JP2022035271A - NAD production promoter - Google Patents
NAD production promoter Download PDFInfo
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- JP2022035271A JP2022035271A JP2020139472A JP2020139472A JP2022035271A JP 2022035271 A JP2022035271 A JP 2022035271A JP 2020139472 A JP2020139472 A JP 2020139472A JP 2020139472 A JP2020139472 A JP 2020139472A JP 2022035271 A JP2022035271 A JP 2022035271A
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- Prior art keywords
- nad
- production promoter
- placenta extract
- nad production
- placenta
- Prior art date
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Images
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- Coloring Foods And Improving Nutritive Qualities (AREA)
- Non-Alcoholic Beverages (AREA)
- Cosmetics (AREA)
- Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)
- Medicines Containing Material From Animals Or Micro-Organisms (AREA)
Abstract
Description
本発明は、ＮＡＤ産生促進剤に関する。本発明は、特には安全性が高く、外用剤としても内服剤としても適用可能なＮＡＤ産生促進剤に関する。 The present invention relates to a NAD production promoter. The present invention relates to a NAD production promoter which is particularly safe and can be applied as an external preparation or an internal preparation.
ニコチンアミドアデニンジヌクレオチド（以下、ＮＡＤと指称する）は、生体内において、脱水素酵素の補酵素として機能することが知られている。ＮＡＤは、特には生体内の解糖系及びクエン酸回路に関与しており、エネルギーの産生に大きく影響する。 Nicotinamide adenine dinucleotide (hereinafter referred to as NAD) is known to function as a coenzyme for dehydrogenase in vivo. NAD is particularly involved in glycolysis and the citric acid cycle in the living body, and has a great influence on energy production.
細胞内ＮＡＤ量の維持に必須の酵素であるニコチンアミドフォスフォリボシルトランスフェラーゼ（ＮＡＭＰＴ）の働きは年齢とともに低下することが知られており（例えば、非特許文献１を参照）、皮膚のＮＡＤ量も年齢を重ねるごとに減少することが知られている（例えば、非特許文献２を参照）。 It is known that the action of nicotinamide phosphoribosyltransferase (NAMPT), which is an enzyme essential for maintaining the intracellular NAD amount, decreases with age (see, for example, Non-Patent Document 1), and the skin NAD amount also It is known that it decreases with age (see, for example, Non-Patent Document 2).
一方、ニコチンアミドリボシド（以下、ＮＲと指称する）などのＮＡＤ中間代謝産物が老化関連疾患の病態を改善することが知られており（例えば、非特許文献３を参照）、ＮＲは牛乳に多く含まれていることも知られている（例えば、非特許文献４を参照）。 On the other hand, NAD intermediate metabolites such as nicotinamide riboside (hereinafter referred to as NR) are known to improve the pathological condition of aging-related diseases (see, for example, Non-Patent Document 3), and NR is used in milk. It is also known that a large amount is contained (see, for example, Non-Patent Document 4).
ＮＡＤの産生を促進し、特には加齢個体におけるＮＡＤの産生の回復を促進して、老化の防止につながる物質の開発が望まれる。 It is desired to develop a substance that promotes the production of NAD, particularly promotes the recovery of the production of NAD in an aged individual, and leads to the prevention of aging.
本発明者らは、プラセンタ抽出物とコラーゲンペプチドを併用して生体に適用することにより、細胞内のＮＡＤの回復を促進することができることを発見し、本発明を完成させるに至った。 The present inventors have discovered that the combined use of placenta extract and collagen peptide in a living body can promote the recovery of intracellular NAD, and have completed the present invention.
すなわち、本発明は一実施形態によれば、ＮＡＤ産生促進剤であって、プラセンタ抽出物とコラーゲンペプチドとを含む。 That is, according to one embodiment, the present invention is a NAD production promoter, which comprises a placenta extract and a collagen peptide.
前記ＮＡＤ産生促進剤において、前記コラーゲンペプチドが、Ｈｙｐを含むジペプチドもしくはトリペプチドを含むことが好ましい。 In the NAD production promoter, it is preferable that the collagen peptide contains a dipeptide containing Hyp or a tripeptide.
前記ＮＡＤ産生促進剤において、前記コラーゲンペプチドが、Ａｌａ－Ｈｙｐを含むことが好ましい。 In the NAD production promoter, it is preferable that the collagen peptide contains Ala-Hyp.
前記ＮＡＤ産生促進剤において、前記プラセンタ抽出物が、乾燥重量あたり６ｐｐｍ以上のＮＲを含むことが好ましい。 In the NAD production promoter, it is preferable that the placenta extract contains NR of 6 ppm or more per dry weight.
前記ＮＡＤ産生促進剤において、前記プラセンタ抽出物と、前記コラーゲンペプチドとの重量比が、２０００：１～１０：１であることが好ましい。 In the NAD production promoter, the weight ratio of the placenta extract to the collagen peptide is preferably 2000: 1 to 10: 1.
本発明は、別の実施形態によれば、上述のいずれか１項に記載のＮＡＤ産生促進剤を含む皮膚外用剤、化粧品、内服剤、飲食品組成物、または医薬部外品に関する。 According to another embodiment, the present invention relates to a skin external preparation, a cosmetic product, an internal preparation, a food / drink composition, or a quasi-drug containing the NAD production promoting agent according to any one of the above.
本発明によれば、細胞内のＮＡＤ産生を有意に促進することができるＮＡＤ産生促進剤を提供することが可能になる。ＮＡＤ産生促進剤は、皮膚外用剤並びに内服剤として用いることができ、生体の老化防止に非常に有用となりうる。 According to the present invention, it becomes possible to provide an NAD production promoter capable of significantly promoting intracellular NAD production. The NAD production promoter can be used as an external skin preparation and an internal preparation, and can be very useful for preventing aging of a living body.
以下に、図面を参照して本発明の実施の形態を説明する。ただし、本発明は、以下に説明する実施の形態によって限定されるものではない。 Hereinafter, embodiments of the present invention will be described with reference to the drawings. However, the present invention is not limited to the embodiments described below.
［第１実施形態：ＮＡＤ産生促進剤］
本発明は、第１実施形態によれば、ＮＡＤ産生促進剤に関する。当該ＮＡＤ産生促進剤は、プラセンタ抽出物と、コラーゲンペプチドとを含む。
[First Embodiment: NAD production promoter]
The present invention relates to a NAD production promoter according to the first embodiment. The NAD production promoter contains a placenta extract and a collagen peptide.
本実施形態において、プラセンタ抽出物とは、哺乳動物の胎盤由来の抽出物を言うものとする。哺乳動物としては、ヒト、ウシ、ブタ、ヒツジ、ウマが挙げられるが、それらには限定されない。好ましくは、ブタの胎盤由来の抽出物であってよい。また、プラセンタ抽出物は、加熱処理を経たものであってもよく、非加熱のいわゆる「生プラセンタ」と呼ばれるプラセンタ抽出物であってもよい。 In the present embodiment, the placenta extract refers to an extract derived from the placenta of a mammal. Mammals include, but are not limited to, humans, cows, pigs, sheep and horses. Preferably, it may be an extract derived from porcine placenta. Further, the placenta extract may be a placenta extract that has undergone heat treatment or may be an unheated so-called "raw placenta" placenta extract.
生プラセンタは、プラセンタに含まれるサイトカイン等の有用な活性成分（例えばＴＧＦβ１、ＥＧＦ、ＦＧＦ１、ＩＧＦ）を出来る限り損なわないように調製したものを使用することが好ましい。この「生プラセンタ」は、例えば以下のように調製することができる。採取した胎盤をトリミングして不要な組織片や血液等を取り除いた後、低温殺菌等の手法を用いて殺菌し、凍結保存する。その後、解凍することにより（すなわち凍結融解することにより）胎盤抽出液を抽出した後、遠心分離により固液分離する。固液分離して得られた上澄み液をプラセンタエキス原液という。このプラセンタエキス原液からウイルスや細菌を除去することにより、生プラセンタを得ることができる。ウイルスや細菌の除去方法としては、例えば複数の濾過膜を利用した濾過処理等、酸や熱を使用しない方法を用いることが好ましい。こうして得られた生プラセンタは、その調製段階において加熱や酸による殺菌方法を使用しないため、サイトカイン等の有用な活性成分が多く残存しているという利点を有する。 It is preferable to use the raw placenta prepared so as not to impair useful active ingredients (for example, TGFβ1, EGF, FGF1, IGF) such as cytokines contained in the placenta as much as possible. This "raw placenta" can be prepared, for example, as follows. After trimming the collected placenta to remove unnecessary tissue pieces and blood, the placenta is sterilized by a method such as pasteurization and cryopreserved. Then, the placental extract is extracted by thawing (that is, by freezing and thawing), and then solid-liquid separation is performed by centrifugation. The supernatant obtained by solid-liquid separation is called placenta extract stock solution. Raw placenta can be obtained by removing viruses and bacteria from this placenta extract stock solution. As a method for removing viruses and bacteria, it is preferable to use a method that does not use acid or heat, for example, a filtration treatment using a plurality of filtration membranes. Since the raw placenta thus obtained does not use a sterilization method using heating or acid in the preparation stage, it has an advantage that a large amount of useful active ingredients such as cytokines remains.
プラセンタ抽出物としては、上記生プラセンタから、高分子タンパク及びその凝集体を除去したものが好ましい。ここでいう高分子タンパク質とは、分子量が概ね１００キロダルトンを超えるタンパク質をいう。これにより、変性した高分子タンパクによる成分の凝集を生じにくくすることができるため、ＮＲの変性や劣化を抑制し、ＮＲの含有量をより高めることができる。また、低分子タンパク質や遊離アミノ酸の含有割合を高め、体内への吸収効率を高めることができる。低分子タンパク質とは、分子量が概ね２０キロダルトン以下のタンパク質をいう。特に総窒素量を定量すると０.０１～０．１％となるものが好ましい。 The placenta extract is preferably the raw placenta from which high molecular weight proteins and aggregates thereof have been removed. The high molecular weight protein referred to here is a protein having a molecular weight of more than about 100 kilodaltons. As a result, it is possible to prevent the aggregation of the components due to the denatured high molecular protein, so that the NR denaturation and deterioration can be suppressed and the NR content can be further increased. In addition, the content ratio of small molecule proteins and free amino acids can be increased, and the absorption efficiency into the body can be enhanced. A small molecule protein is a protein having a molecular weight of approximately 20 kilodaltons or less. In particular, when the total amount of nitrogen is quantified, it is preferably 0.01 to 0.1%.
高分子タンパク及びその凝集体を除去する方法としては、例えばフィルター濾過分離を用いることができる。具体的には、生プラセンタについて、濾過膜を用いて分子量分画処理することができる。濾過膜としては、例えば孔径が０．２２μｍ以下の精密濾過膜や、分画分子量が２０キロダルトン以下の限外濾過膜を用いることができる。 As a method for removing the high molecular weight protein and its aggregate, for example, filter filtration separation can be used. Specifically, the raw placenta can be subjected to molecular weight fractionation treatment using a filtration membrane. As the filtration membrane, for example, a microfiltration membrane having a pore size of 0.22 μm or less and an ultrafiltration membrane having a molecular weight cut-off of 20 kilodaltons or less can be used.
この方法により生プラセンタをさらに精製することで、ナイアシン等の水溶性ビタミン及びＮＡＤ中間代謝産物の配合割合を高めることができる。ここでいうＮＡＤ中間代謝産物とは、ＮＲ、ニコチンアミドモノヌクレオチド、ニコチン酸リボシド、ニコチン酸モノヌクレオチド、ニコチン酸アデニンジヌクレオチドをいう。こうしたプラセンタ抽出物としては、ＮＲを多く含むことが好ましく、特に乾燥重量あたりのＮＲ量が６ｐｐｍ以上であることが最も好ましい。プラセンタ抽出物中のＮＲ量を６ｐｐｍ以上とすることで、内服又は外用した際に細胞内のＮＡＤ産生を有意に促進することができる。ＮＲ量の上限値は、理論上は特には限定されないが、例えば、ＮＲ量は６ｐｐｍ以上であって、１２００ｐｐｍ以下程度であってよい。 By further purifying the raw placenta by this method, the blending ratio of water-soluble vitamins such as niacin and NAD intermediate metabolites can be increased. The NAD intermediate metabolite as used herein refers to NR, nicotinamide mononucleotide, nicotinic acid riboside, nicotinic acid mononucleotide, and nicotinic acid adenine dinucleotide. The placenta extract preferably contains a large amount of NR, and most preferably the amount of NR per dry weight is 6 ppm or more. By setting the amount of NR in the placenta extract to 6 ppm or more, intracellular NAD production can be significantly promoted when taken internally or externally. The upper limit of the NR amount is not particularly limited in theory, but for example, the NR amount may be 6 ppm or more and 1200 ppm or less.
なお、プラセンタ抽出物は、上記以外にも市販品も用いることができる。市販のプラセンタ抽出物としては、プラセンタエキス、プラセンタエキス末、プラセンタ原末等として市販され、医薬品やサプリメントの原料として使用されているものを広く使用することができる。 As the placenta extract, a commercially available product can be used in addition to the above. As the commercially available placenta extract, those commercially available as placenta extract, placenta extract powder, placenta raw powder and the like, which are used as raw materials for pharmaceuticals and supplements, can be widely used.
本実施形態によるＮＡＤ産生促進剤に含まれるコラーゲンタンパク質は、生体由来コラーゲンの加水分解物であってよい。 The collagen protein contained in the NAD production promoter according to the present embodiment may be a hydrolyzate of collagen derived from a living body.
より具体的には、ウシやブタなどの哺乳類や魚類の組織、例えば、皮膚、骨及び腱などの結合組織から抽出したコラーゲンタンパク、もしくはコラーゲンタンパク質の熱変性物であるゼラチンから加水分解等により得られたものを使用してもよく、また人工的に合成したものを用いても良い。コラーゲンタンパク質より得る場合には、コラーゲンタンパク質溶解液を、コラゲナーゼ酵素固定化カラムにアプライし、カラム法による酵素分解を行う。カラムを通した酵素反応終了溶液を分取し、０．２２～０．４５μｍのフィルターで濾過を行い、そのろ液を凍結乾燥にて粉末化しコラーゲントリペプチドを得た後、コラーゲントリペプチド粉末を再溶解しＨＰＬＣ（ゲル濾過およびＯＤＳカラム）において各々のジペプチドおよびトリペプチド含有画分を精製する。更に、単一のコラーゲントリペプチド成分を得るために、イオン交換クロマト法およびカーボンカラムを用いて精製し得ることができる。また、人工合成により得る場合には、ペプチド合成機器を用いて固相法により人工合成する。使用する機器のプログラムに従いＣ末端よりＦｍｏｃ法によりペプチド鎖を延長する。固相法ペプチド合成用支持体である担体を用いて、副反応を防止するために、あらかじめＦｍｏｃおよびＢｏｃによりα－アミノ基、δ－アミノ基を保護したオルニチンとＦｍｏｃによりβ－アミノ基を保護したβ－アラニンのＦｍｏｃアミノ誘導体を用いる。Ｆｍｏｃ－Ｏｒｎ（Ｂｏｃ）を担体に結合させ、ピペリジンなどによりα－アミノ基を脱保護後、Ｆｍｏｃ－Ｏｒｎ（Ｂｏｃ）のＣ末端をカップリングさせ、ピペリジンなどで二つ目のオルニチンのα－アミノ基を脱保護し、Ｆｍｏｃ－β－ＡｌａのＣ末端を同様にカップリングさせる。最後にトリフルオロ酢酸などの酸を用いて全ての脱保護と担体除去を行い、０．０１～２％トリフルオロ酢酸水を用いて抽出したものを凍結乾燥することでジペプチドおよびトリペプチドを製造することができ、ＨＰＬＣ(逆送カラム)などで精製することによって得ることができる。 More specifically, it is obtained by hydrolysis or the like from collagen protein extracted from tissues of mammals and fish such as cows and pigs, for example, connective tissues such as skin, bone and tendon, or gelatin which is a heat denatured product of collagen protein. You may use the one that has been obtained, or you may use the one that has been artificially synthesized. When obtained from collagen protein, the collagen protein lysate is applied to a collagenase enzyme-immobilized column and enzymatically decomposed by the column method. The enzyme reaction completion solution passed through the column is separated, filtered through a filter of 0.22 to 0.45 μm, and the filtrate is pulverized by freeze-drying to obtain a collagen tripeptide, and then the collagen tripeptide powder is prepared. Redissolve and purify each dipeptide and tripeptide-containing fraction on HPLC (gel filtration and ODS column). In addition, it can be purified using ion exchange chromatography and carbon columns to obtain a single collagen tripeptide component. When it is obtained by artificial synthesis, it is artificially synthesized by a solid phase method using a peptide synthesis device. The peptide chain is extended from the C-terminus by the Fmoc method according to the program of the instrument used. Using a carrier that is a support for solid-phase peptide synthesis, in order to prevent side reactions, protect the β-amino group with ornithine and Fmoc that have previously protected the α-amino group and δ-amino group with Fmoc and Boc. The Fmoc amino derivative of β-alanine is used. Fmoc-Orn (Boc) is bound to a carrier, the α-amino group is deprotected with piperidine or the like, the C-terminal of Fmoc-Orn (Boc) is coupled, and the second ornithine α-amino is used with piperidine or the like. The group is deprotected and the C-terminal of Fmoc-β-Ala is similarly coupled. Finally, all deprotection and carrier removal are performed using an acid such as trifluoroacetic acid, and the extract extracted with 0.01 to 2% trifluoroacetic acid water is freeze-dried to produce dipeptides and tripeptides. It can be obtained by purification by HPLC (reverse transport column) or the like.
コラーゲンペプチドは、ヒドロキシプロリン（Ｈｙｐ）を少なくとも含むペプチドであることが好ましく、Ｈｙｐを含むジペプチドまたはトリペプチドから選択されることが好ましい。より具体的には、Ａｌａ－Ｈｙｐ－Ｇｌｙ、Ｐｒｏ－Ｈｙｐ－Ｇｌｙ、Ｐｒｏ－Ｈｙｐ、Ｌｅｕ－Ｈｙｐ、Ａｌａ－Ｈｙｐのジペプチドまたはトリペプチドから選択される１または２以上の混合物であってよい。中でも、Ａｌａ－Ｈｙｐのジペプチドを含むことが最も好ましい。Ａｌａ－Ｈｙｐはトリペプチドに比べて低分子であることから体内への吸収が良く、またこれらのペプチドのなかでも安定性が高い点で好ましい。 The collagen peptide is preferably a peptide containing at least hydroxyproline (Hyp), and is preferably selected from a dipeptide containing Hyp or a tripeptide. More specifically, it may be one or more mixtures selected from Ala-Hyp-Gly, Pro-Hyp-Gly, Pro-Hyp, Leu-Hyp, Ala-Hyp dipeptides or tripeptides. Of these, it is most preferable to contain an Ala-Hyp dipeptide. Since Ala-Hyp is a small molecule as compared with tripeptides, it is preferable because it is well absorbed into the body and has high stability among these peptides.
プラセンタ抽出物と、コラーゲンペプチドは、プラセンタ抽出物：コラーゲンペプチド重量の比率が、２０００：１～１０：１となるように含まれていることが好ましく、１０００：１～１００：１となるように含まれていることがより好ましい。プラセンタ抽出物と、コラーゲンペプチドが上記比率範囲で含まれていることにより、コラーゲンペプチドがプラセンタ抽出物中のＮＲの安定性に寄与し、ＮＡＤの産生量を増加させることができる。 The placenta extract and collagen peptide are preferably contained so that the ratio of placenta extract: collagen peptide weight is 2000: 1 to 10: 1, preferably 1000: 1 to 100: 1. It is more preferable that it is contained. When the placenta extract and the collagen peptide are contained in the above ratio range, the collagen peptide contributes to the stability of NR in the placenta extract and can increase the production amount of NAD.
本実施形態によるＮＡＤ産生促進剤においては、プラセンタ抽出物と、コラーゲンペプチドとの両者を含むことで、ＮＡＤの産生を促進することができる。より具体的には、コラーゲンペプチドがプラセンタ抽出物に含まれるＮＲの分解を抑制することで、ＮＡＤの中間代謝産物であるＮＲ量の低下を抑制し、結果として生体内で産生させるＮＡＤ量を促進することができると考えられる。また、ＮＡＤ産生促進剤は、従来から知られているプラセンタ抽出物単独の作用である保湿作用や美白作用、抗シワ作用、抗炎症作用、チロシナーゼ阻害作用、創傷治癒促進作用、線維芽細胞増殖促進作用、神経細胞活性化作用、血圧上昇抑制作用、エラスターゼ阻害作用や、コラーゲンペプチド単独の作用である生体内コラーゲンの合成促進効果をも備えている。 In the NAD production promoting agent according to the present embodiment, the production of NAD can be promoted by containing both the placenta extract and the collagen peptide. More specifically, collagen peptide suppresses the decomposition of NR contained in the placenta extract, thereby suppressing the decrease in the amount of NR, which is an intermediate metabolite of NAD, and as a result, promoting the amount of NAD produced in vivo. It is thought that it can be done. In addition, the NAD production promoter has a moisturizing action, a whitening action, an anti-wrinkle action, an anti-inflammatory action, a tyrosinase inhibitory action, a wound healing promoting action, and a fibroblast proliferation promoting action, which are conventionally known actions of placenta extract alone. It also has an action, a nerve cell activating action, a blood pressure increase inhibitory action, an elastase inhibitory action, and an action of promoting the synthesis of collagen in vivo, which is an action of collagen peptide alone.
ＮＡＤ産生促進剤には、プラセンタ抽出物と、コラーゲンペプチドに加えて、任意選択的な成分として、ニコチン酸アミド、ビタミンＣ誘導体、アルブチン、エラグ酸、コウジ酸、トラネキサム酸、グリセリン、１，３－ブチレングリコール、プロピレングリコールを含んでもよい。 In addition to placenta extract and collagen peptide, NAD production promoters include nicotinic acid amides, vitamin C derivatives, arbutin, ellagic acid, succinic acid, tranexamic acid, glycerin, 1,3- Butylene glycol and propylene glycol may be contained.
ＮＡＤ産生促進剤は、プラセンタ抽出物と、コラーゲンペプチドを混合することにより得ることができる。得られたＮＡＤ産生促進剤は、プラセンタ抽出物と、コラーゲンペプチドを含む液体組成物である。ＮＡＤ産生促進剤は、冷蔵で１～３年程度にわたって安定に貯蔵することができ、生細胞のＮＡＤの産生を促進することができる。また、得られた組成物は、特には老化して、ＮＡＤ産生が低減した生細胞においても、ＮＡＤの産生を促進することができるため、ＮＡＤの回復促進剤ということもできる。 The NAD production promoter can be obtained by mixing the placenta extract and the collagen peptide. The obtained NAD production promoter is a liquid composition containing a placenta extract and a collagen peptide. The NAD production promoter can be stably stored in a refrigerator for about 1 to 3 years, and can promote the production of NAD in living cells. In addition, the obtained composition can promote the production of NAD even in living cells in which NAD production is reduced due to aging, so that it can be said to be a recovery promoter for NAD.
ＮＡＤ産生促進剤は、内服剤、飲食品組成物、皮膚外用剤、化粧品、及び医薬部外品に添加して用いることができる。特には、老化防止効果を得るために、飲食品等、化粧品に添加して用いることができる。以下に、ＮＡＤ産生促進剤を添加して用いる各種の組成物について説明する。 The NAD production promoter can be added to internal preparations, food and drink compositions, skin external preparations, cosmetics, and quasi-drugs. In particular, it can be added to cosmetics such as foods and drinks in order to obtain an anti-aging effect. Hereinafter, various compositions used by adding a NAD production promoter will be described.
［第２実施形態：内服剤］
本発明は、第２実施形態によれば内服剤であって、第１実施形態によるＮＡＤ産生促進剤を含む。内服剤は、例えば経口投与剤であってよく、茶剤、カプセル剤、錠剤、丸剤、顆粒剤、細粒剤、シロップ剤、ドライシロップ剤等が挙げられる。
[Second embodiment: oral preparation]
The present invention is an internal preparation according to the second embodiment, and includes the NAD production promoting agent according to the first embodiment. The oral preparation may be, for example, an oral administration preparation, and examples thereof include tea preparations, capsules, tablets, pills, granules, fine granules, syrups, and dry syrups.
これらの内服剤は、第１実施形態によるＮＡＤ産生促進剤を含め、この分野で通常知られた慣用的な方法により製造される。内服剤には、たとえば、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、無機塩などを含めることができる。調製に当っては、更に結合剤、崩壊剤、界面活性剤、潤沢剤、流動性促進剤、矯味剤、着色剤、香料などを配合することもできる。たとえば、錠剤または丸剤とする場合は、所望によりショ糖、ゼラチン、ヒドロキシプロピルセルロースなどの糖衣または胃溶性もしくは腸溶性物質のフィルムで被覆してもよい。液体組成物からなる経口剤とする場合は、薬理学的に許容される乳濁剤、溶液剤、懸濁剤、シロップ剤などとすることができ、例えば、精製水、エタノールなどが担体として利用される。また、さらに所望により湿潤剤、懸濁剤のような補助剤、甘味剤、風味剤、防腐剤などを添加してもよい。 These oral preparations are produced by conventional methods commonly known in the art, including the NAD production promoter according to the first embodiment. Oral preparations can include, for example, starch, lactose, sucrose, mannitol, carboxymethyl cellulose, cornstarch, inorganic salts and the like. In the preparation, a binder, a disintegrant, a surfactant, a moisturizer, a fluidity promoter, a flavoring agent, a coloring agent, a fragrance and the like can be further added. For example, tablets or pills may be coated with a sugar coating such as sucrose, gelatin, hydroxypropyl cellulose or a film of a gastric or enteric substance, if desired. In the case of an oral preparation consisting of a liquid composition, it can be a pharmacologically acceptable emulsion, solution, suspension, syrup, etc., and for example, purified water, ethanol, etc. can be used as a carrier. Will be done. Further, if desired, an auxiliary agent such as a wetting agent or a suspending agent, a sweetening agent, a flavoring agent, a preservative or the like may be added.
内服剤におけるＮＡＤ産生促進剤の有効成分量は、プラセンタ抽出物の乾燥重量を基準として、例えば、通常成人１日当たり５０ｍｇ以上、好ましくは１００ｍｇ以上を摂取するのが好ましい。投与量の上限は、１日当たり、１０，０００ｍｇ以下が好ましく、５，０００ｍｇ以下がより好ましい。よって、ＮＡＤ産生促進剤は、各形態に応じた範囲で前述した摂取量となるように含有されれば良い。 The amount of the active ingredient of the NAD production promoter in the oral preparation is, for example, usually 50 mg or more, preferably 100 mg or more per day for an adult, based on the dry weight of the placenta extract. The upper limit of the dose is preferably 10,000 mg or less, more preferably 5,000 mg or less per day. Therefore, the NAD production promoter may be contained in a range corresponding to each form so as to have the above-mentioned intake amount.
［第３実施形態：飲食品組成物］
本発明は、第３実施形態によれば飲食品組成物であって、第１実施形態によるＮＡＤ産生促進剤を含む。本実施形態による飲食品組成物には、第１実施形態によるＮＡＤ産生促進剤を、飲食品組成物において通常用いられている任意成分と共に配合することができる。このようなヒトまたは動物用の飲食品組成物としては、例えば、パン類、菓子類、麺類、肉製品・水産加工品、穀類の加工品、加工野菜・加工果実、加工卵、乳製品、粉類、即席菓子の素、食用油脂、スープの素、粉末飲料、調味料、食品添加物、飲料類、飼料等が挙げられる。
[Third Embodiment: food and drink composition]
The present invention is a food and drink composition according to a third embodiment, and includes a NAD production promoter according to the first embodiment. The food and drink composition according to the present embodiment can contain the NAD production promoter according to the first embodiment together with any component usually used in the food and drink composition. Examples of such food and drink compositions for humans or animals include breads, confectioneries, noodles, meat products / processed marine products, processed cereal products, processed vegetables / processed fruits, processed eggs, dairy products, and powders. Examples include cereals, instant confectionery ingredients, edible oils and fats, soup ingredients, powdered beverages, seasonings, food additives, beverages, feeds and the like.
また、飲食品組成物は、例えば、ビタミン剤などの栄養補助食品、栄養補助飲料、動物用健康食品、特定保健用食品、栄養機能食品、保健機能食品等が含まれ、通常用いられている各種形態、例えば、散剤、顆粒剤、錠剤、カプセル剤、液剤、フィルム等として製品化することができる。製品化に際しては、第１実施形態によるＮＡＤ産生促進剤とともに、賦形剤、結合剤、崩壊剤、崩壊抑制剤、吸収促進剤、吸着剤、滑沢剤、着色剤、保存剤、香料、風味剤、甘味剤等が配合される。 Further, the food and drink composition includes, for example, dietary supplements such as vitamins, dietary supplements, animal health foods, specified health foods, nutritional functional foods, health functional foods, etc., and various commonly used foods and drink compositions. It can be commercialized in a form such as a powder, a granule, a tablet, a capsule, a liquid, a film or the like. In commercialization, along with the NAD production promoter according to the first embodiment, excipients, binders, disintegrants, disintegrant inhibitors, absorption promoters, adsorbents, lubricants, colorants, preservatives, fragrances, flavors Agents, sweeteners, etc. are blended.
これらの飲食品組成物は、この分野で通常知られた慣用的な方法により製造される。 These food and drink compositions are produced by conventional methods commonly known in the art.
このような飲食品組成物におけるＮＡＤ産生促進剤の有効成分量は、プラセンタ抽出物の重量を基準として、飲食品の形態ごとに応じた範囲で所望の摂取量となるように添加されれば良く、飲食品には、０．１～２０重量％の範囲内で添加することが好ましい。例えば、液状の飲食品に対し０．１～２０重量％、固体状の飲食品に対し０．１～２０重量％、錠剤状の飲食品に対し、０．１～２０重量％の範囲内で添加することが好ましい。さらに具体的には、以下に限定されないが、例えば、サプリメントには、プラセンタ抽出物の乾燥重量を基準として、０．１～２０重量％の範囲内で添加することが好ましい。 The amount of the active ingredient of the NAD production promoter in such a food or drink composition may be added so as to be a desired intake amount within a range corresponding to each form of the food or drink based on the weight of the placenta extract. , It is preferable to add to foods and drinks in the range of 0.1 to 20% by weight. For example, in the range of 0.1 to 20% by weight for liquid foods and drinks, 0.1 to 20% by weight for solid foods and drinks, and 0.1 to 20% by weight for tablet foods and drinks. It is preferable to add it. More specifically, but not limited to the following, for example, it is preferable to add the supplement in the range of 0.1 to 20% by weight based on the dry weight of the placenta extract .
［第４実施形態：皮膚外用剤］
本発明は、第４実施形態によれば皮膚外用剤であって、第１実施形態によるＮＡＤ産生促進剤を含む。より詳細には、皮膚外用剤は化粧品であってよく、老化防止用化粧品、クレンジング用化粧品、頭髪用化粧品、入浴用化粧品、医療用化粧品が挙げられ、また、顔料、化粧水、美容液、乳液、クリーム、ジェル、パック、リポソーム、液状、粘土状、ソリッド粉末状化粧料、エアゾール化粧料、ハップ剤等のスキンケア化粧品、下地クリーム、ファンデーション等のメークアップ化粧品が挙げられる。
[Fourth Embodiment: External skin preparation]
The present invention is a skin external preparation according to the fourth embodiment, and includes a NAD production promoter according to the first embodiment. More specifically, the external skin preparation may be cosmetics, including anti-aging cosmetics, cleansing cosmetics, hair cosmetics, bath cosmetics, medical cosmetics, and pigments, cosmetics, beauty liquids, emulsions. , Cream, gel, pack, liposome, liquid, clay-like, solid powder cosmetics, aerosol cosmetics, skin care cosmetics such as haptics, makeup cosmetics such as foundation creams and foundations.
本実施形態による化粧品には、水、アルコール、界面活性剤（カチオン、アニオン、ノニオン、両性界面活性剤等）、保湿剤（グリセリン、１，３－ブチレングリコール、プロピレングリコール、アミノ酸、尿素、ピロリドンカルボン酸塩、核酸類、単糖類、少糖等およびそれらの誘導体ほか）、増粘剤（多糖類、ポリアクリル酸塩、カルボキシビニルポリマー、ポリビニルピロリドン、ポリビニルアルコール、キチン、キトサン、アルギン酸、カラギーナン、キサンタンガム、メチルセルロース等およびそれらの誘導体ほか）、ワックス、ワセリン、炭化水素飽和脂肪酸、不飽和脂肪酸、シリコン油等およびそれらの誘導体、トリ（カプリル・カプリン酸）グリセリル、トリオクタン酸グリセリル等のトリグリセライド類、ステアリン酸イソプロピル等のエステル油類、天然油脂類（オリブ油、椿油、アボガド油、アーモンド油、カカオ脂、月見草油、ブドウ種子油、マカデミアンナッツ油、ユーカリ油、ローズヒップ油、スクワラン、オレンジラフィー油、ラノリン、セラミド等）、防腐剤（オキシ安息香酸誘導体、デヒドロ酢酸塩、感光素、ソルビン酸、フェノキシエタノール等およびそれらの誘導体ほか）、殺菌剤（イオウ、トリクロカルバアニリド、サリチル酸、ジンクピリチオン、ヒノキチオール等およびそれらの誘導体ほか）、紫外線吸収剤（パラアミノ安息香酸、メトキシケイ皮酸等およびそれらの誘導体ほか）、抗炎症剤（アラントイン、グリチルリチン酸等およびそれらの誘導体ほか）、抗酸化剤（トコフェロール、ＢＨＡ、ＢＨＴ等およびそれらの誘導体ほか）、キレート剤（エデト酸、ヒドロキシエタンジホスホン酸等およびそれらの誘導体ほか）、動植物エキス（アシタバ、アロエ、エイジツ、オウゴン、オウバク、海藻、カリン、カミツレ、甘草、キウイ、キュウリ、クワ、シラカバ、トウキ、ニンニク、ボタン、ホップ、マロニエ、ラベンダー、ローズマリー、ユーカリ、ミルク、各種ペプタイド、プラセンタ、ローヤルゼリー等およびこれらの含有成分精製物または発酵物ほか）、ｐＨ調整剤（無機酸、無機酸塩、有機酸、有機酸塩等およびそれらの誘導体ほか）、ビタミン類（ビタミンＡ類、ビタミンＢ類、ビタミンＣ、ビタミンＤ 類等およびそれらの誘導体ほか）、酸化チタン、タルク、マイカ、シリカ、酸化亜鉛、酸化鉄、シリコンおよびこれらを加工処理した粉体類等を本発明の目的を達成する範囲内で配合することができる。なお、化粧品を構成する成分は上述に限られるものではなく、化粧料に用い得る成分であれば自由に選択が可能である。 The cosmetics according to this embodiment include water, alcohol, surfactants (cations, anions, nonions, amphoteric surfactants, etc.), moisturizers (glycerin, 1,3-butylene glycol, propylene glycol, amino acids, urea, pyrrolidone carboxylics). Acid salts, nucleic acids, monosaccharides, oligosaccharides and their derivatives, etc.), thickeners (polysaccharides, polyacrylic acid salts, carboxyvinyl polymers, polyvinylpyrrolidone, polyvinyl alcohol, chitin, chitosan, alginic acid, carrageenan, xanthan gum , Methyl cellulose, etc. and their derivatives, etc.), wax, vaseline, hydrocarbon saturated fatty acids, unsaturated fatty acids, silicon oil, etc. and their derivatives, triglycerides such as tri (capryl capric acid) glyceryl, glyceryl trioctanoate, stearic acid Ester oils such as isopropyl, natural oils and fats (olib oil, camellia oil, avocado oil, almond oil, cacao oil, evening primrose oil, grape seed oil, macadamian nut oil, eucalyptus oil, rose hip oil, squalane, orange raffy oil, Lanolin, ceramide, etc.), preservatives (oxybenzoic acid derivatives, dehydroacetate, photosensitizers, sorbic acid, phenoxyethanol, etc. and their derivatives, etc.), bactericides (sulfur, trichlorcarbaanilide, salicylic acid, zincpyrythion, hinokithiol, etc.) and them. Anti-inflammatory agents (alantin, glycyrrhizinic acid, etc. and their derivatives, etc.), antioxidants (tocopherol, BHA, BHT, etc.), UV absorbers (paraaminobenzoic acid, methoxycinnamic acid, etc. and their derivatives, etc.) Etc. and their derivatives, etc.), chelating agents (edetic acid, hydroxyetandiphosphonic acid, etc. and their derivatives, etc.), animal and plant extracts (Ashitaba, Aloe, Agetsu, Ogon, Oubaku, seaweed, carin, chamomile, licorice, kiwi, etc. Cucumber, mulberry, white birch, touki, garlic, button, hop, marronnier, lavender, rosemary, eucalyptus, milk, various peptides, placenta, royal jelly, etc. and their contained components purified or fermented products, pH adjuster (inorganic) Acids, inorganic acid salts, organic acids, organic acid salts and their derivatives, etc.), vitamins (vitamin A, vitamin B, vitamin C, vitamin D, etc. and their derivatives, etc.), titanium oxide, talc, The present invention comprises mica, silica, zinc oxide, iron oxide, silicon and powders obtained by processing these. It can be blended within the range that achieves the purpose of. The ingredients constituting the cosmetics are not limited to the above, and any ingredients that can be used in cosmetics can be freely selected.
ハップ剤においては上記成分に加えて、基剤（カオリン、ベントナイト等）、ゲル化剤（ポリアクリル酸塩、ポリビニルアルコール等）を本発明の目的を達成する範囲内で配合することができる。浴剤においては、硫酸塩、炭酸水素塩、ホウ酸塩、色素、保湿剤を本発明の目的を達成する範囲内で適宜配合し、パウダータイプ、液剤タイプに調製が可能である。 In the happing agent, in addition to the above components, a base (kaolin, bentonite, etc.) and a gelling agent (polyacrylic acid salt, polyvinyl alcohol, etc.) can be blended within a range that achieves the object of the present invention. In the bathing agent, a sulfate, a bicarbonate, a borate, a pigment, and a moisturizing agent can be appropriately blended within a range that achieves the object of the present invention, and can be prepared into a powder type and a liquid agent type.
これらの化粧品は、この分野で通常知られた慣用的な方法により製造される。 These cosmetics are manufactured by conventional methods commonly known in the art.
化粧品におけるＮＡＤ産生促進剤の有効成分量は、プラセンタ抽出物の重量を基準として、化粧品の形態ごとに応じた範囲で前述した摂取量となるように添加されれば良く、化粧品には、０．１～２０重量％の範囲内で添加することが好ましい。例えば、液状の化粧品に対し０．１～２０重量％、クリーム状の化粧品に対し０．１～１０重量％、粉末状の化粧品に対し、０．１～５重量％の範囲内で添加することが好ましい。さらに具体的には、以下に限定されないが、例えば、化粧水には、１～１０重量％、化粧用クリームには、１～５重量％の範囲内で添加することが好ましい。 The amount of the active ingredient of the NAD production promoter in cosmetics may be added so as to be the above-mentioned intake amount in a range corresponding to each form of cosmetics based on the weight of placenta extract. It is preferable to add it in the range of 1 to 20% by weight. For example, it should be added in the range of 0.1 to 20% by weight for liquid cosmetics, 0.1 to 10% by weight for creamy cosmetics, and 0.1 to 5% by weight for powdery cosmetics. Is preferable. More specifically, the addition is not limited to the following, but for example, it is preferable to add it in the range of 1 to 10% by weight for the cosmetic water and 1 to 5% by weight for the cosmetic cream.
［第５実施形態：医薬部外品］
本発明は、第５実施形態によれば医薬部外品であって、第１実施形態によるＮＡＤ産生促進剤を含む。医薬部外品としては飴類、ガム類、歯磨き粉類、液体歯磨き剤類、ジェル状歯磨き剤類、制汗剤、飲料類等が含まれる。
[Fifth Embodiment: Quasi-drug]
The present invention is a quasi-drug according to the fifth embodiment and includes the NAD production promoter according to the first embodiment. Quasi-drugs include candies, gums, dentifrices, liquid dentifrices, gel-like dentifrices, antiperspirants, beverages and the like.
ＮＡＤ産生促進剤を含む医薬部外品は、この分野で通常知られた慣用的な方法により製造される。 Quasi-drugs containing NAD production promoters are produced by conventional methods commonly known in the art.
医薬部外品におけるＮＡＤ産生促進剤の有効成分量は、プラセンタ抽出物の重量を基準として、医薬部外品の形態ごとに応じた範囲で前述した摂取量となるように添加されれば良く、医薬部外品には、０．１～２０重量％の範囲内で添加することが好ましい。例えば、固体状の医薬部外品に対し、０．１～２０重量％、液体状の医薬部外品に対し、０．１～２０重量％、ジェル又はペースト状の医薬部外品に対し、０．１～２０重量％の範囲内で添加することが好ましい。さらに具体的には、以下に限定されないが、例えば、ペットガムには、０．０２～５重量％、歯磨き粉に対し、０．０２～１重量％の範囲内で添加することが好ましい。 The amount of the active ingredient of the NAD production promoter in the quasi-drug may be added so as to be the above-mentioned intake amount in a range corresponding to each form of the quasi-drug based on the weight of the placenta extract. It is preferable to add it to the quasi-drug in the range of 0.1 to 20% by weight. For example, 0.1 to 20% by weight for solid quasi-drugs, 0.1 to 20% by weight for liquid quasi-drugs, gel or paste quasi-drugs. It is preferable to add it in the range of 0.1 to 20% by weight. More specifically, but not limited to the following, for example, it is preferable to add 0.02 to 5% by weight for pet gum and 0.02 to 1% by weight for toothpaste.
以下、本発明を、実施例を参照してより詳細に説明する。しかしながら、本発明は以下の実施例に限定されるものではない。 Hereinafter, the present invention will be described in more detail with reference to Examples. However, the present invention is not limited to the following examples.
＜１：プラセンタ抽出物中のＮＲ量の測定＞
試料溶液中のＮＲを蛍光誘導体化し、高速液体クロマトグラフィー（ＨＰＬＣ）を用いた定量分析法を実施した。ＮＲの誘導体化は、ニコチンアミドモノヌクレオチド定量法（Formentini, L. et al., Biochem. Pharmacol. Vol. 77, pp. 1612-20(2009)）に基づき、以下の手順で行った。
<1: Measurement of NR in placenta extract>
NR in the sample solution was fluorescently derivatized and a quantitative analysis method using high performance liquid chromatography (HPLC) was carried out. Derivatization of NR was carried out according to the following procedure based on the nicotinamide mononucleotide quantification method (Formentini, L. et al., Biochem. Pharmacol. Vol. 77, pp. 1612-20 (2009)).
試料溶液としては、プラセンタ抽出物及び牛乳を使用した。使用したプラセンタ抽出物は、ブタ胎盤抽出液を段階的にフィルター濾過処理したものを使用した。段階的なフィルター濾過はまず、孔径０．２２μｍの精密濾過膜（Ｓａｒｔｏｒｉｕｓ社製）を用いて濾過し、次に、分画分子量１０キロダルトンの遠心式限外濾過膜（Ｍｅｒｃｋ Ｍｉｌｌｉｐｏｒｅ社製）を用いた濾過により高分子タンパク質及びその凝集体を除去した。また、牛乳は、無脂乳固形分８．３％以上、乳脂肪分３．５％以上の市販品を使用した。それぞれの試料溶液に１Ｎ水酸化カリウムと２０％アセトフェノンを添加し、４℃で１５分間静置した。その後、８８％ギ酸を加えよく混和し、１００℃で５分間加熱した。この液を孔径０．４５μｍのメンブランフィルターで濾過したものを蛍光誘導体化試料溶液とした。別に、β－ＮＲトリフルオロメタンスルホン酸塩（Ｃａｒｂｏｓｙｎｔｈ社製）を各濃度で水に溶解し、試料溶液と同様の処理を行ったものを蛍光誘導体化標準溶液とした。 Placenta extract and milk were used as the sample solution. The placenta extract used was a porcine placenta extract that had been filtered and filtered in stages. Stepwise filter filtration is performed by first filtering using a microfiltration membrane (manufactured by Sartorius) with a pore size of 0.22 μm, and then using a centrifugal ultrafiltration membrane (manufactured by Merck Millipore) having a molecular weight cut-off of 10 kilodaltons. The high molecular weight protein and its aggregates were removed by the filtration used. As milk, a commercially available product having a non-fat milk solid content of 8.3% or more and a milk fat content of 3.5% or more was used. 1N potassium hydroxide and 20% acetophenone were added to each sample solution, and the mixture was allowed to stand at 4 ° C. for 15 minutes. Then, 88% formic acid was added, the mixture was well mixed, and the mixture was heated at 100 ° C. for 5 minutes. This solution was filtered through a membrane filter having a pore size of 0.45 μm and used as a fluorescent derivatized sample solution. Separately, β-NR trifluoromethanesulfonate (manufactured by Carbosynth) was dissolved in water at each concentration and treated in the same manner as the sample solution to prepare a fluorescent derivatization standard solution.
蛍光誘導体化した試料溶液、標準溶液について以下の条件でＨＰＬＣ分析を行い、標準溶液から得られたピーク面積値で検量線を作成し、試料溶液から得られるピーク面積値からＮＲ濃度を算出した。図１に牛乳に対する相対値を示す。
装置：ＰＵ－２０８９Ｐｌｕｓ（日本分光）
検出器：ＦＰ－２０２５Ｐｌｕｓ（日本分光）
励起波長：３６０ｎｍ
蛍光波長：４４５ｎｍ
カラム：Ｉｎｅｒｔｓｉｌ ＯＤＳ－３（４．６ｍｍ×２５０ｍｍ，５μｍ）(ＧＬサイエンス)
ガードカラム：ＯＤＳ－ＨＧ（４．０ｍｍ×１０ｍｍ，５μｍ）（野村化学）
流速：１ｍＬ／ｍｉｎ
移動相：水（０．０５％トリフルオロ酢酸含有）：アセトニトリル（８３：１７）
HPLC analysis was performed on the fluorescently derivatized sample solution and standard solution under the following conditions, a calibration curve was prepared from the peak area value obtained from the standard solution, and the NR concentration was calculated from the peak area value obtained from the sample solution. FIG. 1 shows the relative value with respect to milk.
Equipment: PU-2089Plus (JASCO Corporation)
Detector: FP-2025Plus (JASCO Corporation)
Excitation wavelength: 360 nm
Fluorescence wavelength: 445 nm
Column: Inertsil ODS-3 (4.6 mm x 250 mm, 5 μm) (GL Science)
Guard column: ODS-HG (4.0 mm x 10 mm, 5 μm) (Nomura Kagaku)
Flow rate: 1 mL / min
Mobile phase: Water (containing 0.05% trifluoroacetic acid): Acetonitrile (83:17)
測定の結果、プラセンタ抽出物は、ＮＲを多く含むことが知られている牛乳（非特許文献４）と比較して、高濃度のＮＲを含有していることが明らかとなった。 As a result of the measurement, it was clarified that the placenta extract contained a high concentration of NR as compared with milk (Non-Patent Document 4), which is known to contain a large amount of NR.
＜２：ＮＡＤ産生促進剤のヒト皮膚に対するＮＡＤ産生促進活性の評価＞
３次元培養皮膚（ＭａｔＴｅｋ社製）の培養液中にＮＡＭＰＴ阻害剤であるＦＫ８６６を添加し、ＮＡＤを枯渇させた状態における、ＮＡＤ産生促進剤のＮＡＤ産生促進活性を測定した。
<2: Evaluation of NAD production promoting activity of NAD production promoting agent on human skin>
FK866, which is a NAMPT inhibitor, was added to the culture solution of three-dimensional cultured skin (manufactured by MatTek), and the NAD production promoting activity of the NAD production promoting agent was measured in a state where NAD was depleted.
３次元培養皮膚の培養液中に５ｎＭのＦＫ８６６を、皮膚上側にＮＡＤ産生促進剤、又はネガティブコントロールとしてＰＢＳをそれぞれ添加し、５％ＣＯ２、３７℃にて４８時間培養した。ＮＡＤ産生促進剤は、培養液中、プラセンタ抽出物が１体積％、５体積％、または２５体積％と、人工合成したジペプチドＡｌａ-Ｈｙｐが０．５ｍＭとなるように調製した。その後、培養皮膚の細胞を溶出させ、ＮＡＤ／ＮＡＤＨ Ａｓｓａｙ Ｋｉｔ－ＷＳＴ（ＤＯＪＩＮＤＯ社製）を用いて、細胞内の総ＮＡＤ量を測定した。同時に細胞溶出液のタンパク量をＢＣＡ法により測定し、各細胞溶出液におけるタンパク量に対するＮＡＤ量を算出した。図２にコントロール（ＰＢＳ）に対する相対値を示す。 3D culture FK866 of 5 nM was added to the culture solution of the skin, NAD production promoter or PBS was added as a negative control on the upper side of the skin, and the cells were cultured at 5% CO 2 and 37 ° C. for 48 hours. The NAD production promoter was prepared so that the placenta extract was 1% by volume, 5% by volume, or 25% by volume and the artificially synthesized dipeptide Ala-Hyp was 0.5 mM in the culture broth. Then, the cells of the cultured skin were eluted, and the total intracellular NAD amount was measured using NAD / NADH Assay Kit-WST (manufactured by DOJINDO). At the same time, the amount of protein in the cell eluate was measured by the BCA method, and the amount of NAD with respect to the amount of protein in each cell eluate was calculated. FIG. 2 shows the relative value with respect to the control (PBS).
図２より、プラセンタ抽出物の濃度依存的に３次元培養皮膚の細胞内ＮＡＤ量の増加が認められたことから、プラセンタ抽出物はＮＡＤ産生促進活性を持つことが示唆された。 From FIG. 2, an increase in the amount of intracellular NAD in the three-dimensional cultured skin was observed depending on the concentration of the placenta extract, suggesting that the placenta extract has NAD production promoting activity.
＜３：プラセンタ抽出物とＡｌａ-Ｈｙｐの相乗効果の検証＞
ヒト皮膚線維芽細胞においてコラーゲン合成促進効果が確認されているジペプチドであるＡｌａ-Ｈｙｐ（特開２０１０－２４２００号公報）の前処理による、プラセンタ抽出物の細胞内ＮＡＤ産生促進活性への影響を調べた。
<3: Verification of synergistic effect between placenta extract and Ala-Hyp>
We investigated the effect of placenta extract on intracellular NAD production promoting activity by pretreatment with Ala-Hyp (Japanese Patent Laid-Open No. 2010-24200), which is a dipeptide whose collagen synthesis promoting effect has been confirmed in human skin fibroblasts. rice field.
正常ヒト皮膚線維芽細胞（クラボウ社製）を１２ウェルプレートに５×１０４個／ウェルとなるように播種し、５％ＣＯ２、３７℃にて２４時間培養し、ＤＭＥＭ／Ｆ１２培地（Ｔｈｅｒｍｏ Ｆｉｓｈｅｒ Ｓｃｉｅｎｔｉｆｉｃ社製）に置換した。人工合成したＡｌａ-Ｈｙｐを０．５ｍＭとなるように添加し、２４時間培養した後、５ｎＭのＦＫ８６６を含有したＤＭＥＭ／Ｆ１２培地に置換し、プラセンタ抽出物を５体積％となるように添加した。さらに２４時間培養後、細胞を溶出させ、ＮＡＤ／ＮＡＤＨ Ａｓｓａｙ Ｋｉｔ－ＷＳＴを用いて、細胞内の総ＮＡＤ量を測定した。同時に細胞溶出液のタンパク質をＢＣＡ法により測定し、各細胞溶出液におけるタンパク質に対するＮＡＤ量を算出した。図３に未処理（コントロール）の細胞に対する相対値を示す。 Normal human skin fibroblasts (manufactured by Kurabo) were seeded in a 12-well plate at 5 × 10 4 cells / well, cultured at 5% CO 2 , 37 ° C. for 24 hours, and DMEM / F12 medium (Thermo). It was replaced with Fisher Scientific (manufactured by Fisher Scientific). Artificially synthesized Ala-Hyp was added to 0.5 mM, cultured for 24 hours, replaced with DMEM / F12 medium containing 5 nM FK866, and placenta extract was added to 5% by volume. .. After further culturing for 24 hours, the cells were eluted and the total intracellular NAD amount was measured using NAD / NADH Assay Kit-WST. At the same time, the protein in the cell eluate was measured by the BCA method, and the amount of NAD for the protein in each cell eluate was calculated. FIG. 3 shows relative values for untreated (control) cells.
線維芽細胞を用いた単層培養試験において、プラセンタ抽出物の添加により、細胞内ＮＡＤ量が増加することが確認された。さらにその増加量は、Ａｌａ-Ｈｙｐの前処理によって亢進することが認められた。 In a monolayer culture test using fibroblasts, it was confirmed that the addition of placenta extract increased the amount of intracellular NAD. Furthermore, it was found that the increased amount was enhanced by the pretreatment of Ala-Hyp.
＜４：ＮＲ安定性試験＞
ＮＲは水溶液中で不安定な成分であり、容易にニコチンアミドとリボースに分解してしまうことが知られている（特表２０１７－５１８３０６号公報）。ここでは、Ａｌａ-ＨｙｐによるＮＲの分解抑制効果を検証した。
<4: NR stability test>
It is known that NR is an unstable component in an aqueous solution and easily decomposes into nicotinamide and ribose (Japanese Patent Laid-Open No. 2017-518306). Here, the effect of Ala-Hyp on suppressing the decomposition of NR was verified.
β－ＮＲトリフルオロメタンスルホン酸塩を２００μＭとなるように調製したものをＮＲ溶液とし、β－ＮＲトリフルオロメタンスルホン酸塩水溶液とＡｌａ-Ｈｙｐ水溶液を１：１で混和し、終濃度をそれぞれ、２００μＭ、５ｍＭとしたものをＮＲ＋Ａｌａ-Ｈｙｐ溶液とした。各溶液について、室温（ＲＴ）、５０℃、及び７５℃で１時間静置した後、孔径０．４５μｍのメンブランフィルターで濾過したものを試料溶液とした。別にβ－ＮＲトリフルオロメタンスルホン酸塩を各濃度で水に溶解し、孔径０．４５μｍのメンブランフィルターで濾過したものを標準溶液とした。各試料溶液及び標準溶液について以下の条件でＨＰＬＣ分析を行い、標準溶液から得られたピーク面積値で検量線を作成し、試料溶液から得られるピーク面積値からＮＲ濃度を算出した。
装置：ＰＵ－２０８９Ｐｌｕｓ（日本分光）
検出器：ＭＤ-２０１０Ｐｌｕｓ（日本分光）
測定波長：２２０ｎｍ
カラム：Ｉｎｅｒｔｓｉｌ ＯＤＳ－３（４．６ｍｍ×２５０ｍｍ，５μｍ）(ＧＬサイエンス)
ガードカラム：ＯＤＳ－ＨＧ（４．０ｍｍ×１０ｍｍ，５μｍ）（野村化学）
流速：１ｍＬ／ｍｉｎ
移動相：水（０．０５％トリフルオロ酢酸含有）
The NR solution was prepared so that β-NR trifluoromethanesulfonate was 200 μM, and the β-NR trifluoromethanesulfonate aqueous solution and the Ala-Hyp aqueous solution were mixed at a ratio of 1: 1 to a final concentration of 200 μM. A solution set at 5 mM was used as an NR + Ala-Hyp solution. Each solution was allowed to stand at room temperature (RT), 50 ° C., and 75 ° C. for 1 hour, and then filtered through a membrane filter having a pore size of 0.45 μm as a sample solution. Separately, β-NR trifluoromethanesulfonate was dissolved in water at each concentration and filtered through a membrane filter having a pore size of 0.45 μm as a standard solution. HPLC analysis was performed on each sample solution and standard solution under the following conditions, a calibration curve was prepared from the peak area value obtained from the standard solution, and the NR concentration was calculated from the peak area value obtained from the sample solution.
Equipment: PU-2089Plus (JASCO Corporation)
Detector: MD-2010Plus (JASCO Corporation)
Measurement wavelength: 220 nm
Column: Inertsil ODS-3 (4.6 mm x 250 mm, 5 μm) (GL Science)
Guard column: ODS-HG (4.0 mm x 10 mm, 5 μm) (Nomura Kagaku)
Flow rate: 1 mL / min
Mobile phase: water (containing 0.05% trifluoroacetic acid)
測定の結果、ＮＲは温度依存的に分解反応が促進されることが確認された。その際、Ａｌａ-Ｈｙｐを添加しておくことで、ＮＲの分解を抑制する傾向が認められた。結果を下記表１に示す。表１から、Ａｌａ-ＨｙｐがＮＲの水溶液中での安定性に寄与する可能性が示唆された。 As a result of the measurement, it was confirmed that the decomposition reaction of NR was promoted in a temperature-dependent manner. At that time, the tendency to suppress the decomposition of NR was observed by adding Ala-Hyp. The results are shown in Table 1 below. Table 1 suggests that Ala-Hyp may contribute to the stability of NR in aqueous solution.
＜処方例＞
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