JP6902768B2 - Bone resorption inhibitor - Google Patents
Bone resorption inhibitor Download PDFInfo
- Publication number
- JP6902768B2 JP6902768B2 JP2016128876A JP2016128876A JP6902768B2 JP 6902768 B2 JP6902768 B2 JP 6902768B2 JP 2016128876 A JP2016128876 A JP 2016128876A JP 2016128876 A JP2016128876 A JP 2016128876A JP 6902768 B2 JP6902768 B2 JP 6902768B2
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- JP
- Japan
- Prior art keywords
- bone resorption
- algae
- extract
- bone
- resorption inhibitor
- 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.)
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Description
本発明は、骨吸収抑制剤に関する。具体的には、安全性が高く、骨吸収抑制作用に優れる骨吸収抑制剤に関する。 The present invention relates to a bone resorption inhibitor. Specifically, the present invention relates to a bone resorption inhibitor having high safety and excellent bone resorption inhibitory action.
骨組織では、破骨細胞によって古い骨が壊され（骨吸収）、骨芽細胞によって新しい骨が作られる（骨形成）、骨代謝が絶えず行われ、骨の強度や血中のカルシウム濃度を調整している。この骨吸収と骨形成のバランスが崩れて正常な骨代謝が行われなくなると、骨粗鬆症や骨転移等の骨疾患が引き起こされる。骨の再構築（リモデリング）において骨代謝回転の亢進，低下あるいは正常のいずれにおいても，骨吸収が相対的に骨形成を上回る病態では骨量は減少する。例えば、骨粗鬆症では、骨吸収亢進型と骨形成抑制型があり、８割を占める閉経後の女性の病態は骨吸収亢進型である。また、がんの骨転移でも、がんの産生する因子によって破骨細胞の骨吸収が亢進し、骨はがんに増殖場所を提供することになる。 In bone tissue, bone-breaking cells destroy old bone (bone resorption), osteoblasts create new bone (bone formation), and bone metabolism is constant, regulating bone strength and blood calcium levels. doing. When the balance between bone resorption and bone formation is lost and normal bone metabolism is not performed, bone diseases such as osteoporosis and bone metastasis are caused. Bone mass decreases in conditions where bone resorption is relatively greater than bone formation, whether bone turnover is increased, decreased, or normal in bone remodeling. For example, in osteoporosis, there are a bone resorption type and a bone formation inhibitory type, and the pathological condition of postmenopausal women, which accounts for 80%, is a bone resorption type. Also, in bone metastasis of cancer, bone resorption of osteoclasts is enhanced by factors produced by the cancer, and the bone provides a place for growth in the cancer.
そのような骨代謝の異常を予防又は改善するために、骨形成を促進する薬剤や骨吸収を抑制する薬剤等について、これまでに種々研究されている。骨代謝に寄与する成分の一つとしてフコイダンやコンドロイチン硫酸等の酸性多糖が知られている。例えば、非特許文献１には、軟骨に多い成分であるコンドロイチン硫酸−Ｅが破骨細胞の分化を抑制することが開示されている。しかしながら、自然界で極僅かしか採取できない希少品であるため、大量に調製することが困難である。 In order to prevent or improve such abnormalities in bone metabolism, various studies have been conducted on agents that promote bone formation, agents that suppress bone resorption, and the like. Acidic polysaccharides such as fucoidan and chondroitin sulfate are known as one of the components contributing to bone metabolism. For example, Non-Patent Document 1 discloses that chondroitin sulfate-E, which is a component abundant in cartilage, suppresses the differentiation of osteoclasts. However, since it is a rare product that can be collected in a very small amount in nature, it is difficult to prepare it in large quantities.
非特許文献２には、フコイダンが破骨細胞の分化を抑制し得ることが開示されている。しかしながら、フコイダンは、褐藻にしか含まれておらず、緑藻や紅藻には含まれていない。また、緑藻や紅藻由来の成分が骨吸収抑制に寄与するかについては、一切明らかにされていない。
Non-Patent
また、アルギン酸は、褐藻などに含まれる多糖類であり、増粘剤、安定剤、ゲル化剤、保湿剤等として食品分野、化粧品分野、医療分野等において広く利用されている。しかしながら、アルギン酸が骨吸収抑制に寄与することは知られていない。 Alginic acid is a polysaccharide contained in brown algae and the like, and is widely used in the food field, cosmetic field, medical field and the like as a thickener, stabilizer, gelling agent, moisturizer and the like. However, it is not known that alginic acid contributes to the suppression of bone resorption.
本発明は、前記現状に鑑みて、安全性が高く、優れた骨吸収抑制作用を有する、新たな骨吸収抑制剤を提供することを課題とする。 In view of the above situation, it is an object of the present invention to provide a new bone resorption inhibitor having high safety and excellent bone resorption inhibitory action.
本発明者は、前記課題を解決するために鋭意研究を行ったところ、意外にも、緑藻及び／又は紅藻の抽出物が、優れた骨吸収抑制作用を有することを見出した。また、本発明者は、アルギン酸及び／又はその塩が優れた骨吸収抑制作用を有することを見出した。本発明は、これらの知見に基づいて更に検討を重ねることにより完成したものである。 As a result of diligent research to solve the above problems, the present inventor has surprisingly found that an extract of green algae and / or red algae has an excellent bone resorption inhibitory effect. The present inventor has also found that alginic acid and / or a salt thereof has an excellent bone resorption inhibitory effect. The present invention has been completed by further studies based on these findings.
即ち、本発明は、下記に掲げる態様の発明を提供する。
項１−１． 緑藻綱に属する藻類及び／又は紅藻綱に属する藻類の抽出物を有効成分とする骨吸収抑制剤。
項１−２． 前記抽出物が、水性溶媒の抽出物である、項１−１に記載の骨吸収抑制剤。
項１−３． 前記抽出物が、ミル目、アオサ目、ヒビミドロ目、イワズタ目、プラシノコックス目、スギノリ目、ウシケノリ目、テングサ目、イギス目、オゴノリ目、及びチノリモ目に属する藻類からなる群より選択される少なくとも一種の藻類の抽出物である、項１−１又は１−２に記載の骨吸収抑制剤。
項１−４． 骨疾患の予防又は治療に使用される、項１−１〜１−３のいずれか一項に記載の骨吸収抑制剤。
項１−５． 飲食品である、項１−１〜１−４のいずれか一項に記載の骨吸収抑制剤。
項１−６． 医薬品である、項１−１〜１−４のいずれか一項に記載の骨吸収抑制剤。
項２−１． アルギン酸及び／又はその塩を有効成分とする骨吸収抑制剤。
項２−２． 骨疾患の予防又は治療に使用される、項２−１に記載の骨吸収抑制剤。
項２−３． 飲食品である、項１〜４のいずれか一項に記載の骨吸収抑制剤。
項２−４． 医薬品である、項１〜４のいずれか一項に記載の骨吸収抑制剤。
That is, the present invention provides the inventions of the following aspects.
Item 1-1. A bone resorption inhibitor containing an extract of algae belonging to Chlorophycean and / or algae belonging to Red algae as an active ingredient.
Item 1-2.
Item 1-3. The extract is selected from the group consisting of algae belonging to the orders Mill, Aosa, Hibimidoro, Iwazuta, Prasinocox, Suginori, Bangiophyceae, Gelidiaceae, Igis, Gracilaria, and Porphyridiophyceae.
Item 1-4.
Item 1-5.
Item 1-6. The bone resorption inhibitor according to any one of Items 1-1 to 1-4, which is a pharmaceutical product.
Item 2-1. A bone resorption inhibitor containing alginic acid and / or a salt thereof as an active ingredient.
Item 2-2.
Item 2-3.
Item 2-4. The bone resorption inhibitor according to any one of Items 1 to 4, which is a pharmaceutical product.
本発明によれば、骨吸収抑制作用が高い骨吸収抑制剤を提供することができる。そのため、骨代謝の改善を効果的に図ることができる。本発明の骨吸収抑制剤は、緑藻綱に属する藻類及び／又は紅藻綱に属する藻類の抽出物、あるいはアルギン酸及び／又はその塩を有効成分とするものであるため、安全性が高い。本発明の骨吸収抑制剤は飲食品の形態で摂取することができ、骨代謝の改善や、良好な骨代謝の維持を簡便に行うことができる。また、本発明の骨吸収抑制剤は、骨吸収抑制作用が優れるので、骨粗鬆症、骨転移、関節リウマチ、骨ページェット病、副甲状腺機能亢進症、歯周病等の骨代謝異常による骨疾患の予防又は治療に使用することができる。 According to the present invention, it is possible to provide a bone resorption inhibitor having a high bone resorption inhibitory effect. Therefore, it is possible to effectively improve bone metabolism. The bone resorption inhibitor of the present invention is highly safe because it contains an extract of algae belonging to Chlorophycean and / or algae belonging to Red algae, or alginic acid and / or a salt thereof as an active ingredient. The bone resorption inhibitor of the present invention can be ingested in the form of food and drink, and can easily improve bone metabolism and maintain good bone metabolism. Further, since the bone resorption inhibitor of the present invention has an excellent bone resorption inhibitory effect, it can be used for bone diseases caused by abnormal bone metabolism such as osteoporosis, bone metastasis, rheumatoid arthritis, Paget's disease of bone, hyperparathyroidism, and periodontal disease. It can be used for prevention or treatment.
１．緑藻綱に属する藻類及び／又は紅藻綱に属する藻類の抽出物を使用する骨吸収抑制剤
本発明の骨吸収抑制剤は、緑藻綱に属する藻類及び／又は紅藻綱に属する藻類の抽出物を有効成分とすることを特徴とする。以下、当該骨吸収抑制剤を「骨吸収抑制剤（Ａ）」と表記することもある。以下、本発明の骨吸収抑制剤（Ａ）について詳述する。
1. 1. Bone resorption inhibitor using an extract of algae belonging to Chlorophycean and / or algae belonging to Chlorophycean The bone resorption inhibitor of the present invention is an extract of algae belonging to Chlorophycean and / or algae belonging to Red algae. Is a feature of the active ingredient. Hereinafter, the bone resorption inhibitor may be referred to as "bone resorption inhibitor (A)". Hereinafter, the bone resorption inhibitor (A) of the present invention will be described in detail.
有効成分
本発明の骨吸収抑制剤（Ａ）では、有効成分として、緑藻綱に属する藻類及び／又は紅藻綱に属する藻類の抽出物を使用する。
Active Ingredient In the bone resorption inhibitor (A) of the present invention, an extract of algae belonging to Chlorophycean and / or algae belonging to Red algae is used as the active ingredient.
緑藻綱に属する藻類及び／又は紅藻綱に属する藻類の抽出物は、抽出原料として緑藻綱に属する藻類及び／又は紅藻綱に属する藻類を使用し、水性溶媒で抽出処理することで得ることができる。 An extract of algae belonging to Chlorophycean and / or algae belonging to Chlorophycean can be obtained by using an alga belonging to Chlorophycean and / or algae belonging to Chlorophycean as an extraction raw material and extracting with an aqueous solvent. Can be done.
抽出原料として使用される緑藻綱に属する藻類の種類については、特に制限されないが、例えば、ミル等のミル目；スジアオノリ等のアオサ目；ヒトエグサ等のヒビミドロ目；ウミブドウ、センナリヅタ等のイワズタ目；ブラシノコックス等のブラシノコックス目；等に属する藻類が挙げられる。抽出原料として、これらの緑藻綱に属する藻類の１種を単独で使用してもよく、また２種以上を組み合わせて使用してもよい。 The type of algae belonging to the Chlorophycean used as an extraction raw material is not particularly limited, but for example, Mills such as Mill; Sea lettuce such as Monostroma nitidum; Hibimidoro such as Monostroma nitidum; Brushes of Nocox and the like; algae belonging to the order Nocox; etc. can be mentioned. As the extraction raw material, one kind of algae belonging to these Chlorophyceans may be used alone, or two or more kinds may be used in combination.
抽出原料として使用される紅藻綱に属する藻類の種類については、特に制限されないが、例えば、クロハギンナンソウ、ムカデノリ等のスギノリ目；スサビノリ等のウシケノリ目；ウミゾウメン等のウミゾウメン目；テングサ、ヒラクサ等のテングサ目；エゴノリ等のイギス目；オゴノリ等のオゴノリ目；チノリモ等のチノリモ目；ダルス等のダルス目；等に属する藻類が挙げられる。抽出原料として、これらの紅藻綱に属する藻類の１種を単独で使用してもよく、また２種以上を組み合わせて使用してもよい。 The type of algae belonging to the order Red Algae used as an extraction raw material is not particularly limited, but for example, Porphyridiophyceae such as Porphyridiophyceae and Porphyridiophyceae; Porphyridiophyceae such as Gracilaria; Gelidiaceae, etc. Examples include algae belonging to the order Gelidiaceae; the order Igis such as Egonori; the order Ogonori such as Gracilaria; the order Porphyridiophyceae; the order Darus such as Dars; and the like. As the extraction raw material, one of these algae belonging to the class Red algae may be used alone, or two or more of them may be used in combination.
これらの抽出原料の中でも、より一層効果的に骨吸収抑制作用を発揮させるという観点から、好ましくは、ミル目、アオサ目、ヒビミドロ目、イワズタ目、プラシノコックス目、スギノリ目、ウシケノリ目、テングサ目、イギス目、オゴノリ目、又はチノリモ目に属する藻類；より好ましくは、ミル目、アオサ目、ヒビミドロ目、スギノリ目、又はウシケノリ目に属する藻類；更に好ましくは、ミル、スジアオノリ、ヒトエグサ、スサビノリ、クロハギンナンソウ；特に好ましくは、スサビノリ、スジアオノリが挙げられる。
なお、本明細書における藻類の名称、分類は、吉田・鈴木・吉永２０１５．日本産海藻目録（２０１５年改訂版）に準拠する。
Among these extracted raw materials, from the viewpoint of exerting a bone resorption inhibitory effect even more effectively, preferably, Mills, Ulvae, Hibimidoro, Iwazuta, Prasinocox, Neopyropia yezoensis, Bangiophyceae, and Monostroma Algae belonging to the order Mill, Sea lettuce, Ogonori, or Chinorimo; more preferably, algae belonging to the order Mill, Ulva, Hibimidoro, Suginori, or Bangiophyceae; Kurohaginnansou; Particularly preferably, Susabinori and Sujiaonori are mentioned.
The names and classifications of algae in this specification are referred to as Yoshida, Suzuki, and Yoshinaga 2015. Compliant with the Japanese seaweed catalog (2015 revised edition).
抽出原料として使用される緑藻綱に属する藻類及び／又は紅藻類綱に属する藻類は、いずれの産地由来のものであってもよく、いずれの時期に収穫されたものであってもよい。 The algae belonging to the class Chlorophycean and / or the algae belonging to the class Red algae used as the extraction raw material may be derived from any production area and may be harvested at any time.
抽出原料として使用される緑藻綱に属する藻類及び／又は紅藻綱に属する藻類の部位については、特に制限されず、全藻であってもよく、また緑藻綱及び／又は紅藻綱に属する藻類の先端部、基部、縁辺部、中帯部、葉状部、茎状部、付着器等の一部であってもよい。これらの抽出対象部位の中でも、少なくとも食用として使用される葉状部を含んでいることが望ましい。 The site of algae belonging to Chlorophycean and / or algae belonging to Red algae used as an extraction raw material is not particularly limited and may be whole algae, and algae belonging to Chlorophycean and / or Red algae. It may be a part of a tip portion, a base portion, an edge portion, a middle band portion, a foliate portion, a stalk-shaped portion, an algae, and the like. Among these extraction target sites, it is desirable that at least a foliate portion used for food is included.
抽出原料として使用される緑藻綱に属する藻類及び／又は紅藻綱に属する藻類は、生のまま使用してもよく、その粉砕物又は細切物であってもよい。また、脱水又は乾燥させた緑藻綱に属する藻類及び／又は紅藻綱に属する藻類を、必要に応じて粉砕又は細切したものであってもよい。 The algae belonging to the class Chlorophycean and / or the algae belonging to the class Red algae used as extraction raw materials may be used raw, or may be crushed or shredded thereof. Further, dehydrated or dried algae belonging to the class Chlorophycean and / or algae belonging to the class Red algae may be crushed or shredded as necessary.
抽出溶媒として使用される水性溶媒は、緑藻綱に属する藻類及び／又は紅藻綱に属する藻類に含まれる水溶性成分を抽出可能であることを限度として特に制限されないが、水、又は含水アルコールが挙げられ、好ましくは水が挙げられる。含水アルコールとしては、水と低級アルコール類（メタノール、エタノール、１−プロパノール、２−プロパノール、１−ブタノール、２−ブタノール等）の混合物が挙げられる。 The aqueous solvent used as the extraction solvent is not particularly limited as long as the water-soluble components contained in the algae belonging to the Chlorophycean and / or the algae belonging to the Red algae can be extracted, but water or hydrous alcohol is used. It is mentioned, preferably water. Examples of the hydrous alcohol include a mixture of water and lower alcohols (methanol, ethanol, 1-propanol, 2-propanol, 1-butanol, 2-butanol, etc.).
抽出処理の手法については、藻類の酸性多糖抽出物の製造に使用される一般的な抽出手法であれば特に限定されないが、例えば、浸漬法、パーコレーション法等が挙げられる。また、抽出処理は複数回繰り返して行ってもよく、複数回の抽出処理で得られた抽出物を合わせて有効成分として使用してもよい。 The extraction treatment method is not particularly limited as long as it is a general extraction method used for producing an acidic polysaccharide extract of algae, and examples thereof include a dipping method and a percolation method. Further, the extraction process may be repeated a plurality of times, or the extracts obtained by the a plurality of extraction processes may be combined and used as an active ingredient.
抽出処理後に得られた抽出液を、必要に応じてろ過または遠心分離によって固形物を除去することにより、緑藻綱に属する藻類及び／又は紅藻綱に属する藻類の抽出物が回収できる。本発明の骨吸収抑制剤では、抽出処理により得られた液状の抽出物をそのまま使用してもよいが、必要に応じて、一部又は全ての溶媒を除去して濃縮物若しくは乾燥物として使用してもよい。 Extracts of algae belonging to Chlorophycean and / or algae belonging to Red algae can be recovered by removing solids from the extract obtained after the extraction treatment by filtration or centrifugation, if necessary. In the bone resorption inhibitor of the present invention, the liquid extract obtained by the extraction treatment may be used as it is, but if necessary, a part or all of the solvent is removed and used as a concentrate or a dried product. You may.
また、本発明で使用される緑藻綱に属する藻類及び／又は紅藻綱に属する藻類の抽出物は、抽出処理後に得られた抽出液、その濃縮物若しくは乾燥物を更に精製処理に供したものであってもよい。精製処理としては、カラムクロマトグラフィー、脱塩、活性炭処理、再結晶法、分配精製等が挙げられる。これらの処理は、同一処理を複数回繰り返して実施してもよいし、２以上の異なる処理を組み合わせて実施してもよい。なかでも、より一層優れた骨吸収抑制効果を奏する抽出物を効率良く得るために、イオン交換樹脂処理による精製処理に供することが好ましい。イオン交換樹脂処理としては、例えば、得られた抽出液又はその濃縮液を、陰イオン交換樹脂を充填したカラムに供した後に、塩化ナトリウム溶液等を用いて濃度勾配法により、陰イオン交換樹脂に吸着した成分を溶出させて回収する方法が挙げられる。 Further, the extracts of algae belonging to Chlorophycean and / or algae belonging to Red algae used in the present invention are those obtained by further purifying the extract, its concentrate or dried product obtained after the extraction treatment. It may be. Examples of the purification treatment include column chromatography, desalting, activated carbon treatment, recrystallization method, partition purification and the like. These processes may be performed by repeating the same process a plurality of times, or may be performed by combining two or more different processes. Among them, in order to efficiently obtain an extract having an even more excellent bone resorption inhibitory effect, it is preferable to subject it to a purification treatment by an ion exchange resin treatment. As the ion exchange resin treatment, for example, the obtained extract or a concentrated solution thereof is applied to a column packed with an anion exchange resin, and then the anion exchange resin is prepared by a concentration gradient method using a sodium chloride solution or the like. Examples thereof include a method of eluting and recovering the adsorbed component.
緑藻綱に属する藻類及び／又は紅藻綱に属する藻類の抽出物は、更に粉末化や乳化等の処理に供して、所望の形状に調整してもよい。 The algae belonging to the class Chlorophycean and / or the extracts of the algae belonging to the class Red algae may be further subjected to treatments such as powdering and emulsification to be adjusted to a desired shape.
緑藻綱に属する藻類及び／又は紅藻綱に属する藻類の抽出物には、緑藻綱に属する藻類及び／又は紅藻綱に属する藻類に由来する水溶性成分が含まれている。緑藻綱に属する藻類及び／又は紅藻綱に属する藻類の抽出物に含まれる水溶性成分として、具体的には、酸性多糖が挙げられる。限定的な解釈を望むものではないが、緑藻綱に属する藻類及び／又は紅藻綱に属する藻類の抽出物に含まれる酸性多糖、好ましくは硫酸基を有する硫酸化多糖が、骨吸収抑制効果に寄与していると考えられる。緑藻綱に属する藻類及び／又は紅藻綱に属する藻類の抽出物に含まれる酸性多糖の種類については、抽出原料として使用される緑藻綱に属する藻類及び／又は紅藻綱に属する藻類の種類に応じて異なるが、例えば、ラムナン硫酸、キシロアラビノガラクタン硫酸、アラビナン硫酸、アラビノラムナン硫酸、グルクロノキシロラムナン硫酸、グルクロノキシロガラクタン硫酸、カラゲナン（ラムダλ、イオタι、カッパκ）、ポルフィラン、フノラン、アガロペクチン等が挙げられる。具体的には、酸性多糖として、例えば、ミルの抽出物の場合は、キシロアラビノガラクタン硫酸、アラビナン硫酸；スジアオノリの抽出物の場合は、アラビノラムナン硫酸；ヒトエグサの抽出物の場合はラムナン硫酸；スサビノリの抽出物の場合はポルフィラン；クロハギンナンソウの抽出物の場合はカラゲナンが含まれている。 Extracts of algae belonging to the Chlorophycean and / or algae belonging to the Red Algae contain water-soluble components derived from the algae belonging to the Chlorophycean and / or the algae belonging to the Red Algae. Specific examples of the water-soluble component contained in the extract of algae belonging to Chlorophycean and / or algae belonging to Red algae include acidic polysaccharides. Although not limited interpretation is desired, acidic polysaccharides contained in extracts of algae belonging to Chlorophycean and / or algae belonging to Red algae, preferably sulfated polysaccharides having a sulfate group, have an effect of suppressing bone resorption. It is considered to be contributing. Regarding the types of acidic polysaccharides contained in the extracts of algae belonging to Chlorophycean and / or algae belonging to Porphyran, refer to the types of algae belonging to Chlorophycean and / or algae belonging to Porphyran used as extraction raw materials. Depending on, for example, ramnan sulphate, xylolarabinogalactan sulphate, arabinan sulphate, arabino ramnan sulphate, glucuronoxyloramnan sulphate, glucuronoxylogalactan sulphate, carrageenan (lambda λ, iotaι, kappaκ), porphyran, funoran. , Agaropectin and the like. Specifically, as acidic polysaccharides, for example, xylolarabinogalactan sulfate, arabinan sulfate in the case of mill extract; arabinolamnan sulfate in the case of sujiaonori extract; ramnan sulfate in the case of human exa extract; In the case of the extract of Porphyran; in the case of the extract of Kurohaginnansou, it contains carrageenan.
添加成分
本発明の骨吸収抑制剤（Ａ）は、前述した緑藻綱に属する藻類及び／又は紅藻綱に属する藻類の抽出物以外に、本発明の効果を損なわない範囲で、剤型に応じて、他の添加成分を含有していてもよい。本発明の骨吸収抑制剤（Ａ）に含有され得る添加成分としては、例えば、水、油脂類、ロウ類、炭化水素類、脂肪酸類、高級アルコール類、エステル類、植物抽出エキス類、水溶性高分子、界面活性剤、アルコール、多価アルコール、ｐＨ調整剤、酸化防止剤、防腐剤、香料、粉体、増粘剤、色素、キレート剤等が挙げられる。これらの添加成分は、１種単独で使用してもよく、また２種以上を組み合わせて使用してもよい。また、これらの添加成分の含有量については、使用する添加成分の種類や本発明の骨吸収抑制剤（Ａ）の剤型等に応じて適宜設定される。
Additive component The bone resorption inhibitor (A) of the present invention can be used according to the dosage form, in addition to the above-mentioned extracts of algae belonging to Chlorophycean and / or algae belonging to Red algae, as long as the effects of the present invention are not impaired. It may also contain other additive components. Examples of the additive component that can be contained in the bone resorption inhibitor (A) of the present invention include water, oils and fats, waxes, hydrocarbons, fatty acids, higher alcohols, esters, plant extracts, and water-soluble. Examples thereof include polymers, surfactants, alcohols, polyhydric alcohols, pH adjusters, antioxidants, preservatives, fragrances, powders, thickeners, pigments, chelating agents and the like. These additive components may be used alone or in combination of two or more. The content of these additive components is appropriately set according to the type of additive component to be used, the dosage form of the bone resorption inhibitor (A) of the present invention, and the like.
本発明の骨吸収抑制剤（Ａ）は、骨吸収を抑制する他の薬理成分を含んでいてもよい。骨吸収を抑制する他の薬理成分としては、例えば、エストロゲン、カルシトニン、エストロゲン受容体調節薬ＳＥＲＭ、ビスホスホネート等が挙げられる。また、本発明の骨吸収抑制剤（Ａ）は、ビタミンＤ３、ビタミンＫ等の骨形成を促進する成分を更に含んでいてもよい。 The bone resorption inhibitor (A) of the present invention may contain other pharmacological components that suppress bone resorption. Other pharmacological components that suppress bone resorption include, for example, estrogen, calcitonin, estrogen receptor regulator SERM, bisphosphonate and the like. In addition, the bone resorption inhibitor (A) of the present invention may further contain components such as vitamin D3 and vitamin K that promote bone formation.
他の添加成分として、例えば、本発明の骨吸収抑制剤（Ａ）として経口用固形製剤を調製する際には、賦形剤、結合剤、崩壊剤、滑沢剤、矯味矯臭剤、着色剤等、常法で用いられているものが挙げられる。そのような担体の例として、賦形剤としては、乳糖、白糖、ブドウ糖、マンニット、ソルビット、デキストリン、デンプン、結晶セルロース、カルボキシメチルセルロース、ヒドロキシプロピルセルロース、デキストラン、プルラン、無水ケイ酸、リン酸カルシウム、炭酸カルシウム、硫酸カルシウム等が挙げられる。結合剤としては、結晶セルロース、白糖、マンニトール、デキストリン、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、ポリビニルピロリドン、アラビアゴム、デキストラン、プルラン、水、エタノール等が挙げられる。崩壊剤としては、デンプン、カルボキシメチルセルロース、ヒドロキシプロピルセルロース、デキストリン、結晶セルロース等が挙げられる。滑沢剤としては、ステアリン酸およびその金属塩、タルク、ホウ酸、脂肪酸ナトリウム塩、ラウリル硫酸ナトリウム、ラウリル硫酸マグネシウム、無水ケイ酸等が挙げられる。矯味矯臭剤としては白糖、橙皮、クエン酸、酒石酸等が挙げられる。 As other additive components, for example, when preparing an oral solid preparation as the bone resorption inhibitor (A) of the present invention, an excipient, a binder, a disintegrant, a lubricant, a flavoring agent, a coloring agent Etc., those used in the conventional method can be mentioned. Examples of such carriers include, as excipients, lactose, sucrose, glucose, mannit, sorbit, dextrin, starch, crystalline cellulose, carboxymethyl cellulose, hydroxypropyl cellulose, dextran, purulan, silicic anhydride, calcium phosphate, calcium carbonate. Calcium, calcium sulfate and the like can be mentioned. Examples of the binder include crystalline cellulose, sucrose, mannitol, dextrin, hydroxypropyl cellulose, hydroxypropyl methyl cellulose, polyvinylpyrrolidone, gum arabic, dextran, pullulan, water, ethanol and the like. Examples of the disintegrant include starch, carboxymethyl cellulose, hydroxypropyl cellulose, dextrin, crystalline cellulose and the like. Examples of the lubricant include stearic acid and its metal salt, talc, boric acid, fatty acid sodium salt, sodium lauryl sulfate, magnesium lauryl sulfate, and silicic anhydride. Examples of the flavoring agent include sucrose, orange peel, citric acid, tartaric acid and the like.
本発明の骨吸収抑制剤を飲食品とする場合は、他の添加成分として、食品素材、前述の担体等の他、糖類、糖アルコール類、塩類、油脂類、アミノ酸類、有機酸類、ビタミン類、カルシウム類、果汁、野菜汁、香料、アルコール類、グリセリン等が挙げられる。 When the bone resorption inhibitor of the present invention is used as a food or drink, other additive components include food materials, the above-mentioned carriers, sugars, sugar alcohols, salts, fats and oils, amino acids, organic acids, and vitamins. , Calcium, fruit juice, vegetable juice, flavors, alcohols, glycerin and the like.
本発明の骨吸収抑制剤（Ａ）における緑藻綱に属する藻類及び／又は紅藻綱に属する藻類の抽出物の含有量としては、特に限定されず、剤型や製品形態、用法等に応じて適宜設計することができるが、例えば、抽出物の乾燥重量で５〜８０質量％、好ましくは３０〜８０質量％、より好ましくは５０〜８０質量％が挙げられる。 The content of the extract of algae belonging to Chlorophycean and / or algae belonging to Red algae in the bone resorption inhibitor (A) of the present invention is not particularly limited, and depends on the dosage form, product form, usage, etc. Although it can be appropriately designed, for example, the dry weight of the extract is 5 to 80% by mass, preferably 30 to 80% by mass, and more preferably 50 to 80% by mass.
剤型
本発明の骨吸収抑制剤（Ａ）の剤型については、特に限定されず、固体状、半固体状、又は液体状のいずれであってもよく、当該骨吸収抑制剤の種類や用途に応じて適宜設定すればよい。
Dosage Form The dosage form of the bone resorption inhibitor (A) of the present invention is not particularly limited and may be solid, semi-solid, or liquid, and the type and use of the bone resorption inhibitor. It may be set appropriately according to.
投与方法
本発明の骨吸収抑制剤（Ａ）は、経口、経腸、皮下、注射等、任意の投与形態で使用できるが、投与が容易であり、かつ効果が高い点で、経口投与が好ましい。
Administration Method The bone resorption inhibitor (A) of the present invention can be used in any administration form such as oral, enteral, subcutaneous, and injection, but oral administration is preferable because it is easy to administer and highly effective. ..
本発明の骨吸収抑制剤（Ａ）の摂取量については、特に限定されず、製品形態、用途等に応じて適宜設定されるが、例えば、経口摂取量としては、緑藻綱に属する藻類及び／又は紅藻綱に属する藻類の抽出物の乾燥重量換算で、成人一日あたり、好ましくは５０〜５００ｍｇ、より好ましくは２００〜５００ｍｇである。本発明の骨吸収抑制剤は、一日あたりの量が上述の範囲となるように、１回又は数回に分けて投与してもよい。 The intake amount of the bone resorption inhibitor (A) of the present invention is not particularly limited and is appropriately set according to the product form, use, etc. For example, the oral intake amount includes algae belonging to the Chlorophycean family and /. Alternatively, in terms of dry weight of an extract of algae belonging to the order Chlorophycean, it is preferably 50 to 500 mg, more preferably 200 to 500 mg per day for an adult. The bone resorption inhibitor of the present invention may be administered once or in several divided doses so that the daily amount is within the above range.
製品形態
本発明の骨吸収抑制剤（Ａ）の製品形態については、特に限定されず、投与形態に応じて適宜選択すればよい。例えば、本発明の骨吸収抑制剤の投与形態が経口投与である場合は、経口投与が可能であることを限度として特に限定されないが、具体的には、飲食品及び内服用医薬品が挙げられる。
Product form The product form of the bone resorption inhibitor (A) of the present invention is not particularly limited and may be appropriately selected depending on the administration form. For example, when the administration form of the bone resorption inhibitor of the present invention is oral administration, the present invention is not particularly limited as long as oral administration is possible, and specific examples thereof include foods and drinks and oral medicines.
本発明の骨吸収抑制剤（Ａ）を飲食品の製品形態にする場合、本発明の有効成分である緑藻綱に属する藻類及び／又は紅藻綱に属する藻類の抽出物をそのまま又は他の食品素材や添加成分と組み合わせて所望の形態に調製すればよい。このような飲食品としては、一般の飲食品の他、特定保健用食品、機能性表示食品、栄養補助食品、病者用食品等が挙げられる。これらの飲食品の形態としては、特に制限されないが、具体的には、カプセル剤（ソフトカプセル剤、ハードカプセル剤）、錠剤、顆粒剤、粉剤、ゼリー剤、トロミ剤等のサプリメント；栄養ドリンク、果汁飲料、炭酸飲料、乳酸飲料等の飲料；団子、アイス、シャーベット、グミ、キャンディー等の嗜好品等が挙げられる。これらの飲食品の中でも、好ましくはサプリメント、より好ましくは錠剤、ゼリー剤、トロミ剤が挙げられる。 When the bone resorption inhibitor (A) of the present invention is made into a product form of food and drink, the algae belonging to Chlorophycean and / or the algae belonging to Red algae, which are the active ingredients of the present invention, are used as they are or other foods. It may be prepared in a desired form in combination with a material or an additive component. Examples of such foods and drinks include general foods and drinks, foods for specified health use, foods with functional claims, dietary supplements, foods for the sick, and the like. The form of these foods and drinks is not particularly limited, but specifically, supplements such as capsules (soft capsules, hard capsules), tablets, granules, powders, jellies, and tromi agents; nutritional drinks, fruit juice beverages, etc. , Carbonated drinks, lactic acid drinks and the like; luxury products such as dumplings, ice cream, sherbet, gummy and candy. Among these foods and drinks, supplements are preferable, and tablets, jellies and tromi agents are more preferable.
本発明の骨吸収抑制剤（Ａ）が飲食品である場合、本発明の有効成分である緑藻綱に属する藻類及び／又は紅藻綱に属する藻類の抽出物の含有量としては、特に限定されず、摂取量と製品形態に応じて適宜設計することができるが、例えば、前記抽出物の乾燥重量で５〜５０質量％、好ましくは２０〜５０質量％が挙げられる。 When the bone resorption inhibitor (A) of the present invention is a food or drink, the content of the extract of algae belonging to Chlorophycean and / or algae belonging to Red algae, which is the active ingredient of the present invention, is particularly limited. However, it can be appropriately designed according to the intake amount and the product form, and examples thereof include 5 to 50% by mass, preferably 20 to 50% by mass, based on the dry weight of the extract.
本発明の骨吸収抑制剤（Ａ）を内服用の医薬品の製品形態にする場合、本発明の有効成分である緑藻綱に属する藻類及び／又は紅藻綱に属する藻類の抽出物を、そのまま又は他の添加成分と組み合わせて所望の形態に調製すればよい。このような内服用の医薬品としては、具体的には、カプセル剤（ソフトカプセル剤、ハードカプセル剤）、錠剤、顆粒剤、粉剤、ゼリー剤、シロップ剤、トロミ剤等が挙げられる。これらの内服用の医薬品の中でも、好ましくはカプセル剤、錠剤、顆粒剤、粉剤、トロミ剤が挙げられる。 When the bone resorption inhibitor (A) of the present invention is used as a product form of a pharmaceutical product for internal use, the extract of algae belonging to Chlorophycean and / or algae belonging to Red algae, which is the active ingredient of the present invention, may be used as it is or It may be prepared in a desired form in combination with other additive components. Specific examples of such medicines for internal use include capsules (soft capsules, hard capsules), tablets, granules, powders, jellies, syrups, tromis and the like. Among these medicines for internal use, capsules, tablets, granules, powders, and tromi agents are preferable.
本発明の骨吸収抑制剤（Ａ）が内服用の医薬品である場合、本発明の有効成分である緑藻綱に属する藻類及び／又は紅藻綱に属する藻類の抽出物の含有量としては、特に限定されず、摂取量と製品形態に応じて適宜設計することができるが、例えば、抽出物の乾燥重量で３０〜８０質量％、好ましくは５０〜８０質量％が挙げられる。 When the bone resorption inhibitor (A) of the present invention is a pharmaceutical product for internal use, the content of the extract of algae belonging to Chlorophycean and / or algae belonging to Red algae, which is the active ingredient of the present invention, is particularly high. It is not limited and can be appropriately designed according to the intake amount and the product form, and examples thereof include 30 to 80% by mass, preferably 50 to 80% by mass, based on the dry weight of the extract.
また、本発明の骨吸収抑制剤（Ａ）が医薬品である場合、他の製品形態としては、例えば、ひざ、関節等の局所投与用、又は全身投与用の注射剤等が挙げられる。 When the bone resorption inhibitor (A) of the present invention is a pharmaceutical product, other product forms include, for example, an injection for local administration of knees, joints, etc., or an injection for systemic administration.
用途
本発明の骨吸収抑制剤（Ａ）は、骨吸収を抑制し得るので、骨吸収の抑制により症状が改善され得る疾患の治療又は予防目的で使用することができる。骨吸収の抑制により症状が改善され得る疾患としては、特に限定されず、例えば、骨粗鬆症、骨ページェット病、副甲状腺機能亢進症等の骨代謝異常による骨疾患、及び罹患者の多い関節リウマチ、歯周病等が挙げられる。また、骨粗鬆症は、骨吸収が亢進することによって発症している骨吸収亢進型と、骨形成が抑制されていることによって発症している骨形成抑制型に大別されるが、本発明の骨吸収抑制剤（Ａ）は、骨吸収亢進型の骨粗鬆症の予防又は治療に卓越した効果を奏することができる。
Uses Since the bone resorption inhibitor (A) of the present invention can suppress bone resorption, it can be used for the purpose of treating or preventing a disease in which symptoms can be improved by suppressing bone resorption. Diseases whose symptoms can be improved by suppressing bone resorption are not particularly limited, and include, for example, bone diseases due to abnormal bone metabolism such as osteoporosis, Paget's disease of bone, and hyperparathyroidism, and rheumatoid arthritis, which is often affected. Examples include periodontal disease. In addition, osteoporosis is roughly classified into a bone resorption-enhancing type caused by increased bone resorption and a bone formation-suppressing type caused by suppression of bone formation. The resorption inhibitor (A) can exert an outstanding effect in the prevention or treatment of bone resorption-type osteoporosis.
また、骨吸収が亢進することによって骨代謝異常が生じることがあり、この傾向は高齢者で多く認められている。従って、本発明の骨吸収抑制剤（Ａ）は、骨吸収が亢進している骨代謝異常の改善に使用でき、特に骨吸収が亢進している高齢者の骨代謝異常の改善に好適に使用できる。 In addition, increased bone resorption may cause abnormal bone metabolism, and this tendency is often observed in the elderly. Therefore, the bone resorption inhibitor (A) of the present invention can be used for improving bone metabolism abnormalities in which bone resorption is enhanced, and is particularly preferably used for improving bone metabolism abnormalities in elderly people with enhanced bone resorption. it can.
更に、がんの骨転移が認められるがん患者では、骨吸収が亢進していることが多く認められている。そのため、本発明では、がんの骨転移の予防目的で使用することもできる。 Furthermore, it is often observed that bone resorption is enhanced in cancer patients with bone metastasis of cancer. Therefore, in the present invention, it can also be used for the purpose of preventing bone metastasis of cancer.
２．アルギン酸及び／又はその塩を使用した骨吸収抑制剤
本発明の骨吸収抑制剤は、アルギン酸及び／又はその塩を有効成分とすることを特徴とする。以下、当該骨吸収抑制剤を「骨吸収抑制剤（Ｂ）」と表記することもある。以下、本発明の骨吸収抑制剤（Ｂ）について詳述する。
2. Bone resorption inhibitor using alginic acid and / or a salt thereof The bone resorption inhibitor of the present invention is characterized by containing alginic acid and / or a salt thereof as an active ingredient. Hereinafter, the bone resorption inhibitor may be referred to as "bone resorption inhibitor (B)". Hereinafter, the bone resorption inhibitor (B) of the present invention will be described in detail.
有効成分
アルギン酸とは、Ｄ−マンヌロン酸とＬ−グルロン酸の２種のウロン酸が直鎖状に重合した高分子多糖である。
アルギン酸の塩としては、可食性のもの、又は薬学的に許容されるものであることを限度として、特に制限されないが、例えば、ナトリウム塩、カリウム塩等のアルカリ金属塩；カルシウム塩、マグネシウム塩等のアルカリ土類金属塩；アンモニウム塩；モノエタノールアミン塩、ジエタノールアミン塩等のアミン塩；アルギニン、リジン、ヒスチジン、オルニチン等の塩基性アミノ酸塩等が挙げられる。これらの塩の中でも、好ましくはアルカリ金属塩、更に好ましくはナトリウム塩が挙げられる。これらの塩は、１種単独で使用してもよいし、２種以上を組み合わせて使用してもよい。
本発明における有効成分として、アルギン酸、アルギン酸塩の双方を使用することができるが、アルギン酸塩が好ましい。
The active ingredient alginic acid is a high molecular weight polysaccharide in which two kinds of uronic acids, D-mannuronic acid and L-gluuronic acid, are linearly polymerized.
The salt of alginic acid is not particularly limited as long as it is edible or pharmaceutically acceptable, but for example, alkali metal salts such as sodium salt and potassium salt; calcium salt, magnesium salt and the like. Alkaline earth metal salts; ammonium salts; amine salts such as monoethanolamine salts and diethanolamine salts; basic amino acid salts such as arginine, lysine, histidine, ornithine and the like. Among these salts, an alkali metal salt is preferable, and a sodium salt is more preferable. These salts may be used alone or in combination of two or more.
Both alginic acid and alginate can be used as the active ingredient in the present invention, but alginate is preferable.
本発明におけるアルギン酸及び／又はその塩は、精製物であってもよいし、粗精製物であってもよい。粗精製物としては、例えば、アルギン酸及び／又はその塩を含む原料の抽出物等が挙げられる。アルギン酸及び／又はその塩を含む抽出原料としては、海藻、好ましくは褐藻綱に属する藻類が挙げられる。また、アルギン酸及び／又はその塩は、市販品であってもよい。 The alginic acid and / or a salt thereof in the present invention may be a purified product or a crude product. Examples of the crude product include extracts of raw materials containing alginic acid and / or a salt thereof. Examples of the extraction raw material containing alginic acid and / or a salt thereof include seaweeds, preferably algae belonging to the class Brown algae. Further, alginic acid and / or a salt thereof may be a commercially available product.
褐藻綱に属する藻類としては、例えば、ガゴメコンブ、マコンブ、オニコンブ、リシリコンブ、ワカメ、アラメ、カジメ、クロメ、マクロシスティス、レッソニア等のコンブ目；モズク、オキナワモズク等のナガマツモ目；ヒジキ、アカモク、ダービリア、アスコフィラム等のヒバマタ目；カヤモノリ、ハバノリ等のカヤモノリ目；ムチモ目；ウスバオオギ目；クロガシラ目；アミジグサ目；チロプテリス目；アスコセイラ目；等に属する藻類が挙げられ、なかでも、アルギン酸及び／又はその塩をより多く得られる点で、好ましくはコンブ目、又はヒバマタ目の藻類、より好ましくは、マクロシスティス、レッソニア、カジメ、マコンブ、ダービリア、又はアスコフィラムが挙げられる。 Examples of algae belonging to the brown algae include kelp, Fucales, Fucales, Fucales, Fucales, Fucales, Fucales, Fucales, Fucales, Fucales, Fucales, Fucales, Fucales, Fucales, Fucales, Fucales, Fucales, Fucales, Fucales. , Fucales such as Ascophyllum; Fucales such as Kayamonori and Habanori; Muchimo; Usbaogi; Kurogashira; The algae of the order Kelp or Fucales are preferably used, and more preferably, Macrocystis, Lessonia, Kajime, Macomb, Daviria, or Ascophyllum can be mentioned.
抽出原料からアルギン酸及び／又はその塩を抽出する方法としては、特に限定されず公知の方法を用いればよく、例えば、抽出原料を水性溶媒で抽出処理し、必要に応じて抽出物を精製する方法が挙げられる。抽出処理、精製処理としては、前述の骨吸収抑制剤（Ａ）における抽出処理、精製処理と同様の方法が挙げられる。 The method for extracting alginic acid and / or a salt thereof from the extraction raw material is not particularly limited, and a known method may be used. For example, a method in which the extraction raw material is extracted with an aqueous solvent and the extract is purified if necessary. Can be mentioned. Examples of the extraction treatment and purification treatment include the same methods as those for the extraction treatment and purification treatment of the bone resorption inhibitor (A) described above.
添加成分
本発明の骨吸収抑制剤（Ｂ）は、前述したアルギン酸及び／又はその塩以外に、本発明の効果を損なわない範囲で、剤型に応じて、他の添加成分を含有していてもよい。本発明の骨吸収抑制剤（Ｂ）に含有され得る他の添加成分としては、前述の骨吸収抑制剤（Ａ）における他の添加成分と同様のものが挙げられる。
Additive component The bone resorption inhibitor (B) of the present invention contains other additive components in addition to the above-mentioned alginic acid and / or a salt thereof, depending on the dosage form, as long as the effects of the present invention are not impaired. May be good. Examples of other additive components that can be contained in the bone resorption inhibitor (B) of the present invention include the same as the other additive components in the bone resorption inhibitor (A) described above.
本発明の骨吸収抑制剤（Ｂ）におけるアルギン酸及び／又はその塩の含有量としては、特に限定されず、剤型や製品形態、用法等に応じて適宜設計することができるが、例えば、５〜８０質量％、好ましくは５０〜８０質量％、より好ましくは７０〜８０質量％が挙げられる。 The content of alginic acid and / or a salt thereof in the bone resorption inhibitor (B) of the present invention is not particularly limited and can be appropriately designed according to the dosage form, product form, usage and the like. -80% by mass, preferably 50-80% by mass, more preferably 70-80% by mass.
剤型
本発明の骨吸収抑制剤（Ｂ）の剤型については、特に限定されず、前述の骨吸収抑制剤（Ａ）における剤型と同様のものが挙げられる。
Dosage Form The dosage form of the bone resorption inhibitor (B) of the present invention is not particularly limited, and examples thereof include the same dosage forms as those of the bone resorption inhibitor (A) described above.
投与方法
本発明の骨吸収抑制剤（Ｂ）の投与方法については、特に限定されず、前述の骨吸収抑制剤（Ａ）における投与方法と同様の方法が挙げられる。
Administration Method The administration method of the bone resorption inhibitor (B) of the present invention is not particularly limited, and examples thereof include the same method as the administration method of the bone resorption inhibitor (A) described above.
本発明の骨吸収抑制剤（Ｂ）の摂取量については、特に限定されず、製品形態、用法等に応じて適宜設定されるが、例えば、経口摂取量としては、アルギン酸及び／又はその塩換算で、成人一日あたり、好ましくは５０〜２００ｍｇ、より好ましくは１００〜２００ｍｇが挙げられる。本発明の骨吸収抑制剤は、一日あたりの量が上述の範囲となるように、１回又は数回に分けて投与してもよい。 The intake amount of the bone resorption inhibitor (B) of the present invention is not particularly limited and is appropriately set according to the product form, usage, etc. For example, the oral intake amount is converted to alginic acid and / or a salt thereof. The amount is preferably 50 to 200 mg, more preferably 100 to 200 mg per day for an adult. The bone resorption inhibitor of the present invention may be administered once or in several divided doses so that the daily amount is within the above range.
製品形態
本発明の骨吸収抑制剤（Ｂ）の製品形態については、特に限定されず、前述の骨吸収抑制剤（Ａ）における製品形態と同様の形態が挙げられる。
Product form The product form of the bone resorption inhibitor (B) of the present invention is not particularly limited, and examples thereof include the same form as the product form of the bone resorption inhibitor (A) described above.
本発明の骨吸収抑制剤（Ｂ）が飲食品である場合、有効成分であるアルギン酸及び／又はその塩の含有量としては、特に限定されず、摂取量と製品形態に応じて適宜設計することができるが、例えば、５〜５０質量％、好ましくは２５〜５０質量％が挙げられる。 When the bone resorption inhibitor (B) of the present invention is a food or drink, the content of the active ingredient alginic acid and / or a salt thereof is not particularly limited, and should be appropriately designed according to the intake amount and the product form. However, for example, 5 to 50% by mass, preferably 25 to 50% by mass can be mentioned.
本発明の骨吸収抑制剤（Ｂ）が内服用の医薬品である場合、有効成分であるアルギン酸及び／又はその塩の含有量としては、特に限定されず、摂取量と製品形態に応じて適宜設計することができるが、例えば、３０〜７０質量％、好ましくは５０〜７０質量％が挙げられる。 When the bone resorption inhibitor (B) of the present invention is a pharmaceutical product for internal use, the content of the active ingredient alginic acid and / or a salt thereof is not particularly limited, and is appropriately designed according to the intake amount and the product form. However, for example, 30 to 70% by mass, preferably 50 to 70% by mass can be mentioned.
用途
本発明の骨吸収抑制剤（Ｂ）は、骨吸収を抑制し得るので、骨吸収の抑制により症状が改善され得る疾患の治療又は予防目的で使用することができ、前述の骨吸収抑制剤（Ａ）における用途と同様の用途に適用できる。
Uses Since the bone resorption inhibitor (B) of the present invention can suppress bone resorption, it can be used for the purpose of treating or preventing diseases in which the symptoms can be improved by suppressing bone resorption, and the above-mentioned bone resorption inhibitor can be used. It can be applied to the same applications as those in (A).
このように本発明の骨吸収抑制剤は、骨吸収抑制作用に優れる。そのため、本発明の骨吸収抑制剤は、骨代謝改善用途に使用することができる。また、本発明の骨吸収抑制剤は、骨疾患の予防又は治療に使用することができる。 As described above, the bone resorption inhibitor of the present invention is excellent in the bone resorption inhibitory action. Therefore, the bone resorption inhibitor of the present invention can be used for improving bone metabolism. In addition, the bone resorption inhibitor of the present invention can be used for the prevention or treatment of bone diseases.
次に、本発明を実施例によりさらに詳細に説明するが、本発明は、これらの例によってなんら限定されるものではない。 Next, the present invention will be described in more detail with reference to Examples, but the present invention is not limited to these examples.
調製例１
＜海藻由来の抽出物の調製＞
下記に示す原料海藻の乾燥体を、粉砕機で０．０１〜０．１ｍｍ程度の大きさに粉砕した。得られた粉砕乾燥体に５倍量のエタノールを添加し、室温にて３０分間撹拌した。これを吸引ろ過機（ろ紙Ｎｏ．５Ｃ）でろ過した後、得られた残渣に２０倍量の純水を加え、１００℃で３０分加熱処理した。次いで、冷却後、遠心分離（８，０００×Ｇ）して、遠心上清をロータリーエバポレーターで濃縮し、得られた濃縮液に、得られた濃縮液に４倍量のアセトンを加え、濃縮液中の沈殿物を純水に溶解し、得られた溶液を純水中で一晩透析した。透析後の溶液を、イオン交換樹脂（三菱化学ＤＩＡＩＯＮ ＳＥＰＡＢＥＡＤＳ ＳＡ１０Ａ）を充填したカラムに供して吸着させた後、０．１Ｍ、０．２Ｍ、０．５Ｍ、１．０Ｍ、１．５Ｍ、及び２．０Ｍ ＮａＣｌ溶液を順にカラムに流し、吸着成分を溶出させた。各濃度のＮａＣｌ溶液により得られた溶出画分をそれぞれ透析し、ガラス繊維ろ紙（ＷｈａｔｍａｎＧＦ／Ａ）にてろ過後、凍結乾燥して、粉末状の溶出画分を得た。得られた溶出画分のうち、１．０Ｍ、１．５Ｍ及び２．０Ｍ ＮａＣｌ溶出画分を海藻由来の抽出物とした。
Preparation Example 1
<Preparation of seaweed-derived extract>
The dried raw material seaweed shown below was pulverized with a pulverizer to a size of about 0.01 to 0.1 mm. Five times the amount of ethanol was added to the obtained pulverized and dried product, and the mixture was stirred at room temperature for 30 minutes. This was filtered through a suction filter (filter paper No. 5C), 20 times the amount of pure water was added to the obtained residue, and heat treatment was performed at 100 ° C. for 30 minutes. Then, after cooling, centrifugation (8,000 × G) was performed, and the centrifugal supernatant was concentrated with a rotary evaporator. To the obtained concentrated solution, 4 times the amount of acetone was added to the obtained concentrated solution, and the concentrated solution was added. The precipitate inside was dissolved in pure water, and the obtained solution was dialyzed in pure water overnight. The solution after dialysis was applied to a column packed with an ion exchange resin (Mitsubishi Chemical DIAION SEPABEADS SA10A) and adsorbed, and then 0.1M, 0.2M, 0.5M, 1.0M, 1.5M, and 2 A 0.0M NaCl solution was flowed through the column in order to elute the adsorbed components. The elution fractions obtained from the NaCl solutions of each concentration were dialyzed, filtered through glass fiber filter paper (WhatmanGF / A), and then freeze-dried to obtain a powdery elution fraction. Of the obtained eluted fractions, 1.0M, 1.5M and 2.0M NaCl-eluting fractions were used as seaweed-derived extracts.
＜原料海藻＞
ミル（Ｃｏｄｉｕｍ ｆｒａｇｉｌｅ）（株式会社海の研究舎より購入）
スジアオノリ（Ｅｎｔｅｒｏｍｏｒｐｈａ ｐｒｏｌｉｆｅｒａ）（株式会社海の研究舎および三島食品より購入）
ヒトエグサ（Ｍｏｎｏｓｔｒｏｍａ ｎｉｔｉｄｕｍ）（株式会社海の研究舎より購入）
クロハギンナンソウ（Ｃｈｏｎｄｒｕｓ ｙｅｎｄｏｉ）（有限会社川上海産物店より購入）
スサビノリ（Ｐｙｒｏｐｉａ ｙｅｚｏｅｎｓｉｓ）（海苔）（新富津漁協より購入）
<Raw material seaweed>
Mill (Codium frame) (purchased from Umi no Kenkyusha Co., Ltd.)
Sea lettuce (Entheromorpha prolifera) (purchased from Kai no Kenkyusha Co., Ltd. and Mishima Foods Co., Ltd.)
Monostroma nitidum (purchased from Umi no Kenkyusha Co., Ltd.)
Kurohaginnansou (Chondrus yendoi) (purchased from Kawa Shanghai Product Store Co., Ltd.)
Neopyropia yezoensis (seaweed) (purchased from Shin-Futtsu Fisheries Cooperative)
実施例、比較例
調製例１で得られた海藻由来の抽出物、又は表１に示す市販の試料を骨吸収アッセイに供し、骨吸収作用を評価した。骨吸収アッセイ及び骨吸収作用の評価は下記の方法で行った。各実施例、比較例に用いた試料を表１に示す。
Examples, Comparative Examples The seaweed-derived extracts obtained in Preparation Example 1 or the commercially available samples shown in Table 1 were subjected to a bone resorption assay to evaluate the bone resorption effect. The bone resorption assay and the evaluation of the bone resorption effect were performed by the following methods. Table 1 shows the samples used in each example and comparative example.
＜骨吸収（ＰＩＴ）アッセイ法＞
骨吸収作用の測定は、Ｐｒｉｍａｒｙ Ｃｅｌｌ社より破骨細胞培養キットＯＳＣ１１ないしＯＳＣ１２を用い、ラット破骨前駆細胞によって行った。具体的には、まず、凍結保存された破骨前駆細胞をすばやく解凍し、洗浄用メディウムで懸濁、遠心した（２００×Ｇ）。上清を除去した後、細胞に分化培養用メディウム（血清、Ｍ−ＣＳＦ（５０ｎｇ／ｍｌ）、ＲＡＮＫＬ（１５ｎｇ／ｍｌ）を含むα−ＭＥＭ）を加えて、４×１０4ｃｅｌｌ／ｗｅｌｌ（１００μｌ）となるように９６ｗｅｌｌオステオアッセイプレート（Ｃｏｒｎｉｎｇ社製３９８８または３９８９）に播種した。その後、５％ＣＯ2存在下の３７℃インキュベータで培養し、播種後３日目に培養用メディウムを交換するとともに、ＰＢＳに溶解した試料（表１に記載の有効成分）を培養用メディウム中１００μｇ／ｍｌ（アレンドロン酸ナトリウム三水和物は１０μｇ／ｍｌ）となるように添加し、それ以降３日毎に、同様に培養用メディウムを交換し、各試料を添加する処理を行った。播種して２１日間の培養後、プレートの培養液を取り除き、５％次亜塩素酸ナトリウム（ＮａＣｌＯ）液を１００μｌ加え室温にて５分間置いた。ＮａＣｌＯ液を除き、１５０μｌの純水を加えて洗浄する工程を２回繰り返し、３時間以上風乾してから、顕微鏡下で骨吸収窩すなわち骨（合成骨表面）の溶けた部分（ＰＩＴ）を観察・撮影した。なお、使用したオステオアッセイプレートは、骨の構造を模した合成表面であり、無機結晶性リン酸カルシウムがコーティングされている。各試料の代わりにＰＢＳ（Ｃａ2+，Ｍｇ2+フリーリン酸緩衝生理食塩水）を添加した場合をコントロールとした。
<Bone resorption (PIT) assay>
The bone resorption effect was measured by rat osteoclast progenitor cells using osteoclast culture kits OSC11 to OSC12 from Primery Cell. Specifically, first, the cryopreserved osteoclast precursor cells were quickly thawed, suspended in a washing medium, and centrifuged (200 × G). After removing the supernatant, a medium for differentiation culture (serum, α-MEM containing M-CSF (50 ng / ml) and RANKL (15 ng / ml)) was added to the cells, and 4 × 10 4 cell / well (100 μl) was added. ) Was seeded on a 96-well Osteoassay plate (3988 or 3899 manufactured by Corning). Then, the cells were cultured in a 37 ° C. incubator in the presence of 5% CO 2 , the culture medium was replaced on the 3rd day after sowing, and a sample dissolved in PBS (active ingredient shown in Table 1) was 100 μg in the culture medium. The culture medium was added so as to be / ml (10 μg / ml for alendronate sodium trihydrate), and the culture medium was similarly exchanged every 3 days thereafter, and each sample was added. After seeding and culturing for 21 days, the culture solution on the plate was removed, 100 μl of 5% sodium hypochlorite (NaClO) solution was added, and the mixture was allowed to stand at room temperature for 5 minutes. The process of removing the NaClO solution, adding 150 μl of pure water and washing is repeated twice, and after air-drying for 3 hours or more, the bone resorption fossa, that is, the melted part (PIT) of the bone (synthetic bone surface) is observed under a microscope.・ I took a picture. The osteoassay plate used is a synthetic surface that imitates the structure of bone and is coated with inorganic crystalline calcium phosphate. The control was the case where PBS (Ca 2+ , Mg 2+ free phosphate buffered saline) was added instead of each sample.
＜骨吸収作用の算出とグラフ化＞
Ｉｍａｇｅ Ｊソフトウェアにより、撮影した画像内の骨吸収を起こしている面積を計算しグラフ化した。具体的には、ＪＰＥＧ方式で保存した各画像を、Ｉｍａｇｅ Ｊソフトウェアを用いて、画像の全面積に対する骨吸収部位の面積の割合をスコア化し、コントロールとともにグラフに表した。
<Calculation and graphing of bone resorption>
ImageJ software calculated and graphed the area of bone resorption in the captured image. Specifically, each image stored by the JPEG method was scored using ImageJ software to score the ratio of the area of the bone resorption site to the total area of the image, and was shown in a graph together with the control.
ＰＩＴアッセイを用いた実験を繰り返し行った。その結果を図１〜６に示す。図１、３及び５は、各種試料を添加して２１日間培養した後のオステオアッセイプレートセルの表面の様子を示す。図の白い部分は骨吸収窩（生体での骨溶解に相当）である。図２、４及び６は、それぞれ図１、３及び５の画像の全面積に対する骨吸収窩（骨吸収部位）の面積の割合を示すグラフである。図１及び図２から、緑藻（ミル、スジアオノリ、ヒトエグサ）の抽出物を添加した場合、コントロールと比較して、骨吸収が抑制されることが認められた。 Experiments using the PIT assay were repeated. The results are shown in FIGS. 1 to 6. FIGS. 1, 3 and 5 show the state of the surface of the osteoassay plate cell after adding various samples and culturing for 21 days. The white part in the figure is the bone resorption fossa (corresponding to osteolysis in the living body). FIGS. 2, 4 and 6 are graphs showing the ratio of the area of the bone resorption fossa (bone resorption site) to the total area of the images of FIGS. 1, 3 and 5, respectively. From FIGS. 1 and 2, it was confirmed that when the extract of green algae (Mill, Sujiaonori, Monostroma nitidum) was added, bone resorption was suppressed as compared with the control.
また、図３及び４にみられるように、紅藻クロハギンナンソウ、及び緑藻ミルの抽出物は、コントロールと比較して、非常に高い骨吸収抑制作用を示した。 In addition, as seen in FIGS. 3 and 4, the extracts of the red alga Kurohaginnansou and the green alga mill showed a very high bone resorption inhibitory effect as compared with the control.
また、図５及び６にみられるように、紅藻スサビノリ、及び緑藻スジアオノリの抽出物は、コントロールと比較して、非常に高い骨吸収抑制作用を示した。また、これらの抽出物は、１０分の１量のアレンドロン酸（ボナロン）の骨吸収抑制効果と同等の効果を示した。アレンドロン酸（ボナロン）は、臨床で広く使用されている骨粗鬆症治療薬である。また、これらの抽出物は、コンドロイチン硫酸Ｅと比べて高い骨吸収抑制作用を示した。 In addition, as seen in FIGS. 5 and 6, the extracts of the red alga Neopyropia yezoensis and the green alga Neopyropia yezoensis showed a very high bone resorption inhibitory effect as compared with the control. Moreover, these extracts showed the same effect as the bone resorption inhibitory effect of 1/10 amount of alendronic acid (Bonaron). Alendronic acid (Bonaron) is a widely used clinically used treatment for osteoporosis. In addition, these extracts showed a higher bone resorption inhibitory effect than chondroitin sulfate E.
本実験例における骨吸収アッセイには、初代培養のラット破骨前駆細胞のみを使用し、骨芽細胞（破骨細胞分化誘導物質ＲＡＮＫＬおよび破骨細胞形成抑制因子ＯＣＩＦを産生）を共存させず、分化誘導剤としてＲＡＮＫＬを添加した系を用いた。また、本アッセイでは象牙片を用いず、オステオアッセイプレートを用いた。用いたオステオアッセイプレートには、無機リン酸カルシウムのみがコーティングされているので、象牙片のようにコラーゲンや酸性多糖の豊富な健康な骨のモデルではなく、加齢により弾力を維持する成分が減少しているモデルと考えられる。従って、本実験例から、緑藻綱に属する藻類及び紅藻綱に属する藻類の抽出物は、加齢により弾力を維持する成分が減少している骨組織の状態において、極めて高く骨吸収を抑制し得ることがわかった。骨吸収亢進の代表的な疾患である骨粗鬆症の患者の８０％以上が閉経後の女性であるといわれている。この治療薬として用いられてきたエストロゲン製剤は、副作用として女性器発がんのリスクを高め、また優れた骨吸収抑制剤であるビスホスホネート製剤は、消化器粘膜に障害を起こすリスクがある。本発明の骨吸収抑制剤は、前述のようなリスクは低いと想定され、骨吸収亢進による疾患に広く適用可能である。 In the bone resorption assay in this experimental example, only primary-cultured rat osteoclast progenitor cells were used, and osteoblasts (producing osteoclast differentiation inducer RANKL and osteoclast formation inhibitor OCIF) were not allowed to coexist. A system to which RANKL was added was used as a differentiation inducer. In this assay, ivory pieces were not used, but an Osteoassay plate was used. Since the osteoassay plate used was coated with only inorganic calcium phosphate, it was not a model of healthy bone rich in collagen and acidic polysaccharides like ivory pieces, but the components that maintain elasticity decreased with age. It is considered to be a model. Therefore, from this experimental example, the extracts of algae belonging to Chlorophycean and algae belonging to Red algae suppress bone resorption extremely high in the state of bone tissue in which the component that maintains elasticity decreases with aging. Turned out to get. It is said that more than 80% of patients with osteoporosis, which is a typical disease of bone resorption, are postmenopausal women. The estrogen preparation used as this therapeutic agent increases the risk of female genital carcinogenesis as a side effect, and the bisphosphonate preparation, which is an excellent bone resorption inhibitor, has a risk of causing damage to the gastrointestinal mucosa. The bone resorption inhibitor of the present invention is assumed to have a low risk as described above, and can be widely applied to diseases caused by increased bone resorption.
Claims (4)
前記抽出物が、前記藻類のエタノール処理残渣の水抽出物である骨吸収抑制剤。 The active ingredient is an extract of algae belonging to Mill, Neopyropia yezoensis, Monostroma nitidum, Monostroma nitidum, and / or Neopyropia yezoensis .
Wherein the extract, water extract der Rukotsu absorption inhibitor of the ethanol treatment residues of the algae.
前記抽出物が、前記藻類のエタノール処理残渣の水抽出物である、骨吸収抑制用飲食品。 The active ingredient is an extract of algae belonging to Mill, Neopyropia yezoensis, Monostroma nitidum, Monostroma nitidum, and / or Neopyropia yezoensis.
A food or drink for suppressing bone resorption, wherein the extract is a water extract of the ethanol-treated residue of the algae.
前記抽出物が、前記藻類のエタノール処理残渣の水抽出物である、骨吸収抑制用医薬品。
The active ingredient is an extract of algae belonging to Mill, Neopyropia yezoensis, Monostroma nitidum, Monostroma nitidum, and / or Neopyropia yezoensis.
Wherein the extract, the a water extract of the ethanol the residue was treated algae, bone resorption suppressing pharmaceutical products.
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