆症を治療することが可能になると期待される。 The drugs for treating osteoporosis are roughly classified into three types: drugs that suppress the bone resorption system, drugs that stimulate the osteogenic system, and drugs that promote calcium absorption from the intestinal tract. The present inventors have previously reported that the extract of Hyuga Natsumikan can be an effective therapeutic agent for osteoporosis by suppressing the bone resorption system and stimulating the bone formation system (Patent Document 1). ). In addition, if a drug that promotes calcium absorption can be found, it is expected that osteoporosis can be more effectively treated based on different mechanisms of action.
本発明は、新規なカルシウム吸収促進剤を提供することを目的とする。 An object of this invention is to provide a novel calcium absorption promoter.
本発明者は、日向夏みかんの処理物がカルシウム吸収促進効果を有することを見出し、本願発明を完成させた。 The present inventor has found that the processed product of Hyuga Natsumikan has a calcium absorption promoting effect, and has completed the present invention.
したがって、本発明は以下の態様を包含する。
(1)日向夏みかんの処理物を含む、カルシウム吸収促進剤。
(2)日向夏みかんの処理物が、日向夏みかんの抽出物である、(1)に記載のカルシウム吸収促進剤。
(3)日向夏みかんの抽出物が、分子量50,000〜100,000のアラビノガラクタンを含む、(2)に記載のカルシウム吸収促進剤。
(4)アラビノガラクタンが、
β1,3結合したガラクトースを主鎖とし、主鎖のガラクトースの6位から分岐した側鎖を有し、側鎖が1,6結合したβガラクトース、及び1,5結合したαアラビノースを含む、
(3)に記載のカルシウム吸収促進剤。
(5)(1)〜(4)のいずれかに記載のカルシウム吸収促進剤を含む、カルシウム吸収促進用食品組成物又は医薬品。
(6)(1)〜(4)のいずれかに記載のカルシウム吸収促進剤を添加することを含む、カルシウム吸収促進用食品組成物又は医薬品の製造方法。
Accordingly, the present invention includes the following aspects.
(1) A calcium absorption promoter containing a processed product of Hyuga Natsumikan.
(2) The calcium absorption enhancer according to (1), wherein the processed product of Hyuga summer mandarin is an extract of Hyuga summer mandarin.
(3) The calcium absorption enhancer according to (2), wherein the extract of Hinata Natsumikan contains arabinogalactan having a molecular weight of 50,000 to 100,000.
(4) The arabinogalactan is
β1,3-linked galactose as the main chain, including a side chain branched from the 6-position of the main chain galactose, including 1,6-linked β-galactose and 1,5-linked α-arabinose,
The calcium absorption promoter according to (3).
(5) A food composition for promoting calcium absorption or a pharmaceutical comprising the calcium absorption promoter according to any one of (1) to (4).
(6) A method for producing a calcium absorption-promoting food composition or pharmaceutical comprising adding the calcium absorption promoter according to any one of (1) to (4).
本発明により、カルシウム吸収促進効果を有する新たな剤、食品、及び医薬品等が提供される。 According to the present invention, a new agent, food, medicine and the like having a calcium absorption promoting effect are provided.
1.カルシウム吸収促進剤
一態様において、本発明は、日向夏みかんの処理物を含む、カルシウム吸収促進剤に関する。日向夏みかん(本明細書では「日向夏」とも記載する)は宮崎県特産の柑橘類で、果肉の部分だけではなく果皮の一部分と果肉を共に食する極めてユニークな果物である。
1. Calcium absorption enhancer In one aspect, the present invention relates to a calcium absorption enhancer comprising a processed product of Hyuga Natsumikan. Hyuga Natsukan (also referred to herein as “Hinata Natsu”) is a citrus fruit produced in Miyazaki Prefecture, and is a very unique fruit that eats not only the flesh part but also part of the skin and the flesh.
本明細書において、日向夏みかんの「処理物」には、根、茎、葉、花、及び果実等の日向夏みかんの植物体の何れかの部分に由来する全てのものが包含されるが、好ましくは果実の部分に由来するものである。果実は主に果皮と果肉とに分けられるがどちらも好適に使用され、例えば日向夏みかんを搾汁した後の搾汁残渣が好ましく使用される。これらの植物体の各部は生のまま使用することもできる。生の状態のものもまた本発明における「処理物」に包含される。また、上記の植物体の各部分を更に半乾燥又は乾燥させて使用することもできる。半乾燥又は乾燥は通常の方法で行うことができ、例えば天日により乾燥させる方法や乾燥機により乾燥させる方法により行うことができる。また、植物体の各部又はその半乾燥物若しくは乾燥物は、そのままの形態で使用されても良いが、好適には適当な大きさに粉砕された状態で使用される。 In the present specification, the "processed product" of Hyuga summer mandarin includes all those derived from any part of Hyuga summer mandarin plants such as roots, stems, leaves, flowers and fruits, but preferably Is derived from the fruit part. The fruits are mainly divided into pericarp and flesh, both of which are preferably used. For example, the squeezed residue after squeezing Hinata summer oranges is preferably used. Each part of these plants can also be used raw. Those in the raw state are also included in the “processed product” in the present invention. Moreover, each part of said plant body can be further semi-dried or dried for use. Semi-drying or drying can be performed by a usual method, for example, by a method of drying by the sun or a method of drying by a dryer. In addition, each part of the plant body or its semi-dried product or dried product may be used as it is, but is preferably used in a state of being pulverized to an appropriate size.
本発明の処理物としては、日向夏みかんの抽出物もまた好適に使用される。抽出物としては、上記処理物を抽出溶媒により抽出した抽出液、抽出液を希釈したもの、抽出液を濃縮したもの、抽出液を乾燥させたもの、又はこれらを粗精製したものが包含される。 As the treated product of the present invention, an extract of Hyuga Natsumikan is also preferably used. Examples of the extract include an extract obtained by extracting the treated product with an extraction solvent, a solution obtained by diluting the extract, a solution obtained by concentrating the extract, a product obtained by drying the extract, or a product obtained by roughly purifying these. .
抽出に用いる溶媒は、水、親水性有機溶媒、疎水性有機溶媒、又はこれらの2種以上からなる混合物のいずれであってもよく、好ましくは水である。水の種類は特に限定されず、純水及び水道水等であってよい。また水は精製、殺菌、滅菌、ろ過、浸透圧調整、及び緩衝化等の通常の処理が施されていてよく、例えば、生理的食塩水、リン酸緩衝液等の緩衝液も抽出溶媒として使用可能である。親水性有機溶媒としては、メチルアルコール、エチルアルコール、ブチルアルコール、グリセリン、プロピレングリコール、1,3-ブチレングリコール等のアルコール、アセトン、テトラヒドロフラン、アセトニトリル、1,4-ジオキサン、ピリジン、ジメチルスルホキシド、N,N−ジメチルホルムアミド、及び酢酸等の公知の親水性有機溶媒が挙げられる。疎水性有機溶媒としては、ヘキサン、シクロヘキサン、四塩化炭素、クロロホルム、ジクロロメタン、1,2−ジクロロエタン、ジエチルエーテル、酢酸エチル、ベンゼン、トルエン、n-ヘキサン、及びイソオクタン等の公知の疎水性有機溶媒が挙げられる。また、超臨界流体を用いた抽出も可能である。 The solvent used for extraction may be any of water, a hydrophilic organic solvent, a hydrophobic organic solvent, or a mixture of two or more of these, preferably water. The kind of water is not particularly limited, and may be pure water or tap water. The water may be subjected to usual treatments such as purification, sterilization, sterilization, filtration, osmotic pressure adjustment, and buffering. For example, a buffer solution such as physiological saline or phosphate buffer is also used as an extraction solvent. Is possible. Examples of hydrophilic organic solvents include alcohols such as methyl alcohol, ethyl alcohol, butyl alcohol, glycerin, propylene glycol, and 1,3-butylene glycol, acetone, tetrahydrofuran, acetonitrile, 1,4-dioxane, pyridine, dimethyl sulfoxide, N, Examples thereof include known hydrophilic organic solvents such as N-dimethylformamide and acetic acid. Examples of the hydrophobic organic solvent include known hydrophobic organic solvents such as hexane, cyclohexane, carbon tetrachloride, chloroform, dichloromethane, 1,2-dichloroethane, diethyl ether, ethyl acetate, benzene, toluene, n-hexane, and isooctane. Can be mentioned. Also, extraction using a supercritical fluid is possible.
抽出操作は特に限定せず、常法に従って行えばよい。抽出効率を向上させるため、加熱、攪拌、及び振とう等を併用することもできる。また、抽出効率を向上させる目的で、抽出前に予め日向夏みかん試料に適当な処理を施すこともできる。このような処理としては、例えば粉砕や脱脂が挙げられる。抽出中、又は抽出後に、抽出物をペクチナーゼ、プロテアーゼ、リパーゼ、アミラーゼ等の酵素により処理して、目的物質以外の成分を除去することもできる。 The extraction operation is not particularly limited, and may be performed according to a conventional method. In order to improve extraction efficiency, heating, stirring, shaking, etc. can also be used together. In addition, for the purpose of improving the extraction efficiency, it is possible to apply a suitable treatment to the Hinata Natsumi sample in advance before extraction. Examples of such treatment include pulverization and degreasing. During or after extraction, the extract can be treated with an enzyme such as pectinase, protease, lipase, amylase, etc. to remove components other than the target substance.
一実施形態において、本発明の日向夏みかんの処理物は、アラビノガラクタンを含む。アラビノガラクタンは、本発明の日向夏みかんの処理物における有効成分であってよい。本明細書において、「アラビノガラクタン」とはアラビノース及びガラクトースをその主成分とする多糖を指す。本発明のアラビノガラクタンは、β1,3結合したガラクトースを主鎖とし、主鎖のガラクトースの6位から分岐した側鎖を有する。本明細書において、「主鎖」とは糖鎖分子中で相対的に最も長い鎖を指し、「側鎖」とは主鎖から枝分かれしている相対的に短い鎖を指す。 In one embodiment, the processed Hyuga summer tangerine of the present invention contains arabinogalactan. The arabinogalactan may be an active ingredient in the processed product of Hyuga summer tangerine of the present invention. In this specification, “arabinogalactan” refers to a polysaccharide mainly composed of arabinose and galactose. The arabinogalactan of the present invention has a β1,3-linked galactose as a main chain and a side chain branched from the 6-position of the main chain galactose. In this specification, “main chain” refers to the relatively longest chain in the sugar chain molecule, and “side chain” refers to a relatively short chain branched from the main chain.
本発明のアラビノガラクタンは、好ましくは側鎖として1,6結合したβガラクトース、及び1,5結合したαアラビノースを含み得る。さらに好ましくは、側鎖の上記1,6結合はβ1,6結合であり、上記1,5結合はα1,5結合である。 The arabinogalactan of the present invention may preferably comprise 1,6-linked β-galactose and 1,5-linked α-arabinose as side chains. More preferably, the 1,6 bond in the side chain is a β1,6 bond, and the 1,5 bond is an α1,5 bond.
本明細書において、側鎖が1,6結合したβガラクトースを含むとは、側鎖が6)-βGal-(1→の構造を含むことを意図し、側鎖中にこの構造が単糖単位で存在してもよいし、二糖単位以上で存在してもよい。側鎖の6)-βGal-(1→は、β1,6結合により直接主鎖のガラクトースの6位に結合していてもよいし、アラビノース等の他の糖を介して主鎖に結合してもよい。また、ガラクトースは、側鎖中の他の糖と結合していてもよい。例えば、6)-βGal-(1→は、側鎖において、ガラクトースとβ1→6結合を介して(βGal-(1→6)-Gal)、又はアラビノースとβ1→5結合を介して(βGal-(1→5)-Ara)若しくはα1→6結合を介して(αAra-(1→6)-Gal)結合していてもよい。好ましくは、6)-βGal-(1→は、β1→6結合を介して側鎖中の他のガラクトースと結合している。 In this specification, β-galactose containing 1,6-linked side chains means that the side chain contains the structure 6) -βGal- (1 →), and this structure is a monosaccharide unit in the side chain. The side chain 6) -βGal- (1 → is directly linked to the 6-position of the main chain galactose via a β1,6 bond. Alternatively, it may be bonded to the main chain via another sugar such as arabinose, and galactose may be bonded to another sugar in the side chain, for example, 6) -βGal- ( 1 → is in the side chain via galactose and β1 → 6 bond (βGal- (1 → 6) -Gal) or arabinose and β1 → 5 bond (βGal- (1 → 5) -Ara) Alternatively, it may be linked via an α1 → 6 bond (αAra- (1 → 6) -Gal), preferably 6) -βGal- (1 → is a β1 → 6 bond in the side chain. Combined with other galactose.
同様に、本明細書において、側鎖が1,5結合したαアラビノースを含むとは、側鎖が→5)-αAra-(1→の構造を含むことを意図し、側鎖中にこの構造が単糖単位で存在してもよいし、二糖単位以上で存在してもよい。→5)-αAra-(1→は、α1,6結合により直接主鎖のガラクトースの6位に結合していてもよいし、ガラクトース等の他の糖を介して主鎖に結合してもよい。また、アラビノースは、側鎖中の他の糖と結合していてもよい。例えば、→5)-αAra-(1→は、側鎖において、ガラクトースとβ1→5結合を介して(βGal-(1→5)-Ara)若しくはα1→6結合を介して(αAra-(1→6)-Gal)、又はアラビノースとα1→5結合を介して(αAra-(1→5)-Ara)結合していてもよい。好ましくは、5)-αAra-(1→は、α1→5結合を介して側鎖中の他のアラビノースと結合する。 Similarly, in the present specification, the side chain includes α-arabinose with 1,5-linked side chain is intended to include the structure of → 5) -αAra- (1 →), and this structure is included in the side chain. May be present as a monosaccharide unit or may be present as a disaccharide unit or more. → 5) -αAra- (1 → is directly linked to the 6-position of the main chain galactose through an α1,6 bond. It may be bonded to the main chain via other sugars such as galactose, etc. Moreover, arabinose may be bonded to other sugars in the side chain. αAra- (1 → is in the side chain via galactose and β1 → 5 bond (βGal- (1 → 5) -Ara) or α1 → 6 bond (αAra- (1 → 6) -Gal) Or may be bound to arabinose via an α1 → 5 bond (αAra- (1 → 5) -Ara), preferably 5) -αAra- (1 → is connected via an α1 → 5 bond. Binds to other arabinose in the chain.
また、本発明のアラビノガラクタンは、好ましくはその側鎖の末端にβGal (1→及び/又はαAra(1→を有し得る。 The arabinogalactan of the present invention may preferably have βGal (1 → and / or αAra (1 →) at the end of its side chain.
本発明のアラビノガラクタンは、好ましくは側鎖中に1,3結合したガラクトース、すなわち3)-Gal-(1→を含まない。また、本発明のアラビノガラクタンは、好ましくは側鎖中に1,3結合したアラビノース、すなわち3)-Ara-(1→を含まない。 The arabinogalactan of the present invention preferably does not contain 1,3-linked galactose in the side chain, that is, 3) -Gal- (1 →. Also, the arabinogalactan of the present invention preferably has no side chain. Does not include 1,3-linked arabinose, ie 3) -Ara- (1 →.
本発明のアラビノガラクタンにおいて、個々の側鎖に含まれる糖単位の数は限定されず、単糖単位であっても二糖単位以上であってもよい。また、個々の側鎖は、ガラクトース単位又はアラビノース単位のいずれか一方からなってもよく、あるいは一つの側鎖中にこれらの糖単位が混在していてもよい。好ましくは、側鎖中のガラクトースはいずれもβガラクトースであり、アラビノースはいずれもαアラビノースである。 In the arabinogalactan of the present invention, the number of sugar units contained in each side chain is not limited and may be a monosaccharide unit or a disaccharide unit or more. Each side chain may be composed of either a galactose unit or an arabinose unit, or these sugar units may be mixed in one side chain. Preferably, all galactose in the side chain is β-galactose and all arabinose is α-arabinose.
本発明のアラビノガラクタンにおけるガラクトースとアラビノースの比は特に限定しないが、例えば、ガラクトースのモルを1とした場合のアラビノースのモル比は、0.1以上、0.2以上、0.3以上、0.4以上、0.45以上、又は0.5以上、また1.0以下、0.9以下、0.8以下、0.7以下、0.6以下、又は0.55以下であってよい。 The ratio of galactose and arabinose in the arabinogalactan of the present invention is not particularly limited, for example, the molar ratio of arabinose when the mole of galactose is 1, 0.1 or more, 0.2 or more, 0.3 or more, 0.4 or more, 0.45 or more, Alternatively, it may be 0.5 or more, 1.0 or less, 0.9 or less, 0.8 or less, 0.7 or less, 0.6 or less, or 0.55 or less.
本発明のアラビノガラクタンの側鎖は、グルコース、ラムノース、フコース、及びグルクロン酸等の、ガラクトース及びアラビノース以外の糖を、例えば側鎖に少量有してもよい。この場合、ガラクトースのモルを1とした場合のガラクトース及びアラビノース以外の糖のモル比は0.5以下、0.4以下、0.3以下、0.2以下、好ましくは0.15以下、0.1以下、0.05以下、又は0.01以下であってよい。 The side chain of the arabinogalactan of the present invention may have a small amount of sugars other than galactose and arabinose such as glucose, rhamnose, fucose, and glucuronic acid in the side chain. In this case, the molar ratio of saccharides other than galactose and arabinose when the galactose mole is 1, is 0.5 or less, 0.4 or less, 0.3 or less, 0.2 or less, preferably 0.15 or less, 0.1 or less, 0.05 or less, or 0.01 or less. It's okay.
本発明のアラビノガラクタンの分子量は、例えば20,000以上、30,000以上、40,000以上、50,000以上、60,000以上、好ましくは65,000以上、66,000以上、67,000以上、又は68,000以上であってよく、また120,000以下、110,000以下、100,000以下、90,000以下、80,000以下、好ましくは75,000以下、74,000以下、73,000以下、又は72,000以下であってよい。 The molecular weight of the arabinogalactan of the present invention may be, for example, 20,000 or more, 30,000 or more, 40,000 or more, 50,000 or more, 60,000 or more, preferably 65,000 or more, 66,000 or more, 67,000 or more, or 68,000 or more, and 120,000 or less, 110,000 or more. Below, it may be 100,000 or less, 90,000 or less, 80,000 or less, preferably 75,000 or less, 74,000 or less, 73,000 or less, or 72,000 or less.
アラビノガラクタン等の多糖の構造の分析は、当業者に公知の方法、例えばメチル化分析及び/又はNMR等により行うことができる。同様に、多糖の構成成分、及び分子量の分析も、当業者に公知の方法、例えばそれぞれHPLC及びサイズ排除クロマトグラフィー等によって行うことができる。 Analysis of the structure of a polysaccharide such as arabinogalactan can be performed by methods known to those skilled in the art, for example, methylation analysis and / or NMR. Similarly, analysis of polysaccharide constituents and molecular weight can be performed by methods known to those skilled in the art, such as HPLC and size exclusion chromatography, respectively.
本発明の処理物又はカルシウム吸収促進剤は、腸管から体内へのカルシウムの吸収を促すという作用を有する。本発明者は、日向夏みかんの処理物が骨代謝改善効果を有することを以前に見出している。しかし、日向夏みかんの処理物が骨代謝改善効果に加えてカルシウム吸収促進作用を有することは一切示唆されていない。本発明の日向夏みかんの処理物のカルシウム吸収促進作用を利用することで、骨代謝改善作用とは異なる作用機構に基づいて骨粗鬆症を予防及び/又は治療することが可能となる。また、カルシウム吸収促進作用は、骨粗鬆症の予防及び/又は治療に加えて、例えばカルシウム含有食品の栄養価を向上させるためにも利用することができる。ある物質がカルシウム吸収の促進作用を有するか否かは、当業者に知られる方法、例えば反転小腸を作成し、カルシウムを含む外液に物質を添加して、外液から反転小腸内部へのカルシウムの取り込みが増加するか否かを確認することによって、簡単に確認できる。 The processed product or calcium absorption enhancer of the present invention has an action of promoting absorption of calcium from the intestinal tract into the body. The present inventor has previously found that the processed product of Hinata Natsumi has an effect of improving bone metabolism. However, there is no suggestion that the processed product of Hinata Natsumi has a calcium absorption promoting effect in addition to the bone metabolism improving effect. By utilizing the calcium absorption promoting action of the processed product of Hyuga Natsumikan of the present invention, it becomes possible to prevent and / or treat osteoporosis based on an action mechanism different from the bone metabolism improving action. In addition to preventing and / or treating osteoporosis, the calcium absorption promoting action can be used to improve the nutritional value of, for example, calcium-containing foods. Whether or not a substance has an effect of promoting calcium absorption is determined by a method known to those skilled in the art, for example, by creating an inverted small intestine, adding the substance to an external liquid containing calcium, and transferring calcium from the external liquid into the inverted small intestine. This can be easily confirmed by confirming whether or not the increase in uptake is increased.
本発明のカルシウム吸収促進剤は、本発明の日向夏みかんの処理物からなってもよいし、本発明の日向夏みかんの処理物以外に他の成分、例えば賦形剤、結合剤、崩壊剤、界面活性剤、滑沢剤、流動性促進剤、矯味剤、着色剤、及び香料等を含んでもよい。 The calcium absorption promoter of the present invention may consist of the processed product of Hyuga Natsumikan of the present invention, and other components besides the processed product of Hyuga Natsumikan of the present invention, such as excipients, binders, disintegrants, interfaces. Activators, lubricants, fluidity promoters, flavoring agents, colorants, and fragrances may be included.
本発明のカルシウム吸収促進剤は常法により製剤化され得る。投与形態は特に制限されず、必要に応じ適宜選択されるが、一般には錠剤、カプセル剤、顆粒剤、細粒剤、散剤、液剤、シロップ剤、懸濁剤、乳剤、及びエリキシル剤等の経口剤、又は注射剤、点滴剤、坐剤、吸入剤、経皮吸収剤、経粘膜吸収剤、貼付剤、及び軟膏剤等の非経口剤として投与され得る。 The calcium absorption enhancer of the present invention can be formulated by a conventional method. The dosage form is not particularly limited and is appropriately selected as necessary. Generally, oral forms such as tablets, capsules, granules, fine granules, powders, solutions, syrups, suspensions, emulsions, and elixirs are used. Or parenteral preparations such as injections, drops, suppositories, inhalants, transdermal absorbents, transmucosal absorbents, patches, ointments and the like.
経口剤は、例えばデンプン、乳糖、白糖、マンニット、カルボキシメチルセルロース、コーンスターチ、及び無機塩類等の賦形剤を用いて常法に従って製造される。 The oral preparation is produced according to a conventional method using excipients such as starch, lactose, sucrose, mannitol, carboxymethylcellulose, corn starch, and inorganic salts.
この種の製剤には、適宜前記賦形剤の他に、結合剤、崩壊剤、界面活性剤、滑沢剤、流動性促進剤、矯味剤、着色剤、及び香料等を使用することができる。 In addition to the above-mentioned excipients, binders, disintegrating agents, surfactants, lubricants, fluidity promoters, taste-masking agents, coloring agents, and fragrances can be appropriately used for this type of preparation. .
結合剤の具体例としては、結晶セルロース、結晶セルロース・カルメロースナトリウム、メチルセルロース、ヒドロキシプロピルセルロース、低置換度ヒドロキシプロピルセルロース、ヒドロキシプロピルメチルセルロース、ヒドロキシプロピルメチルセルロースフタレート、ヒドロキシプロピルメチルセルロースアセテートサクシネート、カルメロースナトリウム、エチルセルロース、カルボキシメチルエチルセルロース、ヒドロキシエチルセルロース、コムギデンプン、コメデンプン、トウモロコシデンプン、バレイショデンプン、デキストリン、アルファー化デンプン、部分アルファー化デンプン、ヒドロキシプロピルスターチ、プルラン、ポリビニルピロリドン、アミノアルキルメタクリレートコポリマーE、アミノアルキルメタクリレートコポリマーRS、メタクリル酸コポリマーL、メタクリル酸コポリマー、ポリビニルアセタールジエチルアミノアセテート、ポリビニルアルコール、アラビアゴム、アラビアゴム末、寒天、ゼラチン、白色セラック、トラガント、精製白糖、及びマクロゴールが挙げられる。 Specific examples of the binder include crystalline cellulose, crystalline cellulose / carmellose sodium, methylcellulose, hydroxypropylcellulose, low-substituted hydroxypropylcellulose, hydroxypropylmethylcellulose, hydroxypropylmethylcellulose phthalate, hydroxypropylmethylcellulose acetate succinate, carmellose sodium , Ethylcellulose, carboxymethylethylcellulose, hydroxyethylcellulose, wheat starch, rice starch, corn starch, potato starch, dextrin, pregelatinized starch, partially pregelatinized starch, hydroxypropyl starch, pullulan, polyvinylpyrrolidone, aminoalkyl methacrylate copolymer E, aminoalkyl METAKU Rate copolymer RS, methacrylic acid copolymer L, methacrylic acid copolymer, polyvinyl acetal diethylamino acetate, polyvinyl alcohol, gum arabic, gum arabic powder, agar, gelatin, white shellac, tragacanth, purified sucrose, and macrogol.
崩壊剤の具体例としては、結晶セルロース、メチルセルロース、低置換度ヒドロキシプロピルセルロース、カルメロース、カルメロースカルシウム、カルメロースナトリウム、クロスカルメロースナトリウム、コムギデンプン、コメデンプン、トウモロコシデンプン、バレイショデンプン、部分アルファー化デンプン、ヒドロキシプロピルスターチ、カルボキシメチルスターチナトリウム、及びトラガントが挙げられる。 Specific examples of disintegrants include crystalline cellulose, methylcellulose, low-substituted hydroxypropylcellulose, carmellose, carmellose calcium, carmellose sodium, croscarmellose sodium, wheat starch, rice starch, corn starch, potato starch, and partially pregelatinized. Mention is made of starch, hydroxypropyl starch, sodium carboxymethyl starch, and tragacanth.
界面活性剤の具体例としては、大豆レシチン、ショ糖脂肪酸エステル、ステアリン酸ポリオキシル、ポリオキシエチレン硬化ヒマシ油、ポリオキシエチレンポリオキシプロピレングリコール、セスキオレイン酸ソルビタン、トリオレイン酸ソルビタン、モノステアリン酸ソルビタン、モノパルミチン酸ソルビタン、モノラウリン酸ソルビタン、ポリソルベート、モノステアリン酸グリセリン、ラウリル硫酸ナトリウム、及びラウロマクロゴールが挙げられる。 Specific examples of surfactants include soybean lecithin, sucrose fatty acid ester, polyoxyl stearate, polyoxyethylene hydrogenated castor oil, polyoxyethylene polyoxypropylene glycol, sorbitan sesquioleate, sorbitan trioleate, sorbitan monostearate Sorbitan monopalmitate, sorbitan monolaurate, polysorbate, glyceryl monostearate, sodium lauryl sulfate, and lauromacrogol.
滑沢剤の具体例としては、コムギデンプン、コメデンプン、トウモロコシデンプン、ステアリン酸、ステアリン酸カルシウム、ステアリン酸マグネシウム、含水二酸化ケイ素、軽質無水ケイ酸、合成ケイ酸アルミニウム、乾燥水酸化アルミニウムゲル、タルク、メタケイ酸アルミン酸マグネシウム、リン酸水素カルシウム、無水リン酸水素カルシウム、ショ糖脂肪酸エステル、ロウ類、水素添加植物油、及びポリエチレングリコールが挙げられる。 Specific examples of lubricants include wheat starch, rice starch, corn starch, stearic acid, calcium stearate, magnesium stearate, hydrous silicon dioxide, light anhydrous silicic acid, synthetic aluminum silicate, dry aluminum hydroxide gel, talc, Examples include magnesium aluminate metasilicate, calcium hydrogen phosphate, anhydrous calcium hydrogen phosphate, sucrose fatty acid ester, waxes, hydrogenated vegetable oil, and polyethylene glycol.
流動性促進剤の具体例としては、含水二酸化ケイ素、軽質無水ケイ酸、乾燥水酸化アルミニウムゲル、合成ケイ酸アルミニウム、及びケイ酸マグネシウムが挙げられる。 Specific examples of fluidity promoters include hydrous silicon dioxide, light anhydrous silicic acid, dry aluminum hydroxide gel, synthetic aluminum silicate, and magnesium silicate.
また、本発明のカルシウム吸収促進剤は、液剤、シロップ剤、懸濁剤、乳剤、又はエリキシル剤として投与する場合には、矯味矯臭剤及び/又は着色剤を含有してもよい。 In addition, the calcium absorption promoter of the present invention may contain a flavoring agent and / or a coloring agent when administered as a solution, syrup, suspension, emulsion, or elixir.
また、一態様において本発明は、本発明のカルシウム吸収促進剤を被験体に投与することを含む、被験体における骨粗鬆症の予防及び/又は治療方法に関する。 Moreover, in one aspect, the present invention relates to a method for preventing and / or treating osteoporosis in a subject, comprising administering the calcium absorption promoter of the present invention to the subject.
また、一態様において本発明は、骨粗鬆症の予防及び/又は治療における、本発明のカルシウム吸収促進剤の使用に関する。 Moreover, in one aspect, the present invention relates to the use of the calcium absorption promoter of the present invention in the prevention and / or treatment of osteoporosis.
2.カルシウム吸収促進用食品組成物又は医薬品
一態様において、本発明は、本発明のカルシウム吸収促進剤を含む、カルシウム吸収促進用食品組成物又は医薬品に関する。別の態様において、本発明は、本発明のカルシウム吸収促進剤を含む、カルシウム吸収促進用食品組成物又は医薬品に関する。
2. Calcium absorption promoting food composition or pharmaceutical In one aspect, the present invention relates to a calcium absorption promoting food composition or pharmaceutical comprising the calcium absorption promoting agent of the present invention. In another aspect, the present invention relates to a calcium absorption promoting food composition or pharmaceutical comprising the calcium absorption promoter of the present invention.
本発明の食品組成物(単に、「食品」とも記載する)は、常法により調製され得る。例えば、かかる食品の形態としては、通常の「食品」だけでなく、例えば、飴、トローチ等を含む錠剤(タブレット)や糖衣錠の形態、顆粒の形態、粉末飲料、粉末スープ等の粉末の形態、ビスケット等のブロック菓子類の形態、カプセル、ゼリー等の形態、ジャムのようなペーストの形態、チューイングガムのようなガムの形態、茶を含む清涼飲料水、アルコール飲料等の飲料の形態のようにいかなる形態の食品であってもよく、特定保健用食品(例えば、骨粗鬆症予防食品)にもなり得る。本発明のカルシウム吸収促進剤を含む食品には、本発明の所望の効果が損なわれない範囲で、通常、食品原料として用いられる種々の他の成分を配合することができる。他の成分としては例えば水、アルコール類、甘味料、酸味料、着色料、保存剤、香料、賦形剤、安定化剤、pH調整剤、糖類、各種ビタミン類、ミネラル類、抗酸化剤、可溶化剤、結合剤、滑沢剤、懸濁剤、湿潤剤、皮膜形成物質、矯味剤、矯臭剤、界面活性剤、流動性促進剤等が挙げられる。これらの成分は単独で、または組み合わされて使用され得る。同様に、本発明の医薬品は、常法により、例えば上記1でカルシウム吸収促進剤について記載した方法に従って調製され得る。 The food composition of the present invention (also simply referred to as “food”) can be prepared by conventional methods. For example, as the form of such food, not only the usual “food”, but also, for example, tablets (tablets) containing sugarcane, troches, sugar-coated tablets, granules, powdered drinks, powdered soups, etc. Block confectionery such as biscuits, capsules, jelly, etc., jam-like paste, chewing gum-like gum, tea-containing soft drinks, alcoholic beverages, etc. The food may be in the form of a food for specific health use (for example, a food for preventing osteoporosis). The food containing the calcium absorption promoter of the present invention can be blended with various other components that are usually used as food raw materials as long as the desired effects of the present invention are not impaired. Examples of other components include water, alcohols, sweeteners, acidulants, colorants, preservatives, fragrances, excipients, stabilizers, pH adjusters, sugars, various vitamins, minerals, antioxidants, Examples include solubilizers, binders, lubricants, suspending agents, wetting agents, film-forming substances, flavoring agents, flavoring agents, surfactants, and fluidity promoters. These components can be used alone or in combination. Similarly, the medicament of the present invention can be prepared by a conventional method, for example, according to the method described in 1 above for the calcium absorption promoter.
本発明の食品及び医薬品中におけるカルシウム吸収促進剤の含有量は、所望の作用が奏される含有量である限りとくに限定されず、当業者であれば被験体の性別、年齢、体重、身長、及び症状の程度等を考慮して適宜定めることができる。 The content of the calcium absorption promoter in the foods and pharmaceuticals of the present invention is not particularly limited as long as it is a content that exhibits a desired effect, and those skilled in the art will know the sex, age, weight, height, It can be determined as appropriate in consideration of the degree of symptoms and the like.
3.食品組成物又は医薬品の製造方法
一態様において、本発明は、本発明のカルシウム吸収促進剤を添加することを含む、食品組成物又は医薬品の製造方法に関する。食品組成物又は医薬品は、カルシウム吸収促進用のものであってよい。
3. Method for Producing Food Composition or Pharmaceutical In one aspect, the present invention relates to a method for producing a food composition or pharmaceutical, comprising adding the calcium absorption promoter of the present invention. The food composition or medicament may be for promoting calcium absorption.
本発明の食品又は医薬品の製造方法は、本発明のカルシウム吸収促進剤を添加すること以外は、当業者に公知の方法で行うことができる。本発明のカルシウム吸収促進剤の添加は、得られる食品又は医薬品が所望の効果を奏する限り、食品又は医薬品の製造過程中の任意の時点で行うことができる。例えば、本発明のカルシウム吸収促進剤を、製造の初期又は中期段階において他の原料と共に混合してもよいし、製造の最終段階において半製品に添加してもよい。 The method for producing a food or pharmaceutical product of the present invention can be carried out by methods known to those skilled in the art except that the calcium absorption promoter of the present invention is added. The calcium absorption promoter of the present invention can be added at any point during the production process of the food or medicine as long as the obtained food or medicine has the desired effect. For example, the calcium absorption enhancer of the present invention may be mixed with other raw materials at the initial or intermediate stage of production, or may be added to the semi-finished product at the final stage of production.
また、一態様において本発明は、本発明のカルシウム吸収促進剤の食品組成物又は医薬品の製造における使用に関する。 Moreover, in one aspect, the present invention relates to the use of the calcium absorption enhancer of the present invention in the production of a food composition or a pharmaceutical product.
以下、実施例により本発明をさらに具体的に説明するが、本発明の範囲はこれらの実施例に限定されるものではない。 EXAMPLES Hereinafter, the present invention will be described more specifically with reference to examples. However, the scope of the present invention is not limited to these examples.
<実施例1:日向夏処理物の調製>
1)日向夏処理物1及び日向夏処理物2の調製
日向夏搾汁残渣から、日向夏処理物1及び日向夏処理物2を以下の通り調製した。
<Example 1: Preparation of Hyuga Summer Processed Product>
1) Preparation of Hyuga Summer Processed Product 1 and Hyuga Summer Processed Product 2 From Hyuga Summer Juice residue, Hyuga Summer Processed Product 1 and Hyuga Summer Processed Product 2 were prepared as follows.
日向夏をインライン搾汁機(ジョンビーン・テクノロジー社)で搾汁し、搾汁残渣を段ボール箱に回収し、冷凍保管した。続いて、冷凍保管しておいた日向夏搾汁残渣を解凍し、解凍した日向夏搾汁残渣に対して2倍量の60℃温水を加え、15分間撹拌しながら浸漬を行うことで水抽出を行った。続いて、水抽出した日向夏搾汁残渣をチョッパーパルパーにて破砕した後、5mm、1mm、及び0.5mmでの篩別並びにマグネットラップによって異物を除去した。次に、異物を除去した日向夏搾汁残渣破砕物をデカンター搾汁機(三菱化工機)で搾汁(回転数3,900rpm、3,000g)し、遠心分離(流量4〜5m3/h、排出1回/15分)した後に、約8〜9秒間95±1℃で殺菌し、45〜50℃まで冷却を行った。次に、加熱殺菌した溶液に、Aspergillus niger由来のペクチナーゼ(ヤクルト薬品工業)を0.05%w/w添加し、45〜50℃で1時間酵素処理を行い、珪藻土を用いて一次ろ過した後、95±1.5℃に約8〜9秒加温して酵素を失活させ、30℃以下に冷却した。続いて、珪藻土を用いて二次ろ過した後、3μフィルターを用いて異物を除去した。続いて、減圧濃縮後、25℃以下に冷却し、加水によりBxを35.1〜35.5に調整し、80メッシュで異物を除去した。続いて、120±1.5℃で約15秒間殺菌し、30℃以下まで冷却した。続いて、80メッシュ及びマグネットトラップで異物を除去し、フルオープン18L缶に充填して冷凍保管した。 Nuka Hyuga was squeezed with an inline squeezer (John Bean Technology), and the squeezed residue was collected in a cardboard box and stored frozen. Subsequently, the frozen Hyuga summer juice residue that had been frozen was thawed, and twice the amount of 60 ° C hot water was added to the thawed Hinata summer juice residue, followed by immersion for 15 minutes with water extraction. Went. Subsequently, the water-extracted Hyuga summer juice residue was crushed with a chopper pulper, and foreign matters were removed by sieving at 5 mm, 1 mm, and 0.5 mm and magnet wrap. Next, the Hinata summer juice residue crushed material from which foreign matter has been removed is squeezed (rotation speed 3,900 rpm, 3,000 g) with a decanter juicer (Mitsubishi Kako), and centrifuged (flow rate 4-5 m 3 / h, discharged) 1 time / 15 minutes), and then sterilized at 95 ± 1 ° C. for about 8 to 9 seconds and cooled to 45 to 50 ° C. Next, 0.05% w / w of pectinase derived from Aspergillus niger (Yakult Pharmaceutical Co., Ltd.) was added to the heat-sterilized solution, the enzyme treatment was performed at 45-50 ° C. for 1 hour, and primary filtration was performed using diatomaceous earth. The enzyme was inactivated by heating to ± 1.5 ° C. for about 8 to 9 seconds, and cooled to 30 ° C. or lower. Subsequently, after secondary filtration using diatomaceous earth, foreign matters were removed using a 3 μ filter. Subsequently, after concentration under reduced pressure, the mixture was cooled to 25 ° C. or lower, Bx was adjusted to 35.1 to 35.5 by hydration, and foreign matters were removed with 80 mesh. Subsequently, it was sterilized at 120 ± 1.5 ° C. for about 15 seconds and cooled to 30 ° C. or lower. Subsequently, the foreign matter was removed with 80 mesh and a magnet trap, filled into a full-open 18L can and stored frozen.
続いて、得られた日向夏処理物1を乾燥し、得られた粉末の吸湿性を低下させるために等量のデキストリン(松谷化学工業株式会社、兵庫県)と混合して、エキスパウダー(pomace:PO)(日向夏処理物2)を調製した。 Subsequently, the resulting Hyuga summer processed product 1 is dried and mixed with an equivalent amount of dextrin (Matsuya Chemical Co., Ltd., Hyogo Prefecture) to reduce the hygroscopicity of the obtained powder, and the extract powder (pomace : PO) (Hyuga summer processed product 2) was prepared.
2)活性画分1の調製
上記1)で得られた日向夏処理物1を以下の通り活性炭処理した。
まず、上記日向夏処理物1を解凍し、Bx6.8〜7.2程度まで希釈した後、活性炭(大阪ガスケミカル)を1.0%w/w添加し、1時間処理した。続いて、珪藻土を用いて一次ろ過した後、95±1.5℃に約8〜9秒加温した後、25℃以下に冷却した。続いて、珪藻土を用いて二次ろ過した後、3μフィルターを用いて異物を除去した。続いて、減圧濃縮後、25℃以下に冷却し、加水によりBxを35.1〜35.5に調整し、80メッシュで異物を除去した。続いて、80メッシュ及びマグネットトラップで異物を除去し、フルオープン18L缶に充填して冷凍保管した。なお、活性炭処理の前後で、日向夏処理物1中のピークに差がないことを確認している(データ示さず)。
2) Preparation of active fraction 1 The Hyuga summer processed product 1 obtained in 1) above was treated with activated carbon as follows.
First, the above-mentioned Hyuga Summer Processed Product 1 was thawed and diluted to about Bx6.8 to 7.2, and then 1.0% w / w of activated carbon (Osaka Gas Chemical) was added and treated for 1 hour. Subsequently, after primary filtration using diatomaceous earth, the mixture was heated to 95 ± 1.5 ° C. for about 8 to 9 seconds, and then cooled to 25 ° C. or lower. Subsequently, after secondary filtration using diatomaceous earth, foreign matters were removed using a 3 μ filter. Subsequently, after concentration under reduced pressure, the mixture was cooled to 25 ° C. or lower, Bx was adjusted to 35.1 to 35.5 by hydration, and foreign matters were removed with 80 mesh. Subsequently, the foreign matter was removed with 80 mesh and a magnet trap, filled into a full-open 18L can and stored frozen. In addition, before and after the activated carbon treatment, it has been confirmed that there is no difference in the peak in the Hyuga summer processed product 1 (data not shown).
続いて活性炭処理した日向夏処理物1(以下、「日向夏処理物3」)を以下の通り限外濾過し、HPLC上で単一のピークである分画物(活性画分1)(pomace extract:PE)を調製した。 Subsequently, the activated carbon-treated Hyuga summer processed product 1 (hereinafter “Hyuga summer processed product 3”) is ultrafiltered as follows, and a fraction (active fraction 1) that is a single peak on HPLC (pomace) extract: PE) was prepared.
まず、日向夏処理物3を、以下の表1に記載の条件でHPLCに供したところ、図1のクロマトグラムが得られた。 First, when the Hinata summer product 3 was subjected to HPLC under the conditions described in Table 1 below, the chromatogram of FIG. 1 was obtained.
クロマトグラム中に見られるRT約16分のピークを、得るために、まず初めに、トーセルカートリッジフィルター(ADVANTEC)よって前濾過することで、1μm以上の粒径を有する粒子を除いた。次に、Pellicon 2 Cassette Biomax 100 kDa(Millipore)を用いて限外濾過を行い、透過した溶液を回収した。続いて、回収した溶液を、Pellicon 2 Cassette Biomax 30 kDa(Millipore)を用いて限外濾過を行った。タンク内の溶液が半分以下になったら、保持溶液に対して、元の溶液と同程度の量になるまで加水し、Pellicon 2 Cassette Biomax 30 kDa(Millipore)を用いて限外濾過した。また、100 kDaの膜に保持された溶液については、公称孔径0.2μmのmicroza MF ラボモジュール(旭化成ケミカルズ)を用いて精製を行った。上記と同様に、ビーカー内の溶液が半分以下になったら、保持溶液に対して、元の溶液と同程度の量になるまで加水し、繰り返し精製を行った。得られた透過液は100 kDaの膜を透過した溶液に合わせ、30 kDaの膜を用いて限外濾過を行った。上記条件に従うHPLCによって保持液を分析し、単一のピークが得られるまで、加水と限外濾過を繰り返し、最後に保持液を回収することで、活性画分1を調製した。活性画分1を上記条件でHPLCに供した際の結果を図2に示す。
In order to obtain a peak at RT of about 16 minutes seen in the chromatogram, first, particles having a particle size of 1 μm or more were removed by prefiltration through a Tosel cartridge filter (ADVANTEC). Next, ultrafiltration was performed using Pellicon 2
また、HPLCの保持時間について、プルラン(Shodex)又はデキストランを標準試料として分子量を測定したところ、活性画分1の分子量は約68,000〜72,000であることが示された(データ示さず)。 Further, when the molecular weight of the HPLC retention time was measured using pullulan or dextran as a standard sample, it was shown that the molecular weight of the active fraction 1 was about 68,000 to 72,000 (data not shown).
<実施例2:日向夏処理物の反転小腸におけるCa吸収促進>
8週齢雄のSprague Dawleyラット(九動株式会社より購入)をネンブタールで麻酔し、小腸を摘出した。小腸上部、中部および下部から12cmの長さで小腸片を切り取り、反転させ、両端から約1cmのところを糸で結索して、反転小腸を作成した。反転小腸内に、内液として0.9% NaCl 1mLを加えた。
<Example 2: Acceleration of Ca absorption in inverted small intestine of Hyuga summer processed product>
An 8-week-old male Sprague Dawley rat (purchased from Kudo Co., Ltd.) was anesthetized with Nembutal and the small intestine was removed. A small intestine piece was cut at a length of 12 cm from the upper, middle and lower parts of the small intestine, inverted, and tied at about 1 cm from both ends with a thread to create an inverted small intestine. In the inverted small intestine, 1 mL of 0.9% NaCl was added as an internal solution.
続いて、16.9 mM CaCl2、5.8 mM KH2PO4、0.9% NaClからなる外液(pH 6.6)、又は該外液に実施例1で調製したPO又はPEを0.02%添加した溶液に反転小腸を浸し、40分インキュベートした後に反転小腸の内液を回収し、冷凍保存した。内液を使用前に解凍し、10μLをアクアオートカイノス Ca試薬(株式会社カイノス、日本)のR-1溶液180μLと混合し、製造業者の説明書に従って660nmの吸光度に基づいてCa濃度を測定した。 Subsequently, the inverted small intestine was added to an external solution (pH 6.6) composed of 16.9 mM CaCl 2 , 5.8 mM KH 2 PO 4 , 0.9% NaCl, or a solution obtained by adding 0.02% of PO or PE prepared in Example 1 to the external solution. After incubating and incubating for 40 minutes, the internal solution of the inverted small intestine was collected and stored frozen. The internal solution was thawed before use, 10 μL was mixed with 180 μL of R-1 solution of Aqua Auto Cainos Ca reagent (Kainos, Japan), and the Ca concentration was measured based on the absorbance at 660 nm according to the manufacturer's instructions. .
結果を図3に示す。図3は、日向夏処理物1、及びその有効成分と考えられるピークを含む活性画分1が、ラット反転小腸においてカルシウムの吸収を促進することを示している。 The results are shown in Figure 3. FIG. 3 shows that the Hyuga summer processed product 1 and the active fraction 1 containing a peak considered to be an active ingredient thereof promote the absorption of calcium in the rat inverted small intestine.
<実施例3:活性画分に含まれる成分の特定>
1)活性画分2の調製
実施例1で得た日向夏処理物1について、活性炭処理を行わずに、以下の通り活性画分2を調製して、以下の分析に供した。
<Example 3: Identification of components contained in active fraction>
1) Preparation of active fraction 2 With respect to the Hyuga summer processed product 1 obtained in Example 1, the active fraction 2 was prepared as follows without performing the activated carbon treatment, and subjected to the following analysis.
まず、実施例1で得られた日向夏処理物1を、NITROCELLULOSE MEMBRANE 0.22μm(Millipore)によって前濾過することで、粒径の大きい粒子を除いた。続いて、前濾過を行った溶液をUltrafiltration Discs Ultracel 30 kDa(Millipore)を用いて限外ろ過し、保持する画分(以下、「活性画分2」とする)を調製した。
First, the Hyuga summer processed product 1 obtained in Example 1 was pre-filtered with NITROCELLULOSE MEMBRANE 0.22 μm (Millipore) to remove particles having a large particle size. Subsequently, the prefiltered solution was ultrafiltered using
活性画分2は、HPLC分析において活性画分1と同様のピークを示した(データ示さず)。また、HPLCの保持時間について、プルラン(Shodex)又はデキストランを標準試料として分子量を測定したところ、活性画分2に含まれる成分の分子量は約68,000〜72,000であることが示された(データ示さず)。 Active fraction 2 showed the same peak as active fraction 1 in HPLC analysis (data not shown). Moreover, when the molecular weight was measured for the retention time of HPLC using pullulan (Shodex) or dextran as a standard sample, it was shown that the molecular weight of the component contained in the active fraction 2 was about 68,000-72,000 (data not shown). ).
2)活性画分2の酸加水分解物のHPLCによる分析
上記の方法で調製した活性画分2について、1N硫酸で105℃、3時間加熱することにより酸加水分解を行った。この酸加水分解物を以下の表2に記載の条件でHPLCで分析した結果、ガラクトース及びアラビノースを構成糖として含むことを確認した(データ示さず)。また、ガラクトースとアラビノースのモル比は、約1:0.53であった(データ示さず)。
2) Analysis of acid hydrolyzate of active fraction 2 by HPLC The active fraction 2 prepared by the above method was subjected to acid hydrolysis by heating with 1N sulfuric acid at 105 ° C. for 3 hours. As a result of analyzing this acid hydrolyzate by HPLC under the conditions described in Table 2 below, it was confirmed that galactose and arabinose were contained as constituent sugars (data not shown). The molar ratio of galactose to arabinose was about 1: 0.53 (data not shown).
続いて、メチル化分析を行った。具体的には、活性画分2を凍結乾燥して得た多糖試料にNaOH/DMSO溶液2 mlおよびヨウ化メチル0.3 mlを加え、30℃、20分間処理した。20分後、さらにヨウ化メチルを0.7 ml加え、30℃、40分間処理した。メチル化反応液に0.88% KCl 2 mlを加えた後、クロロホルムを2 ml加えて液液分配を行った。上層(水層)を取り除いた後、新たに0.88%KCl 3 mlを加えて液液分配を行い、同様に上層を除去した。その後、クロロホルム層にトルエンを0.5 ml加え、減圧乾固した。メチル化多糖を2 M トリフルオロ酢酸(TFA) 2 mlに溶解し、110℃で4時間加水分解した。その後、トルエンを0.5 ml加え次に3 mlの無水メタノールを加えて減圧乾固した。水素化ホウ素ナトリウム(NaBH4)40 mgを精製水2 mlに溶解し、1 M アンモニア水0.4 mlを加えて調製したNaBH4溶液1.2 mlをサンプルに加えて3分間反応させた後、残りのNaBH4溶液を加え、25℃で12時間放置した。酢酸(0.6 ml)で中和し、トルエンを0.5 ml加えて減圧乾固した後、無水メタノール4 mlを加えて再度減圧乾固した。無水酢酸とピリジンをそれぞれ0.5 mlずつ加え、100℃で1時間アセチル化した。その後、トルエン3 mlを加えて減圧乾固した。次に、蒸留水2 mlとクロロホルム1.5 mlを加えて液液分配を行い、水層を取り除いた後、新たに蒸留水2 mlを加えて同様に上層を除去した。その後、クロロホルム層にトルエンを0.5 ml加えて減圧乾固した。次に、クロロホルム0.5 mlを加えて反応生成物を抽出し、以下の条件でGC/MS分析を行った。
質量分析装置:Shimadzu GCMS-QP2010SE、
キャピラリーカラム:InertCap RTX 5MS、
キャリアーガス:ヘリウム、
分析温度:180℃ 5 min、180-250℃ 2℃/min、250℃ 5min、
インターフェイス温度:250℃。
Subsequently, methylation analysis was performed. Specifically, 2 ml of NaOH / DMSO solution and 0.3 ml of methyl iodide were added to a polysaccharide sample obtained by freeze-drying active fraction 2 and treated at 30 ° C. for 20 minutes. After 20 minutes, 0.7 ml of methyl iodide was further added and treated at 30 ° C. for 40 minutes. After adding 2 ml of 0.88% KCl to the methylation reaction solution, 2 ml of chloroform was added to perform liquid-liquid partitioning. After removing the upper layer (aqueous layer), 3 ml of 0.88% KCl was newly added to perform liquid-liquid distribution, and the upper layer was similarly removed. Thereafter, 0.5 ml of toluene was added to the chloroform layer and dried under reduced pressure. The methylated polysaccharide was dissolved in 2 ml of 2 M trifluoroacetic acid (TFA) and hydrolyzed at 110 ° C. for 4 hours. Thereafter, 0.5 ml of toluene was added, and then 3 ml of anhydrous methanol was added, followed by drying under reduced pressure. Dissolve 40 mg of sodium borohydride (NaBH 4 ) in 2 ml of purified water, add 1.2 ml of NaBH 4 solution prepared by adding 0.4 ml of 1 M aqueous ammonia to the sample and react for 3 minutes, then the remaining NaBH 4 solutions were added and left at 25 ° C. for 12 hours. The mixture was neutralized with acetic acid (0.6 ml), 0.5 ml of toluene was added and evaporated to dryness, then 4 ml of anhydrous methanol was added and again dried under reduced pressure. Acetic anhydride and pyridine were added in 0.5 ml each, and acetylated at 100 ° C. for 1 hour. Thereafter, 3 ml of toluene was added and dried under reduced pressure. Next, 2 ml of distilled water and 1.5 ml of chloroform were added to perform liquid-liquid partition. After removing the aqueous layer, 2 ml of distilled water was newly added to remove the upper layer in the same manner. Thereafter, 0.5 ml of toluene was added to the chloroform layer and dried under reduced pressure. Next, 0.5 ml of chloroform was added to extract the reaction product, and GC / MS analysis was performed under the following conditions.
Mass spectrometer: Shimadzu GCMS-QP2010SE,
Capillary column: InertCap RTX 5MS,
Carrier gas: helium,
Analysis temperature: 180
Interface temperature: 250 ℃.
メチル化分析の結果、試料に含まれる多糖は →3)-Gal-(1→ が主鎖で(ピーク4及び6)、→6)-Gal-(1→ と →5)-Ara-(1→ を含む側鎖(ピーク2及び5)が6位で分岐しているアラビノガラクタンであることを明らかにした(表3)。また、このアラビノガラクタンが、末端Gal及び末端Araを有することも明らかとなった(表3、ピーク1及び3)。 As a result of methylation analysis, the polysaccharide contained in the sample is → 3) -Gal- (1 → is the main chain (peaks 4 and 6), → 6) -Gal- (1 → and → 5) -Ara- (1 → The side chain containing 2 (peaks 2 and 5) was clarified to be arabinogalactan branched at position 6 (Table 3), and the arabinogalactan had terminal Gal and terminal Ara Were also revealed (Table 3, peaks 1 and 3).
続いて、二次元NMR(HSQC)分析を行った。具体的には、活性画分2を凍結乾燥して得た多糖試料を重水に溶解し、試料管(178 x 4 mmφ)に入れて、1H-NMRと13C-NMRを測定し、HSQC (Hetero-nuclear Single Quantum Coherence)測定を行った。標準物質として1,4-ジオキサンを用いた。核磁気共鳴装置は、BRUKER AV400Mを用いた。 Subsequently, two-dimensional NMR (HSQC) analysis was performed. Specifically, a polysaccharide sample obtained by lyophilizing active fraction 2 was dissolved in heavy water, placed in a sample tube (178 x 4 mmφ), 1 H-NMR and 13 C-NMR were measured, and HSQC (Hetero-nuclear single quantum coherence) measurement was performed. 1,4-Dioxane was used as a standard substance. BRUKER AV400M was used as the nuclear magnetic resonance apparatus.
その結果、ガラクトースとアラビノースの結合様式がそれぞれβ結合とα結合であることが明らかとなった。 As a result, it became clear that the binding mode of galactose and arabinose was β bond and α bond, respectively.
これらの結果から、日向夏みかん由来の活性成分が、β1,3結合したガラクトースを主鎖とし、主鎖のガラクトースの6位から分岐した側鎖を有し、側鎖が1,6結合したβガラクトース、及び1,5結合したαアラビノースを含むアラビノガラクタンであることが示唆された。 From these results, the active ingredient derived from Hinata Natsumikan has β1,3-linked galactose as the main chain, β-galactose with a side chain branched from the 6-position of the main chain galactose, and the side chain 1,6-linked , And 1,5 linked arabinogalactan containing alpha arabinose.
Claims (6)
β1,3結合したガラクトースを主鎖とし、主鎖のガラクトースの6位から分岐した側鎖を有し、側鎖が1,6結合したβガラクトース、及び1,5結合したαアラビノースを含む、
請求項3に記載のカルシウム吸収促進剤。 Arabinogalactan,
β1,3-linked galactose as the main chain, including a side chain branched from the 6-position of the main chain galactose, including 1,6-linked β-galactose and 1,5-linked α-arabinose,
The calcium absorption enhancer according to claim 3.
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JP2015500333A (en) * | 2011-12-13 | 2015-01-05 | アモーフィカル リミテッド. | Amorphous calcium carbonate to treat calcium malabsorption and metabolic bone disorders |
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JP2015500333A (en) * | 2011-12-13 | 2015-01-05 | アモーフィカル リミテッド. | Amorphous calcium carbonate to treat calcium malabsorption and metabolic bone disorders |
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