JP2021070670A - Il-37 production enhancers - Google Patents
Il-37 production enhancers Download PDFInfo
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- JP2021070670A JP2021070670A JP2019200110A JP2019200110A JP2021070670A JP 2021070670 A JP2021070670 A JP 2021070670A JP 2019200110 A JP2019200110 A JP 2019200110A JP 2019200110 A JP2019200110 A JP 2019200110A JP 2021070670 A JP2021070670 A JP 2021070670A
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- gentiana
- ascorbic acid
- extract
- autophagy
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Abstract
Description
本発明は、ゲンチアナの抽出物及び／又はＬ−アスコルビン酸誘導体を有効成分として含有することを特徴とするインターロイキン―３７（ＩＬ−３７）産生促進剤、ＰＩ３Ｋ―ＡＫＴ−ｍＴＯＲ経路阻害剤及びオートファジー調節剤に関するものである。 The present invention comprises an interleukin-37 (IL-37) production promoter, a PI3K-AKT-mTOR pathway inhibitor and an autophagy, which comprises an extract of gentiana and / or an L-ascorbic acid derivative as an active ingredient. It concerns fuzzy regulators.
オートファジーとは、細胞質に出現した隔離膜が細胞質の成分を取り囲むことでオートファゴソームを形成し、オートファゴソームがリソソームと融合することで細胞質の成分を分解する機構である。オートファジーは飢餓への適応反応であり、低アミノ酸状態や低インスリン状態ではオートファジーが一過的に誘導され、細胞質成分を分解することで栄養素を供給する。又一方で、ストレス下で蓄積された損傷細胞小器官やタンパク質を除去する役割も果たし、細胞内の恒常性維持にも寄与する。 Autophagy is a mechanism in which an isolation membrane that appears in the cytoplasm surrounds a component of the cytoplasm to form an autophagosome, and the autophagosome fuses with a lysosome to decompose the component of the cytoplasm. Autophagy is an adaptive response to starvation. In low amino acid and low insulin states, autophagy is transiently induced and supplies nutrients by degrading cytoplasmic components. On the other hand, it also plays a role of removing damaged organelles and proteins accumulated under stress, and contributes to maintenance of intracellular homeostasis.
オートファジーの制御異常は、細胞内に異常タンパク質を蓄積させる。アルツハイマー病、パーキンソン病及びハンチントン病等の神経変性疾患は、細胞内に異常タンパク質が蓄積することが病因のひとつと考えられており、オートファジーを調節することは、このような病気の予防若しくは軽減において非常に重要である（非特許文献１）。 Abnormal autophagy control causes the accumulation of abnormal proteins in cells. Neurodegenerative diseases such as Alzheimer's disease, Parkinson's disease and Huntington's disease are considered to be caused by the accumulation of abnormal proteins in cells, and regulation of autophagy prevents or alleviates such diseases. It is very important in (Non-Patent Document 1).
ＰＩ３Ｋ―ＡＫＴ−ｍＴＯＲ（ＰＩ３キナーゼ／Ａｋｔ／ラパマイシン哺乳類ターゲット）経路は、広範な正常細胞機能に必要とされる主要なシグナル伝達ノードであり、オートファジーの制御においても重要な役割を果たす（非特許文献２）。ＰＩ３Ｋ―ＡＫＴ−ｍＴＯＲ経路の阻害はオートファジーを誘導し、神経変性疾患の予防若しくは軽減に有益であり得る（特許文献１）。 The PI3K-AKT-mTOR (PI3 kinase / Akt / rapamycin mammalian target) pathway is a major signaling node required for a wide range of normal cell functions and also plays an important role in the control of autophagy (non-patented). Document 2). Inhibition of the PI3K-AKT-mTOR pathway induces autophagy and may be beneficial in the prevention or alleviation of neurodegenerative diseases (Patent Document 1).
ＩＬ−３７は、サイトカインのＩＬ−１ファミリーのメンバーであり、ＩＬ−１β、ＩＬ−６及びＴＮＦ−α等の炎症促進性サイトカインによって引き起こされる炎症を減少させ、生体内において炎症に対する防御的な役割を担う抗炎症性のサイトカインである（非特許文献３）。又、ＩＬ−３７は細胞内においてＰＩ３Ｋ−ＡＫＴ−ｍＴＯＲ経路を阻害し、オートファジーを活性化することが知られている（非特許文献２）。 IL-37 is a member of the IL-1 family of cytokines, reduces inflammation caused by pro-inflammatory cytokines such as IL-1β, IL-6 and TNF-α, and plays a protective role against inflammation in vivo. It is an anti-inflammatory cytokine responsible for (Non-Patent Document 3). In addition, IL-37 is known to inhibit the PI3K-AKT-mTOR pathway in cells and activate autophagy (Non-Patent Document 2).
ゲンチアナは、ヨーロッパ等に広く分布している植物であり、根を自然発酵させた後に乾燥したものが生薬として扱われており、食欲増進や消化不良、胃痛、胸やけ、胃炎、下痢、吐き気等の治療に内服するほか、外傷の治療に用いられる。今までに、ゲンチアナの抽出物を有効成分として含有することを特徴とする染毛剤組成物及び感作性抑制剤（特許文献２）、皮膚外用剤（特許文献３）、化粧料用組成物（特許文献４）及び液体口腔用組成物（特許文献５）等が知られている。しかしながら、ゲンチアナの抽出物を有効成分として含有することを特徴とするＩＬ−３７産生促進剤、ＰＩ３Ｋ―ＡＫＴ−ｍＴＯＲ経路阻害剤及びオートファジー調節剤については知られていない。 Gentiana is a plant that is widely distributed in Europe, etc., and the dried roots are treated as crude drugs after being naturally fermented. Appetite promotion, indigestion, stomach pain, heartburn, gastritis, diarrhea, nausea, etc. In addition to being taken internally for the treatment of gentian, it is also used for the treatment of trauma. So far, a hair dye composition and a sensitization inhibitor (Patent Document 2), a skin external preparation (Patent Document 3), and a cosmetic composition, which are characterized by containing an extract of Gentiana as an active ingredient. (Patent Document 4) and liquid oral compositions (Patent Document 5) and the like are known. However, unknown are known about IL-37 production promoters, PI3K-AKT-mTOR pathway inhibitors and autophagy regulators, which are characterized by containing an extract of gentiana as an active ingredient.
そこで、本発明が解決する課題は、ＩＬ−３７産生を高める成分を見出し、これを有効成分とする、作用点が明確であり、且つ優れたＩＬ−３７産生促進剤、ＰＩ３Ｋ―ＡＫＴ−ｍＴＯＲ経路阻害剤及びオートファジー調節剤を提供することである。 Therefore, the problem to be solved by the present invention is to find a component that enhances IL-37 production, and to use this as an active ingredient, an excellent IL-37 production promoter having a clear point of action, PI3K-AKT-mTOR pathway. To provide an inhibitor and an autophagy regulator.
本発明者らは、上記課題の解決に向け鋭意検討を行った結果、ゲンチアナ抽出物及びＬ−アスコルビン酸誘導体に優れたＩＬ−３７産生促進作用を有することを見出し、本発明を完成するに至った。 As a result of diligent studies aimed at solving the above problems, the present inventors have found that the gentiana extract and the L-ascorbic acid derivative have an excellent IL-37 production promoting action, and have completed the present invention. It was.
即ち、本発明は、ゲンチアナの抽出物及び／又はＬ−アスコルビン酸誘導体を有効成分として含有することを特徴とするＩＬ−３７産生促進剤、ＰＩ３Ｋ―ＡＫＴ−ｍＴＯＲ経路阻害剤及びオートファジー調節剤に関する。 That is, the present invention relates to an IL-37 production promoter, a PI3K-AKT-mTOR pathway inhibitor, and an autophagy regulator, which are characterized by containing an extract of gentiana and / or an L-ascorbic acid derivative as an active ingredient. ..
本発明において、ゲンチアナの抽出物とＬ−アスコルビン酸誘導体を併用することで、ＩＬ−３７産生促進作用をより一層向上させることができる。 In the present invention, the combined use of the gentiana extract and the L-ascorbic acid derivative can further improve the IL-37 production promoting action.
本発明のゲンチアナ抽出物及びＬ−アスコルビン酸誘導体は、ＩＬ−３７産生促進作用に優れていた。このゲンチアナ抽出物及び／又はＬ−アスコルビン酸誘導体を含有することを特徴とするＰＩ３Ｋ―ＡＫＴ−ｍＴＯＲ経路阻害剤及びオートファジー調節剤は、アルツハイマー病、パーキンソン病、前頭側頭型痴呆、レビー小体型痴呆、ＰＤ痴呆、多系統委縮症、ハンチントン病、筋萎縮性側索硬化症及びクローン病等の神経変性疾患に対して予防及び処置等の効果を発揮することができる。又、本発明のＩＬ−３７産生促進剤、ＰＩ３Ｋ―ＡＫＴ−ｍＴＯＲ経路阻害剤及びオートファジー調節剤は、作用が緩和な植物の抽出物又はビタミン類を有効成分とすることから、副作用がなく安全性が高い。従って、化粧品、医薬部外品、医薬品及び食品に安心して使用できる。 The gentiana extract and the L-ascorbic acid derivative of the present invention were excellent in the IL-37 production promoting action. PI3K-AKT-mTOR pathway inhibitors and autophagy regulators characterized by containing this Gentian extract and / or L-ascorbic acid derivative include Alzheimer's disease, Parkinson's disease, frontotemporal dementia, and Levy body type. It can exert effects such as prevention and treatment for neurodegenerative diseases such as dementia, PD dementia, multisystem atrophy, Huntington's disease, amyotrophic lateral sclerosis and Crohn's disease. Further, the IL-37 production promoter, PI3K-AKT-mTOR pathway inhibitor and autophagy regulator of the present invention are safe without side effects because they contain plant extracts or vitamins having a mild action as active ingredients. High in sex. Therefore, it can be safely used in cosmetics, quasi-drugs, pharmaceuticals and foods.
更に、ゲンチアナ抽出物とＬ−アスコルビン酸誘導体を併用することで、ＩＬ−３７産生促進作用をより一層向上させることが可能であり、神経変性疾患に対してより高い予防及び処置等の効果を発揮することができる。 Furthermore, by using the gentiana extract and the L-ascorbic acid derivative in combination, it is possible to further improve the IL-37 production promoting action, and exert higher effects such as prevention and treatment for neurodegenerative diseases. can do.
本発明のＩＬ−３７とは、 ＩＬ−１ファミリーに属するサイトカインである。ＩＬ―３７ａ〜ＩＬ―３７ｅの５つのアイソフォームがあり、末梢単核球細胞、単球、形質細胞、樹状細胞、上皮細胞、胸腺、子宮及び睾丸等多くの器官で検出されている。ｉｎｔｅｒｌｅｕｋｉｎ−３７、ｉｎｔｅｒｌｅｕｋｉｎ３７、ＩＬ３７、ＩＬ１Ｆ７、ＩＬ−１Ｆ７、ＩＬ−１Ｈ、ＩＬ−１Ｈ４、ＦＩＬ１、ＦＩＬ１（ＺＥＴＡ）、ＦＩＬ１Ｚ、ＩＬ−１ＲＰ１及びＩＬ１ＲＰ１とも呼ばれる。 IL-37 of the present invention is a cytokine belonging to the IL-1 family. There are five isoforms, IL-37a to IL-37e, which have been detected in many organs such as peripheral mononuclear cells, monocytes, plasma cells, dendritic cells, epithelial cells, thymus, uterus and testicles. Also called interleukin-37, interleukin37, IL37, IL1F7, IL-1F7, IL-1H, IL-1H4, FIL1, FIL1 (ZETA), FIL1Z, IL-1RP1 and IL1RP1.
本発明におけるＰＩ３Ｋとは、ホスファチジルイノシトール３―キナーゼとも呼ばれ、イノシトールリン脂質のイノシトール環３位のヒドロキシル基のリン酸化を行う酵素である。 PI3K in the present invention is also called phosphatidylinositol 3-kinase, and is an enzyme that phosphorylates the hydroxyl group at the 3-position of the inositol ring of inositol phospholipid.
本発明におけるＡＫＴとは、プロテインキナーゼＢとも呼ばれ、グルコースの代謝やアポトーシス、細胞増殖、転写、細胞遊走といった複数の細胞プロセスにおいて重要な役割を果たすセリン／スレオニンキナーゼである。ＡＫＴは、イノシトールリン脂質が、ＰＩ３Ｋをはじめとしたキナーゼの触媒作用を受けた際に活性化され、このシグナル伝達経路がＰＩ３Ｋ−ＡＫＴ経路と呼ばれる。 AKT in the present invention, also called protein kinase B, is a serine / threonine kinase that plays an important role in a plurality of cellular processes such as glucose metabolism, apoptosis, cell proliferation, transcription, and cell migration. AKT is activated when inositol phospholipids are catalyzed by kinases such as PI3K, and this signal transduction pathway is called the PI3K-AKT pathway.
本発明におけるｍＴＯＲは、哺乳動物のラパマイシン標的とも呼ばれる細胞内シグナル伝達に関与するプロテインキナーゼである。ＰＩ３Ｋ−ＡＫＴ経路の下流エフェクターであり、細胞の成長、増殖、及び生存を調節する。 MTOR in the present invention is a protein kinase involved in intracellular signal transduction, which is also called a mammalian rapamycin target. It is a downstream effector of the PI3K-AKT pathway that regulates cell growth, proliferation, and survival.
本発明におけるオートファジーとは、細胞内のタンパク質を分解する仕組みであり、自食とも呼ばれる。マクロオートファジー、マイクロオートファジー及びシャペロン介在性オートファジーの３種類が確認されている。オートファジーの制御異常は、細胞内に異常タンパク質を蓄積させ、神経変性疾患の原因となる。つまり、オートファジーを調節することにより、神経変性疾患の治療が可能である。 Autophagy in the present invention is a mechanism for decomposing intracellular proteins, and is also called autophagy. Three types of autophagy have been identified: macro autophagy, micro autophagy and chaperone-mediated autophagy. Abnormal autophagy control causes the accumulation of abnormal proteins in cells and causes neurodegenerative diseases. That is, by adjusting autophagy, it is possible to treat neurodegenerative diseases.
本発明で用いるゲンチアナはリンドウ科リンドウ属の植物であり、学名：Ｇｅｎｔｉａｎａ Ｌｕｔｅａである。 Gentiana used in the present invention is a plant belonging to the gentian Gentianaceae of the Gentianaceae family, and has a scientific name: Gentiana Lutea.
本発明で用いるゲンチアナ抽出物とは、植物体の葉、茎、花、果実、種子、根等の植物体の一部又は全草から抽出したものである。好ましくは、ゲンチアナの根から抽出して得られるものが良い。これらはゲンチアナの名称で生薬として市販されているので、これを使用すれば良い。 The gentiana extract used in the present invention is extracted from a part or whole plant of a plant such as leaves, stems, flowers, fruits, seeds and roots of the plant. Preferably, it is obtained by extracting from the root of Gentiana. These are commercially available as crude drugs under the name of gentiana, so they can be used.
抽出する溶媒としては、例えば、水、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）、液状多価アルコール類（１，３−ブチレングリコール、プロピレングリコール、グリセリン等）、ケトン類（アセトン、メチルエチルケトン等）、アセトニトリル、エステル類（酢酸エチル、酢酸ブチル等）、炭化水素類（ヘキサン、ヘプタン、流動パラフィン等）、エーテル類（エチルエーテル、テトラヒドロフラン、プロピルエーテル等）が挙げられる。好ましくは、水、低級アルコール及び液状多価アルコール等の極性溶媒が良く、特に好ましくは、水、エタノール、１，３−ブチレングリコール及びプロピレングリコールが良い。これらの溶媒は、１種でも２種以上を混合して用いても良い。 Examples of the solvent to be extracted include water, lower alcohols (methanol, ethanol, 1-propanol, 2-propanol, 1-butanol, 2-butanol, etc.) and liquid polyhydric alcohols (1,3-butylene glycol, propylene). Glycol, glycerin, etc.), ketones (acetone, methyl ethyl ketone, etc.), acetonitrile, esters (ethyl acetate, butyl acetate, etc.), hydrocarbons (hexane, heptane, liquid paraffin, etc.), ethers (ethyl ether, tetrahydrofuran, propyl, etc.) Ether, etc.). Polar solvents such as water, lower alcohols and liquid polyhydric alcohols are preferred, and water, ethanol, 1,3-butylene glycol and propylene glycol are particularly preferred. These solvents may be used alone or in admixture of two or more.
上記抽出物は抽出した溶液のまま用いても良く、必要に応じて濃縮、希釈、濾過処理、活性炭等による脱色、脱臭処理等をして用いても良い。更には、抽出した溶液を濃縮乾固、噴霧乾燥、凍結乾燥等の処理を行い、乾燥物として用いても良い。本発明で用いるゲンチアナは天然由来の植物であり、ゲンチアナから抽出される成分は多様な構造の化合物が多数同時に存在する混合物である。従って、含有する成分の構造又は特性を全て明らかにすることは困難であり、抽出物として扱うことが好ましい。 The above extract may be used as it is in the extracted solution, or may be used after concentration, dilution, filtration treatment, decolorization with activated carbon or the like, deodorization treatment, etc., if necessary. Further, the extracted solution may be subjected to treatments such as concentrated drying, spray drying, freeze drying and the like, and used as a dried product. Gentiana used in the present invention is a naturally occurring plant, and the component extracted from gentiana is a mixture in which a large number of compounds having various structures are present at the same time. Therefore, it is difficult to clarify all the structures or properties of the contained components, and it is preferable to treat them as an extract.
本発明に用いられるゲンチアナ抽出物の含有量は、内用の場合、投与量は年齢、体重、症状、治療効果、投与方法、処理時間等により異なるが、通常、成人１人当たりの１日の量として５ｍｇ以上が好ましく、１０〜５００ｍｇがより好ましい。更に、２０〜２００ｍｇが最も好ましい。一方、外用の場合、固形物に換算して０．０００１重量％以上が好ましく、０．００１〜１０重量％がより好ましい。更に、０．０１〜５重量％が最も好ましい。投与量は種々の条件で変動するので、上記投与範囲より少ない量で十分な場合もあるし、又、範囲を超えて投与する必要のある場合もある。 The content of the Gentiana extract used in the present invention varies depending on the age, body weight, symptom, therapeutic effect, administration method, treatment time, etc. for internal use, but is usually the daily amount per adult. 5 mg or more is preferable, and 10 to 500 mg is more preferable. Further, 20 to 200 mg is most preferable. On the other hand, in the case of external use, 0.0001% by weight or more is preferable, and 0.001 to 10% by weight is more preferable in terms of solid matter. Further, 0.01 to 5% by weight is most preferable. Since the dose varies depending on various conditions, an amount smaller than the above-mentioned administration range may be sufficient, or it may be necessary to administer beyond the above range.
本発明におけるＬ−アスコルビン酸誘導体は、一般にビタミンＣ誘導体と言われるものであり、Ｌ−アスコルビン酸も含む。Ｌ−アスコルビン酸誘導体としては、Ｌ−アスコルビン酸リン酸エステル、Ｌ−アスコルビン酸アルキルエステル、Ｌ−アスコルビン酸硫酸エステル、Ｌ−アスコルビン酸配糖体等が挙げられ、具体的には、Ｌ−アスコルビン酸−２−リン酸エステル、Ｌ−アスコルビン酸−３−リン酸エステル、ＤＬ−α−トコフェロール−２−Ｌ−アスコルビン酸リン酸ジエステル等のＬ−アスコルビン酸リン酸エステル、パルミチン酸Ｌ−アスコルビル、イソステアリン酸Ｌ−アスコルビル、ジオレイン酸Ｌ−アスコルビル等のＬ−アスコルビン酸アルキルエステル、Ｌ−アスコルビン酸−２−硫酸エステル、Ｌ−アスコルビン酸−３−硫酸エステル等のＬ−アスコルビン酸硫酸エステル、２−Ｏ−α−Ｄ−グルコピラノシル−Ｌ−アスコルビン酸等のＬ−アスコルビン酸配糖体等が挙げられる。 The L-ascorbic acid derivative in the present invention is generally referred to as a vitamin C derivative, and also includes L-ascorbic acid. Examples of the L-ascorbic acid derivative include L-ascorbic acid phosphate ester, L-ascorbic acid alkyl ester, L-ascorbic acid sulfate ester, L-ascorbic acid glycoside, and the like, and specific examples thereof include L-ascorbic acid. L-ascorbic acid phosphates such as acid-2-phosphate ester, L-ascorbic acid-3-phosphate ester, DL-α-tocopherol-2-L-ascorbic acid phosphate diester, palmitate L-ascorbic acid, L-ascorbic acid alkyl ester such as L-ascorbic isostearate, L-ascorbic acid dioleate, L-ascorbic acid sulfate ester such as L-ascorbic acid-2-sulfate ester, L-ascorbic acid-3-sulfate ester, 2- Examples thereof include L-ascorbic acid glycosides such as O-α-D-glucopyranosyl-L-ascorbic acid.
又、本発明においてはこれらの塩も使用可能でありナトリウム塩、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が用いられる。 Further, in the present invention, these salts can also be used, and alkali metal salts such as sodium salt and potassium salt, and alkaline earth metal salts such as calcium salt and magnesium salt are used.
本発明においては、Ｌ−アスコルビン酸誘導体として好ましくは化１で表されるアスコルビン酸リン酸マグネシウムを使用する。
本発明に用いられるＬ−アスコルビン酸誘導体の含有量は、内用の場合、投与量は年齢、体重、症状、治療効果、投与方法、処理時間等により異なるが、通常、成人１人当たりの１日の量として１０ｍｇ以上が好ましく、２０〜１００ｍｇがより好ましい。一方、外用の場合、固形物に換算して０．０００２重量％以上が好ましく、０．００１〜１０重量％がより好ましい。投与量は種々の条件で変動するので、上記投与範囲より少ない量で十分な場合もあるし、又、範囲を超えて投与する必要のある場合もある。 The content of the L-ascorbic acid derivative used in the present invention varies depending on age, body weight, symptom, therapeutic effect, administration method, treatment time, etc. in the case of internal use, but is usually 1 day per adult. The amount of the above is preferably 10 mg or more, more preferably 20 to 100 mg. On the other hand, in the case of external use, 0.0002% by weight or more is preferable, and 0.001 to 10% by weight is more preferable in terms of solid matter. Since the dose varies depending on various conditions, an amount smaller than the above-mentioned administration range may be sufficient, or it may be necessary to administer beyond the above range.
本発明のゲンチアナ抽出物及び／又はＬ−アスコルビン酸誘導体を含有することを特徴とするＩＬ−３７産生促進剤、ＰＩ３Ｋ―ＡＫＴ−ｍＴＯＲ経路阻害剤及びオートファジー調節剤は、食品、医薬部外品、医薬品、化粧品のいずれにも用いることができ、その剤形としては、例えば、錠剤、丸剤、顆粒剤、カプセル剤、乳濁剤、溶液剤、懸濁剤、シロップ剤、エリキシル剤、軟膏、パップ剤等が挙げられる。上記成分をそのまま使用しても良く、本発明の効果を損なわない範囲で、賦形剤、増量剤、結合剤、湿潤剤、崩壊剤、界面活性剤、滑沢剤、分散剤、緩衝剤、香料、保存料、溶解補助剤、溶剤等を用いることができる。具体的には、乳糖、ショ糖、ソルビット、マンニット、澱粉、沈降性炭酸カルシウム、重質酸化マグネシウム、タルク、ステアリン酸カルシウム、ステアリン酸マグネシウム、セルロース又はその誘導体、アミロペクチン、ポリビニルアルコール、ゼラチン、界面活性剤、水、生理食塩水、エタノール、グリセリン、プロピレングリコール、カカオ脂、ラウリン脂、ワセリン、パラフィン、高級アルコール等である。 The IL-37 production promoter, PI3K-AKT-mTOR pathway inhibitor and autophagy regulator containing the Gentian extract and / or L-ascorbic acid derivative of the present invention are foods, non-pharmaceutical products. , Pharmaceuticals, and cosmetics. The dosage forms include, for example, tablets, pills, granules, capsules, emulsions, solutions, suspending agents, syrups, elixirs, and ointments. , Capsules and the like. The above components may be used as they are, and as long as the effects of the present invention are not impaired, excipients, bulking agents, binders, wetting agents, disintegrants, surfactants, lubricants, dispersants, buffers, etc. Fragrances, preservatives, solubilizers, solvents and the like can be used. Specifically, lactose, sucrose, sorbitol, mannitol, starch, precipitated calcium carbonate, heavy magnesium oxide, talc, calcium stearate, magnesium stearate, cellulose or a derivative thereof, amylopectin, polyvinyl alcohol, gelatin, surface activity. Agents, water, physiological saline, ethanol, glycerin, propylene glycol, cacao butter, lauric acid, vaseline, paraffin, higher alcohol and the like.
次に、本発明を詳細に説明するため、具体的な実施例を挙げて説明する。これらの実施例は効果を具体的に説明するもので、発明の範囲を限定するものではない。 Next, in order to explain the present invention in detail, specific examples will be given and described. These examples specifically explain the effect and do not limit the scope of the invention.
製造例１ ゲンチアナのエタノール抽出物
ゲンチアナの根の乾燥物５００ｇにエタノール５Ｌを加え、５時間還流抽出した。抽出終了後、濾過し、その濾液を濃縮乾固して、ゲンチアナのエタノール抽出物を８．５ｇ得た。
Production Example 1 Gentiana Ethanol Extract 5 L of ethanol was added to 500 g of dried gentiana root, and the mixture was reflux-extracted for 5 hours. After completion of the extraction, the mixture was filtered, and the filtrate was concentrated to dryness to obtain 8.5 g of an ethanol extract of Gentiana.
製造例２ ゲンチアナの熱水抽出物
製造例１で使用したものと同じゲンチアナの根の乾燥物２０ｇに蒸留水１Ｌを加え、１００℃にて１時間抽出した。得られた抽出液を濾過した後、その濾液を濃縮し、凍結乾燥して、ゲンチアナの熱水抽出物を０．９ｇ得た。
Production Example 2 Hot water extract of Gentiana 1 L of distilled water was added to 20 g of the same dried gentiana root as used in Production Example 1, and the mixture was extracted at 100 ° C. for 1 hour. After filtering the obtained extract, the filtrate was concentrated and lyophilized to obtain 0.9 g of a hot water extract of Gentiana.
製造例３ ゲンチアナの１，３−ブチレングリコール抽出物
製造例１で使用したものと同じゲンチアナの根の乾燥物２０ｇに１，３−ブチレングリコール２００ｍＬを加え、常温で７日間抽出した後、濾過し、ゲンチアナの１，３−ブチレングリコール抽出物を１５７ｇ得た。
Production Example 3 Gentiana 1,3-butylene glycol extract Add 200 mL of 1,3-butylene glycol to 20 g of the same dried gentiana root used in Production Example 1, extract at room temperature for 7 days, and then filter. , Gentiana 1,3-butylene glycol extract was obtained in an amount of 157 g.
本発明のゲンチアナ抽出物及び／又はＬ−アスコルビン酸誘導体は、処方例として下記の製剤化を行うことができる。 The gentiana extract and / or L-ascorbic acid derivative of the present invention can be formulated as follows as a formulation example.
処方例１ 飲料
処方 含有量（ｇ）
１．ゲンチアナの１，３−ブチレングリコール抽出物 ０．１
２．アスコルビン酸リン酸マグネシウム ０．１
３．クエン酸 ０．７
４．果糖ブドウ糖液糖 ６０．０
５．香料 ０．１
６．精製水 ３９．０
全量 １００．０
［製造方法］成分６に成分１〜５を加え、攪拌溶解して濾過し、加熱殺菌後、５０ｍＬガラス瓶に充填する。当該飲料を１日１本摂取することで、ゲンチアナ抽出物を５０ｍｇ／日摂取できる。又アスコルビン酸リン酸マグネシウムを５０ｍｇ／日摂取できる。
Prescription example 1 Beverage prescription content (g)
1. 1. Gentiana 1,3-butylene glycol extract 0.1
2. Magnesium Ascorbic Acid Phosphate 0.1
3. 3. Citric acid 0.7
4. Fructose-glucose liquid sugar 60.0
5. Fragrance 0.1
6. Purified water 39.0
Total amount 100.0
[Manufacturing method] Ingredients 1 to 5 are added to ingredient 6, dissolved by stirring, filtered, heat sterilized, and then filled in a 50 mL glass bottle. By ingesting the beverage once a day, 50 mg / day of the gentiana extract can be ingested. In addition, magnesium ascorbic acid phosphate can be ingested at 50 mg / day.
処方例２ 錠剤
処方 含有量（ｇ）
１．ゲンチアナの熱水抽出物 ５．０
２．アスコルビン酸リン酸マグネシウム ５．０
３．トウモロコシデンプン １０．０
４．精製白糖 ２０．０
５．カルボキシメチルセルロースカルシウム １０．０
６．微結晶セルロース ３５．０
７．ポリビニルピロリドン ５．０
８．タルク １０．０
全量 １００．０
［製造方法］成分１〜６を混合し、次いで成分７の水溶液を結合剤として加え、常法により顆粒化する。これに滑沢剤として成分８を加えた後、１錠１００ｍｇの錠剤に打錠する。当該錠剤を１日１２錠摂取することで、ゲンチアナ抽出物を６０ｍｇ／日摂取できる。又アスコルビン酸リン酸マグネシウムを６０ｍｇ／日摂取できる。
Prescription example 2 Tablet prescription Content (g)
1. 1. Gentiana hot water extract 5.0
2. Magnesium Ascorbic Acid Phosphate 5.0
3. 3. Corn starch 10.0
4. Purified sucrose 20.0
5. Carboxymethyl Cellulose Calcium 10.0
6. Microcrystalline Cellulose 35.0
7. Polyvinylpyrrolidone 5.0
8. Talc 10.0
Total amount 100.0
[Manufacturing method] Ingredients 1 to 6 are mixed, and then an aqueous solution of ingredient 7 is added as a binder, and granulated by a conventional method. Ingredient 8 is added as a lubricant to this, and then one tablet is tableted into a 100 mg tablet. By ingesting 12 tablets a day, 60 mg / day of gentiana extract can be ingested. In addition, magnesium ascorbic acid phosphate can be ingested at 60 mg / day.
処方例３ 錠菓
処方 含有量（ｇ）
１．ゲンチアナのエタノール抽出物 １．０
２．アスコルビン酸リン酸マグネシウム １．０
３．乾燥コーンスターチ ４９．０
４．エリスリトール ４０．０
５．クエン酸 ５．０
６．ショ糖脂肪酸エステル ３．０
７．香料 １．０
全量 １００．０
［製造方法］成分１〜５に精製水を適量加えて練和し、押出し造粒した後、乾燥して顆粒を得る。顆粒に成分６及び７を加えて打錠し、１個１ｇの錠菓を得る。当該錠菓を１日６個摂取することで、ゲンチアナ抽出物を６０ｍｇ／日摂取できる。又アスコルビン酸リン酸マグネシウムを６０ｍｇ／日摂取できる。
Prescription example 3 Tablet confectionery prescription content (g)
1. 1. Gentiana ethanol extract 1.0
2. Magnesium Ascorbic Acid Phosphate 1.0
3. 3. Dried cornstarch 49.0
4. Erythritol 40.0
5. Citric acid 5.0
6. Sucrose fatty acid ester 3.0
7. Fragrance 1.0
Total amount 100.0
[Manufacturing method] Purified water is added to components 1 to 5 in an appropriate amount, kneaded, extruded and granulated, and then dried to obtain granules. Ingredients 6 and 7 are added to the granules and tableted to obtain 1 g of each confectionery. By ingesting 6 tablets a day, 60 mg / day of gentiana extract can be ingested. In addition, magnesium ascorbic acid phosphate can be ingested at 60 mg / day.
処方例４ カプセル剤
処方 含有量（ｇ）
１．ゲンチアナのエタノール抽出物 ５．０
２．微結晶セルロース ６０．０
３．トウモロコシデンプン １５．０
４．乳糖 １８．０
５．ポリビニルピロリドン ２．０
全量 １００．０
［製造方法］成分１〜５を混合して顆粒化した後、２号硬カプセルに２５０ｍｇ充填してカプセル剤を得る。当該カプセル剤を１日６個摂取することで、ゲンチアナ抽出物を７５ｍｇ／日摂取できる。
Prescription example 4 Capsule prescription content (g)
1. 1. Gentiana Ethanol Extract 5.0
2. Microcrystalline Cellulose 60.0
3. 3. Corn starch 15.0
4. Lactose 18.0
5. Polyvinylpyrrolidone 2.0
Total amount 100.0
[Manufacturing method] Ingredients 1 to 5 are mixed and granulated, and then 250 mg is filled in a No. 2 hard capsule to obtain a capsule. By ingesting 6 capsules a day, 75 mg / day of gentiana extract can be ingested.
処方例５ トローチ
処方 含有量（ｇ）
１．ゲンチアナの熱水抽出物 １．０
２．マルチトール ５０．０
３．キシリトール ４５．０
４．ショ糖脂肪酸エステル ３．０
５．香料 １．０
全量 １００．０
［製造方法］成分１〜３を混合し、流動層造粒装置で造粒する。得られた顆粒に成分４及び５を加えて打錠し、１個１ｇのトローチを得る。当該トローチを１日６個摂取することで、ゲンチアナ抽出物を６０ｍｇ／日摂取できる。
Prescription example 5 Lozenge prescription content (g)
1. 1. Gentiana hot water extract 1.0
2. Maltitol 50.0
3. 3. Xylitol 45.0
4. Sucrose fatty acid ester 3.0
5. Fragrance 1.0
Total amount 100.0
[Manufacturing method] Ingredients 1 to 3 are mixed and granulated by a fluidized bed granulator. Ingredients 4 and 5 are added to the obtained granules and tableted to obtain 1 g of each troche. By ingesting 6 of the troches a day, 60 mg / day of gentiana extract can be ingested.
処方例６ 軟膏
処方 含有量（ｇ）
１．ゲンチアナの１，３−ブチレングリコール抽出物 １．０
２．ポリオキシエチレンセチルエーテル（３０Ｅ．Ｏ．） ２．０
３．モノステアリン酸グリセリン １０．０
４．流動パラフィン ５．０
５．セタノール ６．０
６．パラオキシ安息香酸メチル ０．１
７．プロピレングリコール １０．０
８．精製水 ６５．９
全量 １００．０
［製造方法］成分２〜５を加熱溶解して混合し、７０℃に保ち油相とする。成分１及び６〜８を加熱溶解して混合し、７５℃に保ち水相とする。油相に水相を加えて乳化して、かき混ぜながら３０℃まで冷却して製品とする。
Prescription example 6 Ointment prescription content (g)
1. 1. Gentiana 1,3-butylene glycol extract 1.0
2. Polyoxyethylene cetyl ether (30EO) 2.0
3. 3. Glycerin monostearate 10.0
4. Liquid paraffin 5.0
5. Cetanol 6.0
6. Methyl paraoxybenzoate 0.1
7. Propylene glycol 10.0
8. Purified water 65.9
Total amount 100.0
[Manufacturing method] Ingredients 2 to 5 are heated and dissolved, mixed, and kept at 70 ° C. to prepare an oil phase. Ingredients 1 and 6 to 8 are heated, dissolved and mixed, and kept at 75 ° C. to prepare an aqueous phase. An aqueous phase is added to the oil phase to emulsify, and the product is cooled to 30 ° C. with stirring.
処方例７ 散剤
処方 含有量（ｇ）
１．アスコルビン酸リン酸マグネシウム ５．０
２．微結晶セルロース ４０．０
３．トウモロコシデンプン ５５．０
全量 １００．０
［製造方法］成分１〜３を混合し、常法により散剤を得る。当該散剤を１日１ｇ摂取することで、アスコルビン酸リン酸マグネシウムを５０ｍｇ／日摂取できる。
Prescription example 7 Powder prescription content (g)
1. 1. Magnesium Ascorbic Acid Phosphate 5.0
2. Microcrystalline Cellulose 40.0
3. 3. Corn starch 55.0
Total amount 100.0
[Manufacturing method] Ingredients 1 to 3 are mixed to obtain a powder by a conventional method. By ingesting 1 g of the powder daily, 50 mg / day of magnesium ascorbic acid can be ingested.
次に、本発明の効果を詳細に説明するため、実験例を挙げる。 Next, in order to explain the effect of the present invention in detail, an experimental example will be given.
実験例１ ヒト表皮角化細胞におけるＩＬ−３７産生に及ぼすゲンチアナ抽出物及びアスコルビン酸リン酸マグネシウムの影響
コンフルエントになったヒト表皮角化細胞（ＨａＣａＴ）にゲンチアナ抽出物（製造例１のエタノール抽出物）及び／又はアスコルビン酸リン酸マグネシウム（昭和電工）を加え、血清を含まないＤＭＥＭ培地にて２４時間培養した後、ＲＮＡｉｓｏ ｐｌｕｓ（ＴＡＫＡＲＡ）を用いて総ＲＮＡの抽出を行った。尚、ゲンチアナ抽出物の終濃度は１２．５又は１２５μｇ／ｍＬにて行った。アスコルビン酸リン酸マグネシウムの終濃度は１ｍＭにて行った。内部標準としてＧＡＰＤＨを用いた。総ＲＮＡを基に、ＳＹＢＲ Ｓｅｌｅｃｔ Ｍａｓｔｅｒ Ｍｉｘ（ライフテクノロジーズ）を用いたリアルタイムＲＴ−ＰＣＲ法により、ＩＬ−３７ｍＲＮＡ発現量を内部標準であるＧＡＰＤＨｍＲＮＡ発現量に対する割合として求めた。尚、各遺伝子の発現量の測定に使用したプライマーは次の通りである。
Experimental Example 1 Effect of Gentiana extract and magnesium ascorbic acid phosphate on IL-37 production in human epidermal keratinized cells Gentian extract (ethanol extract of Production Example 1) was applied to confluent human epidermal keratinized cells (HaCaT). ) And / or magnesium ascorbic acid phosphate (Showa Denko) was added, and the cells were cultured in DMEM medium containing no serum for 24 hours, and then total RNA was extracted using RNAiso plus (TAKARA). The final concentration of the gentiana extract was 12.5 or 125 μg / mL. The final concentration of magnesium ascorbic acid phosphate was 1 mM. GAPDH was used as the internal standard. Based on the total RNA, the IL-37 mRNA expression level was determined as a ratio to the internal standard GAPDH mRNA expression level by a real-time RT-PCR method using SYBR Select Master Mix (Life Technologies). The primers used to measure the expression level of each gene are as follows.
ＩＬ−３７用のプライマーセット
ＴＣＴＴＴＧＣＡＴＴＡＧＣＣＴＣＡＴＣＣ（配列番号１）
ＡＴＣＡＧＴＴＴＣＴＣＣＴＴＣＴＴＣＡＧＣ（配列番号２）
ＧＡＰＤＨ用のプライマーセット
ＴＧＣＡＣＣＡＣＣＡＡＣＴＧＣＴＴＡＧＣ（配列番号３）
ＴＣＴＴＣＴＧＧＧＴＧＧＣＡＧＴＧＡＴＧ（配列番号４）
Primer set for IL-37 TCTTTGCATTAGCCCTCATCC (SEQ ID NO: 1)
ATCAGTTTCTCCTTCTTCAGC (SEQ ID NO: 2)
Primer set for GAPDH TGCACCACCAACTGCTTAGC (SEQ ID NO: 3)
TCTTCTGGGTGTGCAGTGATG (SEQ ID NO: 4)
その結果を表１に示す。表１の通り、ゲンチアナ抽出物及びアスコルビン酸リン酸マグネシウムはヒト表皮角化細胞におけるＩＬ−３７ｍＲＮＡ発現量を増加させた。又、ゲンチアナ抽出物とアスコルビン酸リン酸マグネシウムを併用することにより一層高いＩＬ−３７産生促進作用を示した。尚、製造例２のゲンチアナの熱水抽出物及び製造例３のゲンチアナの１，３−ブチレングリコール抽出物においても同様の効果が認められた。 The results are shown in Table 1. As shown in Table 1, the gentiana extract and magnesium ascorbic acid phosphate increased the expression level of IL-37 mRNA in human epidermal keratinized cells. In addition, the combined use of the gentiana extract and magnesium ascorbic acid phosphate showed a higher IL-37 production promoting effect. The same effect was observed in the hot water extract of gentiana of Production Example 2 and the 1,3-butylene glycol extract of gentiana of Production Example 3.
ゲンチアナ抽出物又はＬ−アスコルビン酸誘導体を用いることにより、ＩＬ−３７の産生が促進され、ＰＩ３Ｋ―ＡＫＴ−ｍＴＯＲ経路を阻害し、オートファジーを誘導することで、アルツハイマー病、パーキンソン病、前頭側頭型痴呆、レビー小体型痴呆、ＰＤ痴呆、多系統委縮症、ハンチントン病、筋萎縮性側索硬化症及びクローン病等の神経変性疾患を予防若しくは軽減する化粧品、医薬部外品、医薬品及び食品を提供することができる。又、ゲンチアナ抽出物とＬ−アスコルビン酸誘導体を併用することにより、これらの効果をより一層高めることができる。 The use of Gentiana extract or L-ascorbic acid derivative promotes IL-37 production, inhibits the PI3K-AKT-mTOR pathway, and induces autophagy, resulting in Alzheimer's disease, Parkinson's disease, and frontotemporal. Cosmetics, non-pharmaceutical products, pharmaceuticals and foods that prevent or reduce neurodegenerative diseases such as type dementia, Levy body type dementia, PD dementia, multisystem atrophy, Huntington's disease, amyotrophic lateral sclerosis and Crohn's disease Can be provided. Further, by using the gentiana extract and the L-ascorbic acid derivative in combination, these effects can be further enhanced.
Claims (4)
The IL-37 production promoter, PI3K-AKT-mTOR pathway inhibitor and autophagy regulator according to any one of claims 1 to 3, wherein the L-ascorbic acid derivative is magnesium ascorbic acid phosphate.
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