JP5553168B2 - Improvement agent of brain function decline - Google Patents
Improvement agent of brain function decline Download PDFInfo
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- JP5553168B2 JP5553168B2 JP2010527818A JP2010527818A JP5553168B2 JP 5553168 B2 JP5553168 B2 JP 5553168B2 JP 2010527818 A JP2010527818 A JP 2010527818A JP 2010527818 A JP2010527818 A JP 2010527818A JP 5553168 B2 JP5553168 B2 JP 5553168B2
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- mannosamine
- memory
- brain function
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- 230000002194 synthesizing effect Effects 0.000 description 1
- 239000011975 tartaric acid Substances 0.000 description 1
- 235000002906 tartaric acid Nutrition 0.000 description 1
- 230000001225 therapeutic effect Effects 0.000 description 1
- 231100000331 toxic Toxicity 0.000 description 1
- 230000002588 toxic effect Effects 0.000 description 1
- 238000012795 verification Methods 0.000 description 1
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Description
本発明は、脳機能低下の改善剤に関し、詳しくは、Ｎ−アセチル−Ｄ−マンノサミンの医薬用途に関する。 The present invention relates to an agent for improving brain function deterioration, and in particular, to a pharmaceutical use of N-acetyl-D-mannosamine.
現在、老化に伴い表れる記憶障害を改善する薬物はない。老化に伴う脳機能の低下によって発症する様々な脳障害は、患者本人ばかりでなく、社会全体に対する影響も大きい。 Currently, there are no drugs that improve the memory impairment that occurs with aging. Various brain disorders that develop due to a decrease in brain function due to aging have a large impact not only on the patient himself but also on society as a whole.
Ｎ−アセチル−Ｄ−グルコサミンの異性体であるＮ−アセチル−Ｄ−マンノサミンは、例えば、医薬品や医薬品原料となるシアル酸（Ｎ−アセチルノイラミン酸）の酵素合成原料として知られている。また、Ｎ−アセチル−Ｄ−マンノサミンは、その誘導体から、シアル酸誘導体を酵素合成することが可能であり、産業上、重要な物質である。Ｎ−アセチル−Ｄ−マンノサミンの製造方法として、Ｎ−アセチルグルコサミンをアルカリ条件下で異性化する際に、ホウ酸またはホウ酸塩を添加することにより、Ｎ−アセチルマンノサミンへのモル変換収率を増大させる方法が知られている（特許文献１）。また、シアル酸を基質としてＮ−アセチルノイラミン酸リアーゼを反応させることにより、Ｎ−アセチル−Ｄ−マンノサミンを製造する方法も知られている（特許文献２）。 N-acetyl-D-mannosamine, which is an isomer of N-acetyl-D-glucosamine, is known, for example, as a raw material for enzyme synthesis of sialic acid (N-acetylneuraminic acid) that is used as a pharmaceutical or a raw material for pharmaceuticals. N-acetyl-D-mannosamine is an industrially important substance because it can enzymatically synthesize sialic acid derivatives from its derivatives. As a method for producing N-acetyl-D-mannosamine, when N-acetylglucosamine is isomerized under alkaline conditions, a molar conversion yield to N-acetylmannosamine is obtained by adding boric acid or borate. A method for increasing the rate is known (Patent Document 1). In addition, a method for producing N-acetyl-D-mannosamine by reacting N-acetylneuraminic acid lyase with sialic acid as a substrate is also known (Patent Document 2).
Ｎ−アセチル−Ｄ−マンノサミンは、シアル酸の合成原料または医薬品の中間体として利用されているが、最終産物として医薬品または食品に使用されていないのが現状である。さらに、Ｎ−アセチル−Ｄ−マンノサミンが脳機能低下の改善に有効であることは知られていない。 N-acetyl-D-mannosamine is used as a raw material for synthesizing sialic acid or an intermediate of pharmaceutical products, but is not currently used as a final product in pharmaceutical products or foods. Furthermore, N-acetyl-D-mannosamine is not known to be effective in improving brain function decline.
本発明は、上記事情に鑑み成されたもので、その解決しようとする課題は、脳機能の低下を原因とする様々な障害を改善するための、有効かつ安全性の高い剤および医薬などを提供することにある。 The present invention has been made in view of the above circumstances, and the problem to be solved is an effective and highly safe agent and medicine for improving various disorders caused by a decrease in brain function. It is to provide.
本発明者らは、上記課題を解決するため鋭意検討した結果、意外にもＮ−アセチル−Ｄ−マンノサミンが老齢動物を用いた動物実験において、記憶を改善する作用を有することを見出し、さらに検証を進め、本発明を完成するに至った。 As a result of intensive studies to solve the above problems, the present inventors have unexpectedly found that N-acetyl-D-mannosamine has an effect of improving memory in animal experiments using old animals, and further verification. The present invention has been completed.
即ち、本発明は以下のとおりである。
〔１〕 Ｎ−アセチル−Ｄ−マンノサミンを含有してなる、脳機能低下の予防または改善剤。
〔２〕 脳機能低下が老化に伴う脳機能低下である前記〔１〕記載の予防または改善剤。
〔３〕 場所の記憶障害、物体の記憶障害、情動障害および運動機能低下からなる群より選ばれる障害の予防または改善を目的とするものである前記〔１〕または〔２〕に記載の予防または改善剤。
〔４〕 医薬である、前記〔１〕〜〔３〕いずれかに記載の予防または改善剤。
〔５〕 保健機能食品または食品添加物である、前記〔１〕〜〔３〕いずれかに記載の予防または改善剤。
〔６〕 Ｎ−アセチル−Ｄ−マンノサミンの有効量および医薬として許容されうる担体を含有してなる、脳機能低下に起因する障害を予防、改善または治療するための医薬組成物。
〔７〕 障害が老化に伴う脳機能低下に起因するものである前記〔６〕記載の医薬組成物。
〔８〕 障害が場所の記憶障害、物体の記憶障害、情動障害および運動機能低下からなる群より選ばれる前記〔６〕記載の医薬組成物。
〔９〕 Ｎ−アセチル−Ｄ−マンノサミンを添加してなる食品。
〔１０〕 脳機能低下に起因する障害の予防、改善または治療用医薬を製造するためのＮ−アセチル−Ｄ−マンノサミンの使用。
〔１１〕 障害が老化に伴う脳機能低下に起因するものである前記〔１０〕記載の使用。
〔１２〕 障害が場所の記憶障害、物体の記憶障害、情動障害および運動機能低下からなる群より選ばれる前記〔１０〕記載の使用。
〔１３〕 Ｎ−アセチル−Ｄ−マンノサミンの有効量をそれを必要とする対象に投与する工程を含む、脳機能低下に起因する障害の予防、改善または治療方法。
〔１４〕 障害が老化に伴う脳機能低下に起因するものである前記〔１３〕記載の方法。
〔１５〕 障害が場所の記憶障害、物体の記憶障害、情動障害および運動機能低下からなる群より選ばれる前記〔１３〕記載の方法。
〔１６〕 Ｎ−アセチル−Ｄ−マンノサミンの有効量をそれを必要とする対象に摂取させる工程を含む、脳機能低下の予防または改善方法。
〔１７〕 脳機能低下が老化に伴う脳機能低下である前記〔１６〕記載の方法。
〔１８〕 場所の記憶障害、物体の記憶障害、情動障害および運動機能低下からなる群より選ばれる障害の予防または改善を目的とするものである前記〔１６〕または〔１７〕に記載の方法。
〔１９〕 前記〔１〕〜〔３〕、〔５〕いずれかに記載の予防または改善剤、および当該予防または改善剤が脳機能低下の予防または改善に使用することができることまたは使用すべきであることを記載した当該予防または改善剤に関する説明を記載した記載物を含む商業用パッケージ。
〔２０〕 前記〔６〕〜〔８〕いずれかに記載の医薬組成物、および当該医薬組成物が脳機能低下に起因する障害の予防、改善または治療に使用することができることまたは使用すべきであることを記載した当該医薬組成物に関する説明を記載した記載物を含む商業用パッケージ。That is, the present invention is as follows.
[1] An agent for preventing or improving brain function deterioration, comprising N-acetyl-D-mannosamine.
[2] The preventive or ameliorating agent according to [1], wherein the decrease in brain function is a decrease in brain function associated with aging.
[3] Prevention or improvement according to the above [1] or [2], which is intended for the prevention or improvement of a disorder selected from the group consisting of location memory disorder, object memory disorder, emotional disorder, and motor function deterioration Improver.
[4] The preventive or ameliorating agent according to any one of [1] to [3], which is a medicine.
[5] The preventive or improving agent according to any one of [1] to [3], which is a health functional food or food additive.
[6] A pharmaceutical composition for preventing, ameliorating or treating a disorder caused by reduced brain function, comprising an effective amount of N-acetyl-D-mannosamine and a pharmaceutically acceptable carrier.
[7] The pharmaceutical composition according to the above [6], wherein the disorder is caused by a decrease in brain function associated with aging.
[8] The pharmaceutical composition of the above-mentioned [6], wherein the disorder is selected from the group consisting of location memory disorder, object memory disorder, emotional disorder, and motor function deterioration.
[9] A food prepared by adding N-acetyl-D-mannosamine.
[10] Use of N-acetyl-D-mannosamine for the manufacture of a medicament for the prevention, amelioration or treatment of disorders caused by brain function deterioration.
[11] The use according to [10] above, wherein the disorder is caused by a decrease in brain function associated with aging.
[12] The use according to [10] above, wherein the disorder is selected from the group consisting of location memory disorder, object memory disorder, emotional disorder and motor function deterioration.
[13] A method for preventing, ameliorating or treating a disorder caused by brain function deterioration, comprising a step of administering an effective amount of N-acetyl-D-mannosamine to a subject in need thereof.
[14] The method described in [13] above, wherein the disorder is caused by a decrease in brain function associated with aging.
[15] The method according to [13] above, wherein the disorder is selected from the group consisting of location memory disorder, object memory disorder, emotional disorder, and motor function deterioration.
[16] A method for preventing or improving brain function deterioration, comprising a step of allowing a subject in need thereof to take an effective amount of N-acetyl-D-mannosamine.
[17] The method according to [16] above, wherein the decrease in brain function is a decrease in brain function associated with aging.
[18] The method according to [16] or [17], which is aimed at preventing or improving a disorder selected from the group consisting of memory disorder at a place, memory disorder at an object, emotional disorder, and motor function deterioration.
[19] The preventive or ameliorating agent according to any one of [1] to [3], [5], and the prophylactic or improving agent can or should be used for the prevention or improvement of brain function deterioration. A commercial package containing a description that describes the preventive or ameliorating agent that states that there is.
[20] The pharmaceutical composition according to any one of the above [6] to [8], and the pharmaceutical composition can or should be used for prevention, improvement or treatment of a disorder caused by a decrease in brain function. A commercial package containing a description that describes the pharmaceutical composition that states that it is.
本発明の脳機能低下の予防または改善剤によると、生体内の様々な細胞を賦活化することによって代謝を改善し、それによって脳の機能低下を遅延させ、あるいは低下した脳の機能を回復させることができる。かかる効果は、含有成分であるＮ−アセチル−Ｄ−マンノサミンが個々の細胞内に糖の代謝を促進させる物質として供給され、最終的に脳の機能改善をもたらすことによって発揮されると考えられる。したがって、Ｎ−アセチル−Ｄ−マンノサミンを有効成分として含有する本発明の医薬組成物は、生体全体の代謝の改善に作用することによって脳機能低下に伴って発症する様々な中枢性疾患（認知症、アルツハイマー型認知症、レビー小体型認知症、前頭側頭型認知症）などを予防、改善または治療することができる。また、本発明の食品は、単糖であるＮ−アセチル−Ｄ−マンノサミンを含むものであることから安全であり、日常的に摂取することにより、脳機能低下の予防または改善が期待できる。 According to the preventive or ameliorating agent for cerebral function lowering of the present invention, metabolism is improved by activating various cells in the living body, thereby delaying cerebral dysfunction or restoring reduced cerebral function. be able to. Such an effect is considered to be exerted by supplying N-acetyl-D-mannosamine, which is a contained component, as a substance that promotes sugar metabolism into individual cells, and finally improving brain function. Therefore, the pharmaceutical composition of the present invention containing N-acetyl-D-mannosamine as an active ingredient can be used for various central diseases (dementia) that develop as brain function decreases by acting on the improvement of metabolism in the whole organism. , Alzheimer's dementia, Lewy body dementia, frontotemporal dementia) and the like. In addition, the food of the present invention is safe because it contains N-acetyl-D-mannosamine, which is a monosaccharide, and prevention or improvement of brain function deterioration can be expected by daily intake.
本発明の脳機能低下の予防または改善剤（以下、単に「剤」と省略する場合がある）は、Ｎ−アセチル−Ｄ−マンノサミンを含有することを特徴とする。 The agent for preventing or improving brain function lowering (hereinafter sometimes simply referred to as “agent”) of the present invention contains N-acetyl-D-mannosamine.
本発明において、Ｎ−アセチル−Ｄ−マンノサミン（以下、ＭａｎＮＡｃと省略する場合がある）とは、下記式（Ｉ）： In the present invention, N-acetyl-D-mannosamine (hereinafter sometimes abbreviated as “ManNAc”) refers to the following formula (I):
で示される、Ｄ−マンノサミンのＮ−アセチル体である。 It is a N-acetyl body of D-mannosamine shown by these.
本発明において、Ｎ−アセチル−Ｄ−マンノサミンとは、上記式（Ｉ）で示される単体に限定されるものではなく、その塩、その溶媒和物またはその誘導体を含む概念である。 In the present invention, N-acetyl-D-mannosamine is not limited to the simple substance represented by the above formula (I) but is a concept including a salt, a solvate or a derivative thereof.
Ｎ−アセチル−Ｄ−マンノサミンの塩としては、薬理学的に許容し得る塩、例えば、無機酸との塩、有機酸との塩、塩基性または酸性アミノ酸との塩などがあげられる。 Examples of the salt of N-acetyl-D-mannosamine include pharmacologically acceptable salts such as salts with inorganic acids, salts with organic acids, salts with basic or acidic amino acids, and the like.
無機酸との塩の例としては、塩酸、臭化水素酸、硝酸、硫酸、リン酸などとの塩があげられる。 Examples of salts with inorganic acids include salts with hydrochloric acid, hydrobromic acid, nitric acid, sulfuric acid, phosphoric acid and the like.
有機酸との塩の例としては、安息香酸、ギ酸、酢酸、トリフルオロ酢酸、フマル酸、シュウ酸、酒石酸、マレイン酸、クエン酸、コハク酸、リンゴ酸、メタンスルホン酸、ベンゼンスルホン酸、ｐ−トルエンスルホン酸などとの塩が挙げられる。 Examples of salts with organic acids include benzoic acid, formic acid, acetic acid, trifluoroacetic acid, fumaric acid, oxalic acid, tartaric acid, maleic acid, citric acid, succinic acid, malic acid, methanesulfonic acid, benzenesulfonic acid, p -Salts with toluenesulfonic acid and the like.
塩基性アミノ酸との塩の例としては、アルギニン、リジン、オルニチンなどとの塩があげられ、酸性アミノ酸との塩の好適な例としては、アスパラギン酸、グルタミン酸などとの塩があげられる。 Examples of salts with basic amino acids include salts with arginine, lysine, ornithine, and preferred examples of salts with acidic amino acids include salts with aspartic acid, glutamic acid, and the like.
Ｎ−アセチル−Ｄ−マンノサミンの溶媒和物としては、好ましくは水和物（例、一水和物、二水和物など）、エタノレートなどがあげられる。 Preferred solvates of N-acetyl-D-mannosamine include hydrates (eg, monohydrate, dihydrate etc.), ethanolate and the like.
Ｎ−アセチル−Ｄ−マンノサミンの誘導体としては、下記式（ＩＩ）に示すものを含む。 N-acetyl-D-mannosamine derivatives include those represented by the following formula (II).
〔式中、Ｒ１、Ｒ２、Ｒ３、Ｒ４およびＲ５は各々独立して水素（Ｈ）、Ｒ６、−Ｃ(＝Ｏ)Ｒ６、−Ｃ（＝Ｏ）ＯＲ６、−Ｃ（＝Ｏ）ＮＲ６Ｒ７を示し、Ｒ６は置換していてもよいＣ１−Ｃ７の鎖状炭化水素または環状炭化水素を示し、Ｒ７は水素（Ｈ）、置換していてもよいＣ１−Ｃ７の鎖状炭化水素または環状炭化水素を示す。〕
置換基としてはＦ、Ｃｌ、Ｂｒを用いることができる。[Wherein R 1 , R 2 , R 3 , R 4 and R 5 are each independently hydrogen (H), R 6 , —C (═O) R 6 , —C (═O) OR 6 , — C (= O) NR 6 R 7 , R 6 represents an optionally substituted C 1 -C 7 chain hydrocarbon or cyclic hydrocarbon, R 7 represents hydrogen (H), substituted Or a C 1 -C 7 chain hydrocarbon or cyclic hydrocarbon. ]
As the substituent, F, Cl, or Br can be used.
Ｎ−アセチル−Ｄ−マンノサミンは、市販品を用いてもよく、公知の方法により製造したものを用いてもよい。Ｎ−アセチル−Ｄ−マンノサミンの製造方法として、Ｎ−アセチルグルコサミンをアルカリ条件下で異性化する方法（特開平１０−１８２６８５号公報）、シアル酸を基質としてＮ−アセチルノイラミン酸リアーゼを反応させることにより製造する方法（特開２００１−７８７９４号公報）があげられるが、これに限定されるものではない。 As N-acetyl-D-mannosamine, a commercially available product may be used, or one produced by a known method may be used. As a method for producing N-acetyl-D-mannosamine, N-acetylglucosamine is isomerized under alkaline conditions (Japanese Patent Laid-Open No. 10-182585), and N-acetylneuraminic acid lyase is reacted with sialic acid as a substrate. However, the production method is not limited to this method (Japanese Patent Laid-Open No. 2001-78794).
本発明において、「脳機能低下」とは、動物の発生から死に至る過程において、当該動物の成熟段階での脳の機能と比較して、様々な要因によりその機能が低下した状態をいう。脳機能低下の要因は、老化が代表例としてあげられ、その他の要因として、ストレス、環境、遺伝的疾患、器質的障害などがあげられるが、個々の動物によって要因は様々であるので、これらに限定されるものではない。また、成熟した脳の段階は、動物の種類によって異なり、一概に定義することはできないが、通常、成体を基準とすればよい。ヒトの場合は、15〜30歳であり、マウスの場合は、7〜20週齢を基準とすることができる。 In the present invention, “decreased brain function” refers to a state in which the function is reduced due to various factors in the process from the development of an animal to death compared to the function of the brain at the mature stage of the animal. A typical example of a decrease in brain function is aging, and other factors include stress, environment, genetic disease, organic disorders, etc. It is not limited. In addition, the stage of the mature brain varies depending on the type of animal and cannot be defined in general. In the case of humans, it is 15 to 30 years old.
本発明が対象とする脳機能低下は、好ましくは老化に伴う脳機能低下であり、脳機能低下は、場所の記憶障害、物体の記憶障害、情動障害、運動機能低下などの障害として現れる。 The decrease in brain function targeted by the present invention is preferably a decrease in brain function due to aging, and the decrease in brain function appears as a disorder such as a location memory disorder, an object memory disorder, an emotional disorder, or a motor function decline.
場所の記憶障害とは、ある時点での自己の空間的位置の認知の障害と過去に経験した場所の認知記憶の障害などをいい、物体の記憶障害とは、接触などを介して知覚した物体の認知障害と、その経験を記銘することの障害などをいう。かかる記憶障害は、例えば、実施例１および図２に記載される場所認知記憶試験および物体認知記憶試験により測定することができる。 Location memory impairment refers to cognitive impairment of one's own spatial position at a certain point in time and cognitive memory impairment of a place experienced in the past. Object memory impairment refers to an object perceived through contact etc. Cognitive impairment and obstacles to memorizing the experience. Such memory impairment can be measured, for example, by the location cognitive memory test and the object cognitive memory test described in Example 1 and FIG.
本発明の剤は、具体的には、前記場所の記憶障害、物体の記憶障害、認知症、アルツハイマー型認知症、レビー小体型認知症および前頭側頭型認知症からなる群より選ばれる障害の予防または改善を目的として投与または摂取することができる。 Specifically, the agent of the present invention has a disorder selected from the group consisting of memory impairment of the place, memory impairment of the object, dementia, Alzheimer's dementia, Lewy body dementia and frontotemporal dementia. It can be administered or taken for the purpose of prevention or amelioration.
かかる目的のため、本発明の剤は、Ｎ−アセチル−Ｄ−マンノサミン単独で、あるいは賦形剤（例えば、乳糖、ショ糖、デンプン、シクロデキストリン等）、場合によっては、香料、色素、調味料、安定剤、保存剤等も含有し、錠剤、丸剤、顆粒、細粒、粉末、ペレット、カプセル、溶液、乳液、懸濁液、シロップおよびトローチ等に製剤化して、医薬または保健機能食品もしくは食品添加物として用いることができる。また、本発明の剤は、研究用試薬として用いることもできる。 For this purpose, the agent of the present invention is N-acetyl-D-mannosamine alone or an excipient (for example, lactose, sucrose, starch, cyclodextrin, etc.), and in some cases, a fragrance, a pigment, a seasoning. , Containing stabilizers, preservatives, etc., formulated into tablets, pills, granules, fine granules, powders, pellets, capsules, solutions, emulsions, suspensions, syrups, troches, etc. It can be used as a food additive. The agent of the present invention can also be used as a research reagent.
本発明の剤に含まれるＮ−アセチル−Ｄ−マンノサミンの量は、本発明の効果を奏する限り特に限定されるものではないが、通常０．０００１〜１００重量％であり、好ましくは０．００１〜９９．９重量％である。 The amount of N-acetyl-D-mannosamine contained in the agent of the present invention is not particularly limited as long as the effect of the present invention is exhibited, but is usually 0.0001 to 100% by weight, preferably 0.001. ˜99.9% by weight.
また、本発明は、有効量のＮ−アセチル−Ｄ−マンノサミンおよび医薬として許容されうる担体を含有する、脳機能低下に起因する障害の予防、改善または治療するための医薬組成物を提供する。 The present invention also provides a pharmaceutical composition for preventing, ameliorating or treating a disorder caused by a decrease in brain function, comprising an effective amount of N-acetyl-D-mannosamine and a pharmaceutically acceptable carrier.
医薬として許容されうる担体としては、例えば、賦形剤（例えば、乳糖、ショ糖、デキストリン、ヒドロキシプロピルセルロース、ポリビニルピロリドン等）、崩壊剤（例えば、デンプン、カルボキシメチルセルロース等）、滑沢剤（例えば、ステアリン酸マグネシウム等）、界面活性剤（例えば、ラウリル硫酸ナトリウム等）、溶剤（例えば、水、食塩水、大豆油等）、保存剤（例えば、p-ヒドロキシ安息香酸エステル等）などがあげられるが、これらに限定されるものではない。 Examples of pharmaceutically acceptable carriers include excipients (eg, lactose, sucrose, dextrin, hydroxypropylcellulose, polyvinylpyrrolidone, etc.), disintegrants (eg, starch, carboxymethylcellulose, etc.), lubricants (eg, , Magnesium stearate, etc.), surfactant (eg, sodium lauryl sulfate, etc.), solvent (eg, water, saline, soybean oil, etc.), preservative (eg, p-hydroxybenzoic acid ester, etc.), etc. However, it is not limited to these.
Ｎ−アセチル−Ｄ−マンノサミンの有効量は、医薬としての効果を奏する限り特に限定されるものではないが、通常０．０００１〜９９．５重量％であり、好ましくは０．００１〜９９．０重量％である。 The effective amount of N-acetyl-D-mannosamine is not particularly limited as long as it has a pharmaceutical effect, but is usually 0.0001 to 99.5% by weight, preferably 0.001 to 99.0. % By weight.
本発明の医薬組成物が予防、改善または治療対象とする障害は、脳機能低下、好ましくは老化に伴う脳機能低下に起因するものである。脳機能低下を起因とする障害としては、場所の記憶障害、物体の記憶障害、認知症、アルツハイマー型認知症、レビー小体型認知症、前頭側頭型認知症などがあげられる。 The disorder which the pharmaceutical composition of the present invention is targeted for prevention, improvement or treatment is caused by a decrease in brain function, preferably a decrease in brain function associated with aging. Disorders caused by brain function deterioration include location memory impairment, object memory impairment, dementia, Alzheimer-type dementia, Lewy body dementia, frontotemporal dementia, and the like.
別の側面から見ると、動物には個体差があり、脳機能低下に起因する障害は、様々な症状を発現し、特定の疾患に分類または診断されうることもある。したがって、本発明の医薬組成物は、例えば、統合失調症（好ましくは遅発性統合失調症）、アルツハイマー病（好ましくは老人性アルツハイマー病）、うつ病、認知症、アルツハイマー型認知症、レビー小体型認知症、前頭側頭型認知症などを予防、改善または治療対象とすることもできる。 Viewed from another aspect, animals vary from individual to individual, and disorders resulting from decreased brain function may develop various symptoms and may be classified or diagnosed as specific diseases. Therefore, the pharmaceutical composition of the present invention is, for example, schizophrenia (preferably delayed schizophrenia), Alzheimer's disease (preferably senile Alzheimer's disease), depression, dementia, Alzheimer's dementia, Lewy small Body type dementia, frontotemporal dementia and the like can also be targeted for prevention, improvement or treatment.
本発明の剤または医薬組成物は、哺乳動物（例、マウス、ラット、ウサギ、ネコ、イヌ、ウシ、ウマ、サル、ヒト）に対して、経口的あるいは非経口的に安全に投与することができる。 The agent or pharmaceutical composition of the present invention can be safely administered orally or parenterally to mammals (eg, mouse, rat, rabbit, cat, dog, cow, horse, monkey, human). it can.
本発明は、Ｎ−アセチル−Ｄ−マンノサミンを添加してなる食品を提供する。 The present invention provides foods to which N-acetyl-D-mannosamine is added.
本発明の「食品」は、食品全般を意味するが、いわゆる健康食品を含む一般食品の他、厚生労働省の保健機能食品制度に規定される特定保健用食品や栄養機能食品等の保健機能食品をも含むものであり、さらにサプリメント、飼料等も本発明の食品に包含される。 “Food” in the present invention means all foods, but in addition to general foods including so-called health foods, health foods such as foods for specified health use and functional foods for nutrition specified in the health function food system of the Ministry of Health, Labor and Welfare. Furthermore, supplements, feeds and the like are also included in the food of the present invention.
食品用途の場合、Ｎ−アセチル−Ｄ−マンノサミンを、例えば、パン、菓子等の一般食品（いわゆる健康食品を含む）に含有させて用いることもできる。また、Ｎ−アセチル−Ｄ−マンノサミンを、賦形剤（例えば、乳糖、ショ糖、デンプン等）、場合によっては、香料、色素等と共に、錠剤、丸剤、顆粒、細粒、粉末、ペレット、カプセル、溶液、乳液、懸濁液、シロップおよびトローチ等に製剤化して、特定保健用食品や栄養機能食品等の保健機能食品、サプリメントとして用いることができる。また、本発明の食品は、飼料用途にも適用することができ、家禽や家畜等には、通常の飼料に添加して摂取または投与することができる。 In the case of food use, N-acetyl-D-mannosamine can be used, for example, in general foods (including so-called health foods) such as bread and confectionery. In addition, N-acetyl-D-mannosamine is mixed with excipients (for example, lactose, sucrose, starch, etc.), and in some cases, flavors, pigments, etc., tablets, pills, granules, fine granules, powders, pellets, It can be formulated into capsules, solutions, emulsions, suspensions, syrups, troches, and the like and used as health functional foods and supplements such as foods for specified health use and nutritional functional foods. The food of the present invention can also be applied to feed applications, and can be taken or administered by adding to normal feed for poultry or livestock.
食品または飼料として摂取する場合、食品または飼料の１日当たりの摂取回数および１回当たりの摂取量の目安を概算し、１日摂取量を規定した上で１日摂取量の食品または飼料に含まれるＮ−アセチル−Ｄ−マンノサミンの量を決定する。Ｎ−アセチル−Ｄ−マンノサミンの含有量は、後述する用量に基づいて決定することができる。 When ingested as food or feed, it is included in the food or feed of the daily intake after the daily intake of the food or feed is estimated and the daily intake is specified. The amount of N-acetyl-D-mannosamine is determined. The content of N-acetyl-D-mannosamine can be determined based on the dose described below.
本発明の剤は、当該剤が脳機能低下の予防または改善に使用することができることまたは使用すべきであることを記載した当該予防または改善剤に関する説明を記載した記載物をも含む商業用パッケージとして提供することもできる。 The agent of the present invention is a commercial package that also includes a description describing the preventive or ameliorating agent describing that the agent can or should be used for the prevention or amelioration of brain function deterioration. Can also be provided.
本発明の医薬組成物は、当該医薬組成物が脳機能低下に起因する障害の予防、改善または治療に使用することができることまたは使用すべきであることを記載した当該医薬組成物に関する説明を記載した記載物をも含む商業用パッケージとして提供することもできる。 The pharmaceutical composition of the present invention describes the pharmaceutical composition that states that the pharmaceutical composition can or should be used for the prevention, amelioration or treatment of disorders caused by reduced brain function. It can also be provided as a commercial package including the described items.
本発明の食品は、含有するＮ−アセチル−Ｄ−マンノサミンの生物学的作用を有効に発揮させるためには、特定保健用食品または栄養機能食品として用いられることが好ましく、その際、「脳機能低下の予防または改善に用いられる」という表示を付すことが推奨される。 The food of the present invention is preferably used as a food for specified health use or a food with nutritional function in order to effectively exert the biological action of the contained N-acetyl-D-mannosamine. It is recommended that the label “used to prevent or improve decline”.
本発明の剤、食品または医薬組成物の摂取または投与量は、摂取または投与対象の年齢、体重、健康状態によって異なり、一概に決定することはできない。例えば、健康の維持および増進や脳機能低下の予防を目的とする場合は、通常、食品の形態にして、一方、脳機能低下に起因する障害の治療や健康回復を目的とする場合には、通常、医薬品または食品の形態にして、Ｎ−アセチル−Ｄ−マンノサミンとして、成人１日当たり０．１〜１０ｇ、好ましくは０．２ｇ〜７ｇを１日１回から数回に分けて摂取または服用することが好ましい。 The intake or dosage of the agent, food or pharmaceutical composition of the present invention varies depending on the age, weight, and health status of the subject of intake or administration, and cannot be generally determined. For example, when aiming to maintain and enhance health and prevent brain function decline, it is usually in the form of food, while when aiming to treat or recover from a disorder caused by brain function decline, Usually, in the form of pharmaceuticals or foods, 0.1 to 10 g, preferably 0.2 to 7 g per day for adults as N-acetyl-D-mannosamine is taken or taken in one to several times a day. It is preferable.
本発明の医薬（剤または医薬組成物）の投与方法としては、上記障害または疾患に対する予防的および治療的な効果が得られる経路であれば特に限定されない。例えば、非経口的投与（静脈内投与、筋肉内投与、組織内直接投与、鼻腔内投与、皮内投与、髄液内投与など）または経口投与により投与することができ、特に、該医薬をヒトに適用するには、静脈内、筋肉内または経口投与によって投与することができる。また、剤型としても特に制限されることなく、各種投与剤型、例えば、経口剤（顆粒剤、散剤、錠剤、カプセル剤、シロップ剤、乳剤、懸濁剤など）、注射剤、点滴剤、外用剤（経鼻投与製剤、経皮製剤、軟膏剤など）として投与することが可能である。 The administration method of the medicament (agent or pharmaceutical composition) of the present invention is not particularly limited as long as it provides a preventive and therapeutic effect on the above-mentioned disorder or disease. For example, it can be administered parenterally (intravenous administration, intramuscular administration, direct administration into tissue, intranasal administration, intradermal administration, intrathecal fluid administration, etc.) or oral administration. Can be administered by intravenous, intramuscular or oral administration. The dosage form is not particularly limited, and various dosage forms such as oral preparations (granule, powder, tablet, capsule, syrup, emulsion, suspension, etc.), injection, infusion, It can be administered as an external preparation (nasal preparation, transdermal preparation, ointment, etc.).
また本発明は、脳機能低下の予防、改善または治療用医薬を製造するためのＮ−アセチル−Ｄ−マンノサミンの使用を提供する。具体的には、Ｎ−アセチル−Ｄ−マンノサミンを使用した脳機能低下の予防、改善または治療用医薬の製造方法を提供する。 The present invention also provides the use of N-acetyl-D-mannosamine for the manufacture of a medicament for preventing, improving or treating brain function deterioration. Specifically, the present invention provides a method for producing a medicament for the prevention, improvement or treatment of brain function deterioration using N-acetyl-D-mannosamine.
本発明の医薬の製造方法は、製剤分野において自体公知の方法を限定なく用いることができる。 As the method for producing the medicament of the present invention, a method known per se in the pharmaceutical field can be used without limitation.
Ｎ−アセチル−Ｄ−マンノサミンは、ヒトの細胞内に中間体として微量含まれており、毒性（例、急性毒性、慢性毒性、遺伝毒性、生殖毒性、心毒性、薬物相互作用、癌原性）を有さず、ヒトに対する安全性は高いと考えられる。 N-acetyl-D-mannosamine is contained in human cells in trace amounts as an intermediate and is toxic (eg, acute toxicity, chronic toxicity, genotoxicity, reproductive toxicity, cardiotoxicity, drug interaction, carcinogenicity) It is considered safe for humans.
本発明の剤、医薬組成物または食品は、実施例で示されるように、特に下記のような効果を有する。すなわち、老化に伴う場所記憶および物体記憶等を改善し、老化に伴い低下した脳機能を改善する。 As shown in Examples, the agent, pharmaceutical composition or food of the present invention has the following effects. That is, location memory and object memory associated with aging are improved, and brain function that has decreased with aging is improved.
以下、実施例を示してさらに具体的に本発明を説明する。以下は代表的な実施例を示すものでこれらに限定されるものではなく、本発明の技術的思想を逸脱しない範囲内で種々の応用が可能である。 Hereinafter, the present invention will be described more specifically with reference to examples. The following are representative examples, and the present invention is not limited to them. Various applications are possible without departing from the technical idea of the present invention.
実施例１：ＭａｎＮＡｃによる老化に伴い低下する物体記憶および場所記憶などの脳機能障害の回復
１）以下の3群の動物（マウス：C57BL6/Njcl、オス）における物体ならびに場所の認知記憶実験を行った。実験の概略を図１に示す。
・老齢対照群：老齢マウス（47週から66週齢まで飼育、n=10）水道水を自由飲水
・老齢ＭａｎＮＡｃ投与群：老齢マウス（47週から66週齢まで飼育、n=10）水道水にＭａｎＮＡｃ（5mg/ml）を溶解し自由飲水
・若齢対照群：若齢マウス（8週から18週齢まで飼育、n=10）水道水を自由飲水
２）実験手法：不安傾向、運動活性を調べるOpen field試験を行い、引き続き場所認知記憶試験および物体認知記憶試験を定法に従い行った（図２参照）。Example 1: Recovery of cerebral dysfunction such as object memory and place memory that decreases with aging by ManNAc 1) Cognitive memory experiments of objects and places in the following three groups of animals (mouse: C57BL6 / Njcl, male) were conducted It was. An outline of the experiment is shown in FIG.
・ Old control group: old mice (bred from 47 to 66 weeks, n = 10) drinking tap water freely ・ Old ManNAc administration group: old mice (bred from 47 to 66 weeks, n = 10) tap water ManNAc (5mg / ml) dissolved in water and free drinking / young control group: young mice (bred from 8 to 18 weeks of age, n = 10) free drinking of tap water 2) Experimental method: anxiety tendency, motor activity An open field test was conducted, followed by a place recognition memory test and an object recognition memory test according to a standard method (see FIG. 2).
３）実験結果（図３、４）
Open field試験（図３）：見知らぬ平面空間における移動距離を、老齢マウスと若齢マウスを比較した。老齢マウスで運動活性が低い傾向にあったが、統計的有意差は検出されなかった（One Way ANOVA, p=0.32）。不安傾向の指標となる中央部分に出る時間は、若齢マウスに比較して老齢マウスでは有意に低下し（One way ANOVA with Tukey's post hoc test, p<0.001）、不安傾向の上昇が認められた。老齢マウスにＭａｎＮＡｃを投与した場合、この不安傾向の上昇は若干減少する傾向にあるが、統計的有意差は認められなかった。3) Experimental results (Figs. 3 and 4)
Open field test (FIG. 3): The distance of movement in an unknown plane space was compared between old mice and young mice. Although motor activity tended to be low in aged mice, no statistically significant difference was detected (One Way ANOVA, p = 0.32). Time spent in the central region, an index of anxiety, was significantly lower in older mice than in younger mice (One way ANOVA with Tukey's post hoc test, p <0.001), with an increased anxiety trend observed . When ManNAc was administered to aged mice, this increase in anxiety tendency tended to decrease slightly, but no statistically significant difference was observed.
場所記憶および物体記憶試験（図４）：若齢マウス（図４Ｂ）では、場所認知記憶課題（図中：place）において新規の場所に置かれた物体に対する探索時間が有意に延長し(paired t-test, p<0.05)、場所の変化を認知記憶できていることが示された。また物体認知記憶（図中：object）においても新奇物体（図中：New）への探索時間が延長し(paired t-test, p<0.001)、物体の変化を認知記憶可能であることが示された。老齢マウス（図４Ａ）ではいずれの試験においても新奇場所（paired t-test, p=0.72）ならびに新奇物体(paired t-test, p=0.94)への探索時間の延長が認められず、これら認知記憶課題の障害が検出された。老齢マウスにＭａｎＮＡｃを投与すると（図４Ｃ）、いずれの課題においても新奇場所(paired t-test, p<0.05)、ならびに新奇物体(paired t-test, p<0.001)に対して探索行動の時間が回復し、若齢マウスと同等の認知記憶能力を示した。 Place memory and object memory test (FIG. 4): In young mice (FIG. 4B), the search time for objects placed in a new place in the place recognition memory task (in the figure: place) was significantly extended (paired t -test, p <0.05), it was shown that it was able to recognize and memorize the change of place. Also, in object recognition memory (in the figure: object), the search time for a novel object (in the figure: New) has been extended (paired t-test, p <0.001), indicating that changes in the object can be recognized and memorized. It was done. In the old mice (Fig. 4A), there was no extension of the search time to a novel place (paired t-test, p = 0.72) and a novel object (paired t-test, p = 0.94) in any of the tests. A memory task failure was detected. When ManNAc was administered to aged mice (Fig. 4C), the time of exploratory behavior for a novel place (paired t-test, p <0.05) and a novel object (paired t-test, p <0.001) in any task Recovered and showed the same cognitive memory ability as young mice.
以上、Open field試験、場所記憶および物体記憶試験の結果を総合すると、ＭａｎＮＡｃは総運動量には影響を与えず、場所記憶と物体記憶を改善することが明らかになった。 As described above, when the results of the open field test, the location memory and the object memory test are combined, it has been revealed that ManNAc does not affect the total momentum and improves the location memory and the object memory.
本発明により、ＭａｎＮＡｃを有効成分として含有する医薬、食品などが提供される。本発明の医薬または食品の服用または摂取により老化に伴う脳機能低下を予防、改善または治療することができる。 According to the present invention, pharmaceuticals, foods and the like containing ManNAc as an active ingredient are provided. By taking or taking the medicament or food of the present invention, it is possible to prevent, ameliorate, or treat a decrease in brain function associated with aging.
本出願は、日本で出願された特願２００８−２２６８５８（出願日：２００８年９月４日）を基礎としており、その内容は本明細書に全て包含されるものである。 This application is based on Japanese Patent Application No. 2008-226858 filed in Japan (filing date: September 4, 2008), the contents of which are incorporated in full herein.
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| JPH09301874A (en) * | 1996-05-16 | 1997-11-25 | Snow Brand Milk Prod Co Ltd | Improving agent for cerebral function |
| US6274568B1 (en) * | 1998-08-06 | 2001-08-14 | Ronald L. Schnaar | Compounds for altering cell surface sialic acids and methods of use therefor |
| JP2006524187A (en) * | 2003-01-31 | 2006-10-26 | ザ プロクター アンド ギャンブル カンパニー | Means to improve the appearance of mammalian keratinous tissue |
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| DE3935906A1 (en) * | 1989-10-27 | 1991-05-02 | Reutter Werner | Galactose for (par)enteral nutrition of intensive care patients - as a glucose substitute in nutrient solns. which is more effective than glucose |
| JPH09301874A (en) * | 1996-05-16 | 1997-11-25 | Snow Brand Milk Prod Co Ltd | Improving agent for cerebral function |
| US6274568B1 (en) * | 1998-08-06 | 2001-08-14 | Ronald L. Schnaar | Compounds for altering cell surface sialic acids and methods of use therefor |
| JP2006524187A (en) * | 2003-01-31 | 2006-10-26 | ザ プロクター アンド ギャンブル カンパニー | Means to improve the appearance of mammalian keratinous tissue |
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