JP2018070510A - Reduced vitamin b2 formulation for endothelial cell protection recovery caused by mitochondrial activation - Google Patents
Reduced vitamin b2 formulation for endothelial cell protection recovery caused by mitochondrial activation Download PDFInfo
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- JP2018070510A JP2018070510A JP2016212385A JP2016212385A JP2018070510A JP 2018070510 A JP2018070510 A JP 2018070510A JP 2016212385 A JP2016212385 A JP 2016212385A JP 2016212385 A JP2016212385 A JP 2016212385A JP 2018070510 A JP2018070510 A JP 2018070510A
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Abstract
Description
本発明は、還元型ビタミンＢ２（ロイコフラビン）を含む製剤、例えば、医薬、機能性製剤に関する発明である。 The present invention relates to preparations containing reduced vitamin B2 (leucoflavin), such as pharmaceuticals and functional preparations.
還元型ビタミンＢ２の薬品として、発明者は過去に、特許文献１のビタミンＢ２還元体を含む医薬を開発、公開している。例えば、ロイコフラビン、モノハイドロフラビン、ロイコフラビンリン酸エステル、ロイコフラビンモノヌクレオチド、ロイコフラビンアデニンジヌクレオチド、又はそれらの薬理学的に許容される塩を有効成分とする免疫賦活・感染防御治療剤（請求項１）、その他、敗血症予防治療剤、敗血症性ショック予防治療剤、マラリア予防治療剤としての用途を見出した。 In the past, the inventor has developed and disclosed a medicine containing the reduced form of vitamin B2 of Patent Document 1 as a drug for reduced vitamin B2. For example, an immunostimulatory / infective preventive agent comprising leucoflavin, monohydroflavin, leucoflavin phosphate ester, leucoflavin mononucleotide, leucoflavin adenine dinucleotide, or a pharmacologically acceptable salt thereof as an active ingredient ( In addition, the present invention has found use as a sepsis preventive / therapeutic agent, a septic shock preventive / therapeutic agent, and a malaria preventive / therapeutic agent.
しかしながら、還元型ビタミンＢ２は、酸化されビタミンＢ２に戻り、安定して還元型ビタミンＢ２の状態を保持することはできなかった。 However, reduced vitamin B2 was oxidized and returned to vitamin B2, and the state of reduced vitamin B2 could not be stably maintained.
また、還元型ビタミンＢ２の製造では、特許文献１に「本発明におけるリボフラビン還元体及び／又はリボフラビン誘導体の還元体、またはそれらの薬理学的に許容される塩は、通常使用されるハイドロサルファイト又は塩化スズ等の還元剤を添加することにより、容易に製造することができる。」とあるように、人体に使用できない還元剤を用いるため、人体への治療、投与に際して、その還元剤を除去する必要があり、コスト、副作用の点から実用化に至っていない。 In addition, in the production of reduced vitamin B2, Patent Document 1 states that “the reduced form of riboflavin and / or reduced form of riboflavin derivative in the present invention, or a pharmacologically acceptable salt thereof is a hydrosulfite that is usually used. Or, it can be easily manufactured by adding a reducing agent such as tin chloride. ”As described above, since a reducing agent that cannot be used in the human body is used, the reducing agent is removed during treatment and administration to the human body. However, it has not been put into practical use in terms of cost and side effects.
そこで、本発明は、還元型ビタミンＢ２を簡易、低コストで製造し、長期間安定保管、流通でき、さらに安全に投与できる、還元型ビタミンＢ２を含む製剤を提供することを目的とする。さらに、知られていない還元型ビタミンＢ２の新たな用途を提供する。 Therefore, an object of the present invention is to provide a preparation containing reduced vitamin B2, which can be produced easily and at low cost, can be stably stored and distributed for a long time, and can be administered safely. Furthermore, it provides a new use of the unknown reduced vitamin B2.
本発明は、上記課題を解決するために、
（１）
ビタミンＢ２と水素を反応させることを特徴とする還元型ビタミンＢ２の製造方法。
（２）
水素水と、前記水素水に溶解した還元型ビタミンＢ２を含むことを特徴とする還元型ビタミンＢ２製剤。
（３）
水素水と、前記水素水に溶解した還元型ビタミンＢ２を含むことを特徴とするミトコンドリア活性化剤。
（４）
水素水と、前記水素水に溶解した還元型ビタミンＢ２を含むことを特徴とする活性酸素除去剤。
（５）
水素水と、前記水素水に溶解した還元型ビタミンＢ２を含むことを特徴とする酸化ストレス除去剤。
（６）
水素水と、前記水素水に溶解した還元型ビタミンＢ２を含むことを特徴とする過剰サイトカイン抑制剤。
（７）
水素水と、前記水素水に溶解した還元型ビタミンＢ２を含むことを特徴とする疲労回復剤。
（８）
水素水と、前記水素水に溶解した還元型ビタミンＢ２を含むことを特徴とする血球数回復剤。
（９）
水素水と、前記水素水に溶解した還元型ビタミンＢ２を含むことを特徴とする肝・腎障害回復剤。
（１０）
水素水と、前記水素水に溶解した還元型ビタミンＢ２を含むことを特徴とする血管内皮細胞保護回復剤。
の構成とした。
In order to solve the above problems, the present invention
(1)
A method for producing reduced vitamin B2, which comprises reacting vitamin B2 with hydrogen.
(2)
A reduced vitamin B2 preparation comprising hydrogen water and reduced vitamin B2 dissolved in the hydrogen water.
(3)
A mitochondrial activator comprising hydrogen water and reduced vitamin B2 dissolved in the hydrogen water.
(4)
A reactive oxygen scavenger comprising hydrogen water and reduced vitamin B2 dissolved in the hydrogen water.
(5)
An oxidative stress remover comprising hydrogen water and reduced vitamin B2 dissolved in the hydrogen water.
(6)
An excessive cytokine inhibitor comprising hydrogen water and reduced vitamin B2 dissolved in the hydrogen water.
(7)
A fatigue recovery agent comprising hydrogen water and reduced vitamin B2 dissolved in the hydrogen water.
(8)
A blood cell number recovery agent comprising hydrogen water and reduced vitamin B2 dissolved in the hydrogen water.
(9)
A hepatic / renal disorder recovery agent comprising hydrogen water and reduced vitamin B2 dissolved in the hydrogen water.
(10)
An agent for protecting and restoring vascular endothelial cells, comprising hydrogen water and reduced vitamin B2 dissolved in the hydrogen water.
The configuration was as follows.
ここで、本発明は、還元型ビタミンＢ２（ロイコフラビン）、即ち、リボフラビン還元型及び／又はリボフラビン誘導体の還元型、またはそれらの薬理学的に許容される塩を有効成分とする。本発明におけるリボフラビン還元型及び／又はリボフラビン誘導体の還元型、又はそれらの薬理学的に許容される塩とは、ビタミンＢ２群を還元したものを意味し、特に限定されない。 Here, the present invention uses reduced vitamin B2 (leucoflavin), that is, a reduced form of riboflavin and / or a riboflavin derivative, or a pharmaceutically acceptable salt thereof as an active ingredient. In the present invention, the reduced form of riboflavin and / or reduced form of riboflavin derivative, or a pharmacologically acceptable salt thereof means a substance obtained by reducing vitamin B2 group, and is not particularly limited.
一般的にリボフラビン、ビタミンＢ２酪酸エステル、フラビンモノヌクレオチド（ビタミンＢ２リン酸エステ；ＦＭＮ）およびフラビンアデニンジヌクレオチド（ＦＡＤ）などを還元して製造する。 In general, it is produced by reducing riboflavin, vitamin B2 butyrate, flavin mononucleotide (vitamin B2 phosphate ester; FMN), flavin adenine dinucleotide (FAD) and the like.
還元型としては、ロイコフラビン、モノハイドロフラビン、ロイコフラビンリン酸エステル、ロイコフラビン酪酸エステル、ロイコフラビンアデニンジヌクレオチッド、ロイコフラビンモノヌクレオチッド、又は薬理学的に許容される塩を有効成分とする。本発明にはこれらのリボフラビン還元型の薬理学的に許容される塩、水和物等も含まれる。 The reduced form includes leucoflavin, monohydroflavin, leucoflavin phosphate, leucoflavin butyrate, leucoflavin adenine dinucleotide, leucoflavin mononucleotide, or a pharmacologically acceptable salt as an active ingredient. And The present invention also includes these riboflavin reduced pharmacologically acceptable salts, hydrates, and the like.
一般的に、リボフラビン、ビタミンＢ２酪酸エステル、フラビンモノヌクレオチド（ビタミンＢ２リン酸エステ；ＦＭＮ）およびフラビンアデニンジヌクレオチド（ＦＡＤ）などを還元して製造する。 Generally, it is produced by reducing riboflavin, vitamin B2 butyrate, flavin mononucleotide (vitamin B2 phosphate ester; FMN), flavin adenine dinucleotide (FAD), and the like.
水素水とは、通常の水素水、過酸化水素水など水素を含むものすべてを指す。還元型ビタミンＢ２を製造する際のビタミンＢ２が溶解した溶液の反応温度は、好ましくは、２５℃以上がよく、水素が抜けにくい暖かい温度が相応しい。また、反応時間は、数分〜数時間が好ましいが、条件により反応速度も変わるので、反応時間も変化させる。また、ビタミンＢ２と水素の反応としては、ビタミンＢ２を溶かした溶液に水素を吹き込んでも良い。ビタミンＢ２群の形態は、水溶液、顆粒、カプセルなど固形物であっても、いずれかのステップで水素と反応できる形状であれば問わない。水素水は、今日、人用の飲料水として使用され、安全性が確認されており、極めて安全に投与でき還元型ビタミンＢ２の提供を可能にする。
Hydrogen water refers to everything including hydrogen, such as normal hydrogen water and hydrogen peroxide water. The reaction temperature of the solution in which vitamin B2 is dissolved in the production of reduced vitamin B2 is preferably 25 ° C. or higher, and a warm temperature at which hydrogen does not easily escape is suitable. The reaction time is preferably from several minutes to several hours, but the reaction time varies depending on the conditions, so the reaction time is also changed. As a reaction between vitamin B2 and hydrogen, hydrogen may be blown into a solution in which vitamin B2 is dissolved. The form of vitamin B2 group is not limited as long as it is a solid substance such as an aqueous solution, a granule, and a capsule as long as it can react with hydrogen in any step. Hydrogen water is used today as a drinking water for humans and has been confirmed to be safe, and can be administered very safely, enabling the provision of reduced vitamin B2.
（１）製法発明
本発明は、ビタミンＢ２群を、水素と接触、反応させ、還元させ、水素水中に保持するだけであるので、極めて容易に、かつ安全性が高く、活性の高い還元型ビタミンＢ２が、極めて低コストで提供できる。また、水素水は、一般に流通するほど普及しており、高濃度製造が可能で、さらに水素水濃度を維持するためアルミ缶、アルミパウチなどの包装容器の十分に発達しており、還元型ビタミンＢ２を低コストで製造し、長期間安定保管、流通を十分に担保することができるようになった。このように、画期的な製法で製造された還元型ビタミンＢ２は、医薬品、注射液、点滴液、うがい液、吸入剤、洗浄液（鼻、口、傷口などの皮膚）、点眼剤、入浴剤、塗布剤、クリーム剤、化粧水、育毛剤、ゼリー剤、飲料水まで幅広く使用できる。
(1) Invention of the invention Since the present invention merely involves contacting, reacting, reducing, and holding vitamin B2 group in hydrogen water, the reduced vitamins are extremely easy, safe and highly active. B2 can be provided at an extremely low cost. In addition, hydrogen water is becoming more popular as it circulates and can be produced at a high concentration. Further, in order to maintain the hydrogen water concentration, packaging containers such as aluminum cans and aluminum pouches are sufficiently developed. B2 can be manufactured at a low cost, and stable storage and distribution for a long time can be sufficiently secured. Thus, reduced vitamin B2 produced by a revolutionary manufacturing method is used for pharmaceuticals, injections, infusions, gargles, inhalants, cleaning solutions (skins such as nose, mouth, wounds, etc.), eye drops, and bath preparations. It can be used in a wide range of applications such as coating agents, creams, lotions, hair restorers, jellies, and drinking water.
（２）製剤発明
還元型ビタミンＢ２は、酸素に触れて容易に酸化され、元のビタミンＢ２に急激に戻ってしまい、活性も低下し、還元型として使用することはできなかったが、本発明では、還元型ビタミンＢ２を水素水で保持するという画期的な方法を見出し、還元型ビタミンＢ２を安定に保ち、長期間保存可能な製剤を可能にした。
(2) Formulation invention Reduced vitamin B2 is easily oxidized upon contact with oxygen, and suddenly returns to the original vitamin B2, the activity is reduced, and cannot be used as a reduced form. Then, an epoch-making method of holding reduced vitamin B2 with hydrogen water was discovered, and a preparation capable of maintaining the reduced vitamin B2 stably and storing it for a long period of time was made possible.
（３）用途発明
１）還元型ビタミンＢ２は、ビタミンＢ２よりも活性酸素除去能力が約１０倍強いこと見出しており、抗酸化作用が強く、生体内においても活性酸素除去作用を強力に発揮することができる。水素水も活性酸素を除去することが知られているが、これらを合わせることで、極めて強力な画期的な活性酸素除去剤、酸化ストレス除去剤を提供することができる。
２）様々な要因により生体内で発生する炎症性物質であるサイトカインに対しても、還元型ビタミンＢ２は、過剰なサイトカインを抑制し、ビタミンＢ２よりも約１０倍抑制することを見出し、炎症や高サイトカイン血症を強力に抑制できる極めて有用な作用を有する。ビタミンＢ２は、効能が知られている各種疾病の治療に際して、多量に投与する必要があり、腎臓機能の低下などの副作用が懸念されている。他方、還元型ビタミンＢ２では、投与量を低くすることができ、ビタミンＢ２で問題になっていた副作用はなく、極めて進歩性が高い。
３）生体内においてエネルギー産生作用においてミトコンドリアの膜電位を測定する実験から、還元型ビタミンＢ２は、エネルギー産生作用が極めて強力であることを見出した。また過剰な乳酸を抑制することからも、細胞の疲労を抑制し、エネルギー産生を高めるという生物の根本的な営みに関与することが示された。このことは、スポーツをはじめ、疾患の治療、老化などに対して幅広く有用性が期待される。さらに、還元型ビタミンＢ２がミトコンドリアに対して、直接作用することを見出した。その結果、ミトコンドリアを、正常体質に維持する方向に活性化する。すなわち、還元型ビタミンＢ２は、ミトコンドリアの活性化剤であり、その効果、あらゆる方面の疾病の予防、改善、治療に効能がある。
４）還元型ビタミンＢ２は、血球数（赤血球、血小板、白血球など）の減少に対して、血球数を回復する作用を有する。このことは、血球数の減少を伴う疾病、また抗がん剤投与時や放射線療法の副作用防止などに対して、幅広く有用性が期待できる。
５）還元型ビタミンＢ２は、肝障害、腎障害に対して、治療的に回復作用を示し、これら疾患に対しても有用性が期待される。
６）還元型ビタミンＢ２は、血管内皮細胞の高グルコース負荷試験において、血管内皮細胞の生存率の上昇が認められた。このことは、還元型ビタミンＢ２が、高グルコース負荷によるダメージ（一つには活性酸素種が関与）から、血管内皮細胞を保護し、生存率を上昇させたことを示している。したがって、糖尿病、血糖スパイクに対しても、血管内皮細胞を糖から守り、血管を正常化させることから、動脈硬化、脳梗塞、心筋梗塞、また認知症などの脳疾患に対しても有用性が期待される。
(3) Application invention 1) Reduced vitamin B2 has been found to be about 10 times stronger in the ability to remove active oxygen than vitamin B2, has a strong antioxidant effect, and exerts an active oxygen removal effect in vivo. be able to. Hydrogen water is also known to remove active oxygen, but by combining these, it is possible to provide an extremely powerful and innovative active oxygen remover and oxidative stress remover.
2) It has been found that reduced vitamin B2 suppresses excess cytokine and suppresses about 10 times as much as vitamin B2 against cytokine which is an inflammatory substance generated in vivo due to various factors. It has an extremely useful action that can strongly suppress hypercytokinemia. Vitamin B2 needs to be administered in a large amount in the treatment of various diseases whose efficacy is known, and there are concerns about side effects such as a decrease in kidney function. On the other hand, with reduced vitamin B2, the dose can be lowered, and there is no side effect that has been a problem with vitamin B2, and the inventive step is extremely high.
3) From an experiment for measuring the membrane potential of mitochondria in an energy production action in vivo, it was found that reduced vitamin B2 has an extremely strong energy production action. Moreover, it was shown that it is concerned in the fundamental activity of the living body which suppresses fatigue of a cell and raises energy production also from suppressing excess lactic acid. This is expected to be useful for sports, illness treatment, and aging. Furthermore, it has been found that reduced vitamin B2 acts directly on mitochondria. As a result, the mitochondria are activated in the direction of maintaining a normal constitution. That is, reduced vitamin B2 is a mitochondrial activator and is effective for its effect and prevention, improvement, and treatment of diseases in all directions.
4) Reduced vitamin B2 has an action of recovering the blood cell count against a decrease in the blood cell count (red blood cells, platelets, white blood cells, etc.). This can be expected to be widely useful for diseases associated with a decrease in blood cell count, anti-cancer agent administration, and prevention of side effects of radiation therapy.
5) Reduced vitamin B2 has a therapeutic recovery effect on liver and kidney disorders and is expected to be useful for these diseases.
6) Reduced vitamin B2 showed an increase in the survival rate of vascular endothelial cells in a high glucose tolerance test of vascular endothelial cells. This indicates that reduced vitamin B2 protected vascular endothelial cells from the damage caused by high glucose load (in part, involving active oxygen species) and increased the survival rate. Therefore, even for diabetes mellitus and blood sugar spike, it protects vascular endothelial cells from sugar and normalizes blood vessels, so it is useful for brain diseases such as arteriosclerosis, cerebral infarction, myocardial infarction, and dementia. Be expected.
上記１）、２）、３）、４）の作用から、これらの病態、疾病に対して、予防剤、治療剤を提供することができる。適応疾病としては、老化・加齢に伴う疾患、炎症性疾患、糖尿病、免疫抑制疾患、癌疾患、パーキンソン病、動脈硬化、脳梗塞などリウマチ、五十肩、変形性関節症、肩こり、腰痛、神経痛、むちうちまた、スポーツなどにおける筋力・体力の向上などに対して、極めて有用な解決方法を提供できる。 From the effects of 1), 2), 3), and 4), a preventive agent and a therapeutic agent can be provided for these pathological conditions and diseases. Applicable diseases include aging / aging-related diseases, inflammatory diseases, diabetes, immunosuppressive diseases, cancer diseases, Parkinson's disease, arteriosclerosis, cerebral infarction, rheumatism, fifty shoulders, osteoarthritis, stiff shoulders, low back pain, neuralgia, In addition, it can provide an extremely useful solution for improving muscle strength and physical strength in sports.
本発明は、以上まとめると以下の病態、症状、疾患に適用でき、それ以外の症例にも適用できる
・呼吸器疾患（ＣＯＰＤ，気管支喘息、肺気腫、肺繊維症、ＡＲＤＳ）
・ウィルス感染（単純ヘルペス、帯状疱疹、ＨＩＶ、インフルエンザ、ＥＢウィルス、サイトメガロウィルス）
・細菌感染症（急性、慢性）
・真菌、カンジダ感染症
・片頭痛、群発頭痛、血管性頭痛、側頭動脈炎
・脳血管疾患、アルツハイマー病、パーキンソン病、筋萎縮性側索硬化症、脳梗塞
・循環器疾患（狭心症、不整脈、末梢動脈疾患）、動脈硬化、心筋梗塞
・糖尿病、腎炎
・多発性硬化症、慢性関節リウマチ、エリテマトーデス
・転移性がん、悪性リンパ腫、神経芽腫
・慢性疲労症候群
・消化器系：ＩＢＤ、膵炎、肝炎、肝硬変、肝障害
・敗血症、外傷、熱症、歯槽膿漏、老化、肥満、アレルギー性疾患
・ビタミンＢ２不足、口内炎、肌あれ、にきび、口角炎、口唇炎、かぶれ、ただれ、湿疹、皮膚炎、舌炎、赤鼻、目の充血、目のかゆみ
・次の場合のビタミンＢ２の補給；肉体疲労時、妊娠、授乳期、病中病後の体力低下時
・血球数（赤血球、血小板、白血球など）の減少疾患
ただし、Ｇ６ＰＤ欠損症、甲状腺機能亢進症、妊婦への処方は忌避される。
The present invention can be applied to the following pathological conditions, symptoms and diseases, and can also be applied to other cases. Respiratory diseases (COPD, bronchial asthma, emphysema, pulmonary fibrosis, ARDS)
・ Virus infection (herpes simplex, herpes zoster, HIV, influenza, EB virus, cytomegalovirus)
・ Bacterial infection (acute, chronic)
・ Fungus, Candida infection / migraine, cluster headache, vascular headache, temporal arteritis / cerebrovascular disease, Alzheimer's disease, Parkinson's disease, amyotrophic lateral sclerosis, cerebral infarction / circulatory disease (angina , Arrhythmia, peripheral arterial disease), arteriosclerosis, myocardial infarction / diabetes, nephritis / multiple sclerosis, rheumatoid arthritis, lupus erythematosus / metastatic cancer, malignant lymphoma, neuroblastoma / chronic fatigue syndrome / digestive system: IBD , Pancreatitis, hepatitis, cirrhosis, liver disorders / sepsis, trauma, fever, alveolar pus leakage, aging, obesity, allergic diseases / vitamin B2 deficiency, stomatitis, skin, acne, keratitis, cheilitis, rash, sore, Eczema, dermatitis, glossitis, red nose, redness of eyes, itching of eyes, supplementation of vitamin B2 in the following cases; physical fatigue, pregnancy, lactation period, physical strength decline after disease, blood count (red blood cells, platelets) , White blood cells, etc.) Disease, however, G6PD deficiency, hyperthyroidism, formulation into pregnant women is avoidance.
投与形態
経口剤（ドリンク、粉末、顆粒、錠剤）、注射液、点滴液、うがい液、吸入剤、洗浄液、点眼剤、入浴剤、塗布剤、クリーム剤、化粧水、育毛剤、ゼリー剤、飲料水など幅広い形態で投与、摂取可能である。
Dosage form Oral (drink, powder, granule, tablet), injection solution, drip solution, gargle solution, inhalant, cleaning solution, eye drops, bathing agent, coating agent, cream agent, lotion, hair restorer, jelly agent, beverage It can be administered and ingested in a wide variety of forms such as water.
以上のことから明らかなように、還元型ビタミンＢ２、及びその製剤は、製法、製剤、用途、いずれにおいても、従来にない優れた効果を奏し、医業、産業への貢献は極めて大きい。還元型ビタミンＢ２は、ビタミンＢ２より、低用量で、かつ活性、有効性が極めて高く、ビタミンＢ２の市場は、将来、還元型ビタミンＢ２に取って代わられるであろう。 As is clear from the above, reduced vitamin B2 and its preparations have excellent effects that have never been achieved in any of the production methods, preparations, and uses, and contribute greatly to the medical industry and industry. Reduced vitamin B2 is much less active and effective than vitamin B2, and the vitamin B2 market will be replaced in the future by reduced vitamin B2.
以下、添付の図面を参照し、本発明の実施の形態について詳細に説明する。なお、本発明は下記実施例に限定されるものではない。 Embodiments of the present invention will be described below in detail with reference to the accompanying drawings. In addition, this invention is not limited to the following Example.
図１に示す試験結果は、大腸菌に過酸化水素水（Ｈ２Ｏ２）１０ｍＭ／ｍｌを添加して、菌数の減少を測定することにより、菌の酸化ストレスに対する影響を検討した結果である。 The test results shown in FIG. 1 are the results of examining the effect on bacterial oxidative stress by adding a hydrogen peroxide solution (H 2 O 2 ) of 10 mM / ml to E. coli and measuring the decrease in the number of bacteria. .
還元型ビタミンＢ２（図中Ｂ２Ｈ２）は、Ｈ２Ｏ２の添加３時間前に２．５，１０μｇ／ｍｌを添加しておき、菌数測定は、Ｈ２Ｏ２添加１時間後に行った。対照薬として抗酸化剤であるビタミンＣ（Ｃ）を１００μｇ／ｍｌ添加して比較した。なお、図中Ｃｏｎｔ．（左）はＨ２Ｏ２無添加、Ｃｏｎｔ．（右）はＨ２Ｏ２添加＋抗酸化剤無添加である。 Reduced vitamin B2 (B2H2 in the figure) was added 2.5 or 10 μg / ml 3 hours before the addition of H 2 O 2 , and the number of bacteria was measured 1 hour after the addition of H 2 O 2 . As a control drug, vitamin C (C), which is an antioxidant, was added at 100 μg / ml for comparison. In the figure, Cont. (Left) No H 2 O 2 added, Cont. (Right) is H 2 O 2 added + no antioxidant added.
その結果、還元型ビタミンＢ２は、低容量でビタミンＣより生菌数の上昇が認められ、極めて強い酸化ストレス防止作用を示した。菌の致死を救ったことは、活性酸素を強力に除去したことが示唆される。 As a result, reduced vitamin B2 showed an extremely strong oxidative stress-preventing action, with an increased number of viable bacteria compared to vitamin C at a low volume. The fact that the lethality of the fungus has been saved suggests that the active oxygen has been removed strongly.
このことは、還元型ビタミンＢ２、さらには本発明の還元型ビタミンＢ２製剤が、活性酸素の関与するすべての疾患・疾病の治療に利用できることを示している。 This indicates that the reduced vitamin B2 and further the reduced vitamin B2 preparation of the present invention can be used for the treatment of all diseases and diseases involving active oxygen.
図２に示す試験結果は、マウスにラジカル発生剤ＡＡＰＨ（２，２’−ａｚｏ−ｂｉｓ（２−ａｍｉｄｉｎｏｐｒｐｐａｎｅ ｄｉｈｙｄｒｏｃｈｌｏｒｉｄｅ）１２５ｍｇ／ｋｇを腹腔内に投与し、その投与２４時間前及び同時に還元型ビタミンＢ２（Ｂ２Ｈ２）２ｍｇ／ｋｇを静脈内投与して、酸化ストレスに対する死亡率を測定した結果である。ｃｏｎｔｒｏｌは、ＡＡＰＨを投与しただけで、還元型ビタミンＢ２の投与がない。 The test results shown in FIG. 2 show that the radical generator AAPH (2,2′-azo-bis (2-amidinoprpane dihydrochloride) 125 mg / kg was intraperitoneally administered to mice, and reduced vitamin B2 24 hours before and simultaneously with the administration. (B2H2) 2 mg / kg was intravenously administered and the mortality rate against oxidative stress was measured.Control was only administered AAPH, but no reduced vitamin B2 was administered.
その結果、還元型ビタミンＢ２は、酸化ストレスに対して、顕著な防止作用（抗酸化）を示し、生体内においても活性酸素除去作用を強力に発揮することが認められた。 As a result, it was confirmed that reduced vitamin B2 exhibited a remarkable preventive action (antioxidation) against oxidative stress and exerted a strong effect of removing active oxygen even in vivo.
このことは、還元型ビタミンＢ２、さらには本発明の還元型ビタミンＢ２製剤が、活性酸素が関与するすべての疾患・疾病の治療に利用できることを示している。 This indicates that the reduced vitamin B2 and the reduced vitamin B2 preparation of the present invention can be used for the treatment of all diseases / illnesses involving active oxygen.
図３に示す試験結果は、マウスの腹腔マクロファージ（１×１０６／ｍｌ）に、毒素ＬＰＳ（リポポリサッカライド）を０．０１μｇ／ｍｌ添加すると、１２時間後に培養液中に過剰なＩＬ６（インターロイキン６）が放出されるため、これを利用して検討した結果である。 The test results shown in FIG. 3 show that when 0.01 μg / ml of the toxin LPS (lipopolysaccharide) was added to peritoneal macrophages (1 × 10 6 / ml) of mice, excess IL6 (inter Since leukin 6) is released, this is the result of examination using this.
これに対して、ＬＰＳと同時に還元型ビタミンＢ２（Ｂ２Ｈ２）２．５μｇ／ｍｌ添加すると、ビタミンＢ２（Ｂ２）の１／１０量で優れた抑制効果が認められた。 On the other hand, when 2.5 μg / ml reduced vitamin B2 (B2H2) was added simultaneously with LPS, an excellent inhibitory effect was observed with 1/10 amount of vitamin B2 (B2).
このことは、還元型ビタミンＢ２、さらには本発明の還元型ビタミンＢ２製剤が極めて低容量で、炎症や高サイトカイン血漿などに対して、有用な作用を示している。 This indicates that the reduced vitamin B2 and further the reduced vitamin B2 preparation of the present invention has a very low volume and has a useful effect on inflammation, high cytokine plasma and the like.
図４に示す試験結果は、マウスに還元型ビタミンＢ２（Ｂ２Ｈ２）２ｍｇ／ｋｇを静脈内に投与し、１日後にマウス腹腔マクロファージを取り出して、ミトコンドリアの膜電位をフローサイトメーターで測定した結果である。ｃｏｎｔｒｏｌは、還元型ビタミンＢ２の投与がない。 The test results shown in FIG. 4 are the results of intravenous administration of reduced vitamin B2 (B2H2) 2 mg / kg to mice, taking out mouse peritoneal macrophages one day later, and measuring the membrane potential of mitochondria with a flow cytometer. is there. Control does not receive reduced vitamin B2.
その結果、還元型ビタミンＢ２は、ｃｏｎｔｒｏｌに比べミトコンドリアの膜電位を顕著に（約１．７倍）上昇させることが見出され、細胞のエネルギー産生を高める作用が認められた。 As a result, reduced vitamin B2 was found to significantly increase (about 1.7 times) the membrane potential of mitochondria compared to control, and an effect of enhancing cellular energy production was observed.
このことは、還元型ビタミンＢ２、さらには本発明の還元型ビタミンＢ２製剤が疲労回復に有効であることを示している。 This indicates that the reduced vitamin B2 and further the reduced vitamin B2 preparation of the present invention is effective for fatigue recovery.
図５は、還元型ビタミンＢ２の過剰な乳酸の抑制効果の確認試験結果である。マウスの腹腔マクロファージに、毒素ＬＰＳ（リポポリサッカライド）を０．０１μｇ／ｍｌ添加すると、１２時間後に培養液中に過剰な乳酸が放出された。これに対して、還元型ビタミンＢ２（Ｂ２Ｈ２）２．５μｇ／ｍをＬＰＳと同時に加えたところ、急激な乳酸の減少が認められた。ｃｏｎｔｒｏｌは、毒素ＬＰＳの添加及び還元型ビタミンＢ２の投与がない。 FIG. 5 shows the results of a test for confirming the inhibitory effect of reduced vitamin B2 on excessive lactic acid. When 0.01 μg / ml of the toxin LPS (lipopolysaccharide) was added to the peritoneal macrophages of mice, excess lactic acid was released into the culture medium after 12 hours. In contrast, when 2.5 μg / m of reduced vitamin B2 (B2H2) was added simultaneously with LPS, a rapid decrease in lactic acid was observed. Control does not have the addition of toxin LPS and administration of reduced vitamin B2.
このことは、還元型ビタミンＢ２は、異常な代謝における乳酸の産生を抑制し、細胞の疲労度を回復させることが示唆された。かつ、ミトコンドリアの膜電位を上げることからも、細胞の疲労を抑制し、エネルギー産生を高めるという生物の根本的な営みに関与することが示唆された。すなわち、還元型ビタミンＢ２及び本願発明の製剤は、ミトコンドリアへの作用を介して、あらゆる方面の疾病、疾患の予防、治療、改善に関与できる。 This suggests that reduced vitamin B2 suppresses the production of lactic acid in abnormal metabolism and restores the fatigue level of the cells. In addition, increasing the membrane potential of mitochondria suggests that it is involved in the fundamental activities of organisms that suppress cell fatigue and increase energy production. That is, the reduced vitamin B2 and the preparation of the present invention can be involved in prevention, treatment and improvement of diseases and diseases in all directions through the action on mitochondria.
また、還元型ビタミンＢ２、さらには本発明の還元型ビタミンＢ２製剤がスポーツをはじめ、疾患の治療、老化などに対して幅広く有用性であることを示している。 Further, it has been shown that reduced vitamin B2 and further reduced vitamin B2 preparation of the present invention are widely useful for sports, disease treatment, aging and the like.
図６に示す試験結果は、マウス（５匹）にシクロフォスファミド（ＣＹ）１２５ｍｇ／ｋｇを腹腔内に投与し、その１，２，３日後の３回、還元型ビタミンＢ２（Ｂ２Ｈ２）２ｍｇ／ｋｇを静脈内に投与して、４，５，６日後に血球数（好中球数）を測定した結果である。 The test results shown in FIG. 6 are as follows. Cyclophosphamide (CY) 125 mg / kg was intraperitoneally administered to mice (5 mice), 3 times after 1, 2 and 3 days, reduced vitamin B2 (B2H2) 2 mg This is a result of measuring blood cell count (neutrophil count) after 4, 5 and 6 days after intravenous administration of / kg.
その結果、ＣＹによる骨髄抑制に対して、還元型ビタミンＢ２は、血球数（好中球数）の回復を５日目、及び６日目に回復が認められた。 As a result, in contrast to bone marrow suppression by CY, reduced vitamin B2 showed recovery of blood cell count (neutrophil count) on the 5th and 6th days.
このことは、還元型ビタミンＢ２、さらには本発明の還元型ビタミンＢ２製剤が骨髄抑制による赤血球、血小板、白血球などの血球数の回復に有効であることを示している。 This indicates that the reduced vitamin B2 and further the reduced vitamin B2 preparation of the present invention is effective in restoring the number of blood cells such as red blood cells, platelets and white blood cells by bone marrow suppression.
図７は、還元型ビタミンＢ２の肝／腎障害に対する回復効果の確認試験結果である。マウス（５〜８匹）に毒素ＬＰＳ（リポポリサッカライド）１２ｍｇ／ｋｇを静脈内に投与し、肝／腎障害を作成した。これに対して、還元型ビタミンＢ２（Ｂ２Ｈ２）２ｍｇ／ｋｇを静脈内に６時間後の治療的に投与したところ、ＬＰＳ投与２４時間後の血漿中の生化学検査指標（ＡＬＰ、ＧＯＴ、ＧＰＴ、ＣＰＫＵＮ，ＣＲＮＮなど）の顕著な改善が認められた。 FIG. 7 is a confirmation test result of the recovery effect of reduced vitamin B2 on liver / kidney injury. Mice (5 to 8) were intravenously administered 12 mg / kg of toxin LPS (lipopolysaccharide) to create liver / kidney injury. In contrast, when reduced vitamin B2 (B2H2) 2 mg / kg was administered intravenously 6 hours later, plasma biochemical indicators (ALP, GOT, GPT, 24 hours after LPS administration) CPKUN, CRNN, etc.) were markedly improved.
このことは、還元型ビタミンＢ２は肝障害、腎障害の治療的回復が認められた。すなわち、還元型ビタミンＢ２、さらには本発明の還元型ビタミンＢ２製剤が障害、腎障害の治療に有効であることを示している。 This indicates that reduced vitamin B2 was therapeutically recovered from liver damage and kidney damage. That is, it shows that the reduced vitamin B2 and further the reduced vitamin B2 preparation of the present invention are effective for treating disorders and renal disorders.
図８の試験結果は、血管内皮細胞の高グルコース負荷試験において、細胞生存率を測定することによって、還元型ビタミンＢ２の耐糖能試験を実施した結果である。 The test results of FIG. 8 are the results of the glucose tolerance test of reduced vitamin B2 by measuring cell viability in a high glucose tolerance test of vascular endothelial cells.
その結果、高グルコース負荷に対して、血管内皮細胞は、生存率を急激に減少させたが、同時に還元型ビタミンＢ２（Ｂ２Ｈ２）を１０μｇ／ｍｌ添加することによって、血管内皮細胞の生存率を顕著に上昇させた。 As a result, the vascular endothelial cells rapidly decreased the survival rate against a high glucose load, but at the same time, 10 μg / ml of reduced vitamin B2 (B2H2) was added to significantly increase the survival rate of the vascular endothelial cells. Was raised.
このことは、還元型ビタミンＢ２が、高グルコース負荷によるダメージから、血管内皮細胞を保護し、生存率を上昇させたことを示している。すなわち還元型ビタミンＢ２、さらには本発明の還元型ビタミンＢ２製剤が血管内皮細胞保護回復剤として有効であること示している。 This indicates that reduced vitamin B2 protected vascular endothelial cells from damage caused by high glucose load and increased survival rate. That is, it shows that reduced vitamin B2 and further the reduced vitamin B2 preparation of the present invention are effective as a vascular endothelial cell protective recovery agent.
本発明は、上記課題を解決するために、
（１）
水素水と、前記水素水に溶解した還元型ビタミンＢ２を含むことを特徴とするミトコンドリア活性化用還元型ビタミンＢ２製剤。
（２）
活性酸素除去作用を有することを特徴とする（１）に記載のミトコンドリア活性化用還元型ビタミンＢ２製剤。
（３）
酸化ストレス除去作用を有することを特徴とする（１）に記載のミトコンドリア活性化用還元型ビタミンＢ２製剤。
（４）
過剰サイトカイン抑制作用を有することを特徴とする（１）に記載のミトコンドリア活性化用還元型ビタミンＢ２製剤。
（５）
疲労回復作用を有することを特徴とする（１）に記載のミトコンドリア活性化用還元型ビタミンＢ２製剤。
（６）
血球数回復作用を有することを特徴とする（１）に記載のミトコンドリア活性化用還元型ビタミンＢ２製剤。
（７）
肝・腎障害回復作用を有することを特徴とする（１）に記載のミトコンドリア活性化用還元型ビタミンＢ２製剤。
（８）
血管内皮細胞保護回復作用を有することを特徴とする（１）に記載のミトコンドリア活性化用還元型ビタミンＢ２製剤。
（９）
癌疾患の予防又は治療作用を有することを特徴とする（１）に記載のミトコンドリア活性化用還元型ビタミンＢ２製剤。
（１０）
認知症の予防又は治療作用を有することを特徴とする（１）に記載のミトコンドリア活性化用還元型ビタミンＢ２製剤。
In order to solve the above problems, the present invention
(1)
A reduced vitamin B2 preparation for mitochondrial activation , comprising hydrogen water and reduced vitamin B2 dissolved in the hydrogen water.
(2)
The reduced vitamin B2 preparation for mitochondrial activation according to (1), which has an action of removing active oxygen.
(3)
The reduced vitamin B2 preparation for mitochondrial activation according to (1), which has an action of removing oxidative stress.
(4)
The reduced vitamin B2 preparation for mitochondrial activation according to (1), which has an excessive cytokine inhibitory action.
(5)
The reduced vitamin B2 preparation for mitochondrial activation according to (1), which has a fatigue recovery action.
(6)
The reduced vitamin B2 preparation for mitochondrial activation according to (1), which has a blood cell count recovery action.
(7)
The reduced vitamin B2 preparation for mitochondrial activation according to (1), which has a liver / kidney injury recovery action.
(8)
The reduced vitamin B2 preparation for mitochondrial activation according to (1), which has an effect of restoring and protecting vascular endothelial cells.
(9)
The reduced vitamin B2 preparation for mitochondrial activation according to (1), which has a preventive or therapeutic action for cancer diseases.
(10)
The reduced vitamin B2 preparation for mitochondrial activation according to (1), which has a preventive or therapeutic effect on dementia.
上記１）、２）、３）、４）の作用から、これらの病態、疾病に対して、予防剤、治療剤を提供することができる。適応疾病としては、老化・加齢に伴う疾患、炎症性疾患、糖尿病、免疫抑制疾患、癌疾患、パーキンソン病、動脈硬化、脳梗塞、リウマチ、五十肩、変形性関節症、肩こり、腰痛、神経痛、むちうちまた、スポーツなどにおける筋力・体力の向上などに対して、極めて有用な解決方法を提供できる。 From the effects of 1), 2), 3), and 4), a preventive agent and a therapeutic agent can be provided for these pathological conditions and diseases. Applicable diseases include aging and aging diseases, inflammatory diseases, diabetes, immunosuppressive diseases, cancer diseases, Parkinson's disease, arteriosclerosis, cerebral infarction , rheumatism, fifty shoulders, osteoarthritis, stiff shoulders, back pain, neuralgia, In addition, it can provide an extremely useful solution for improving muscle strength and physical strength in sports.
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Citations (12)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| JPH1029941A (en) * | 1996-04-01 | 1998-02-03 | Eisai Co Ltd | Vitamin b2-containing medicine |
| JPH11199486A (en) * | 1998-01-13 | 1999-07-27 | Eisai Co Ltd | Vitamin b2-containing medicine composition |
| WO2002074313A1 (en) * | 2001-03-21 | 2002-09-26 | Eisai Co., Ltd. | Drugs containing reduced vitamin b¿2? |
| JP2004518712A (en) * | 2001-02-14 | 2004-06-24 | ラート・マティアス | Compositions of biochemical compounds involved in the bioenergetic metabolism of cells and uses thereof |
| JP2004345988A (en) * | 2003-05-21 | 2004-12-09 | Eisai Co Ltd | Medicine composition containing riboflavin-based compound |
| WO2008062814A1 (en) * | 2006-11-24 | 2008-05-29 | Spring Co., Ltd. | Hydrogen-dissolved aqueous solution and method for prolonging the life duration of hydrogen dissolved in the aqueous solution |
| WO2008156171A1 (en) * | 2007-06-20 | 2008-12-24 | Eureka-Lab Inc. | Method of regulating liquid properties of reducing hydrogen solution and reducing hydrogen solution composition |
| JP2010189432A (en) * | 1997-10-24 | 2010-09-02 | John P Blass | Supplement for metabolic dysfunction of brain |
| JP2011144186A (en) * | 2002-11-19 | 2011-07-28 | Nutropia Ernaehrungsmedizinische Forschungs Gmbh | Composition comprising nadh/nadph |
| WO2011108730A1 (en) * | 2010-03-04 | 2011-09-09 | 国立大学法人大阪大学 | Mononuclear metal complex, hydrogenation reduction catalyst, dehydrogenation catalyst, method for producing hydrogenation reduction product, method for producing hydrogen (h2), and method for producing dehydrogenation reaction product |
| JP2012524033A (en) * | 2009-04-17 | 2012-10-11 | ディーエスエム アイピー アセッツ ビー．ブイ． | Combination of hydroxytyrosol to enhance mitochondrial function and energy production |
| JP2016063804A (en) * | 2013-12-27 | 2016-04-28 | 亀井 一郎 | Mitochondrial activation composition |
-
2016
- 2016-10-29 JP JP2016212385A patent/JP6129395B1/en not_active Expired - Fee Related
Patent Citations (12)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| JPH1029941A (en) * | 1996-04-01 | 1998-02-03 | Eisai Co Ltd | Vitamin b2-containing medicine |
| JP2010189432A (en) * | 1997-10-24 | 2010-09-02 | John P Blass | Supplement for metabolic dysfunction of brain |
| JPH11199486A (en) * | 1998-01-13 | 1999-07-27 | Eisai Co Ltd | Vitamin b2-containing medicine composition |
| JP2004518712A (en) * | 2001-02-14 | 2004-06-24 | ラート・マティアス | Compositions of biochemical compounds involved in the bioenergetic metabolism of cells and uses thereof |
| WO2002074313A1 (en) * | 2001-03-21 | 2002-09-26 | Eisai Co., Ltd. | Drugs containing reduced vitamin b¿2? |
| JP2011144186A (en) * | 2002-11-19 | 2011-07-28 | Nutropia Ernaehrungsmedizinische Forschungs Gmbh | Composition comprising nadh/nadph |
| JP2004345988A (en) * | 2003-05-21 | 2004-12-09 | Eisai Co Ltd | Medicine composition containing riboflavin-based compound |
| WO2008062814A1 (en) * | 2006-11-24 | 2008-05-29 | Spring Co., Ltd. | Hydrogen-dissolved aqueous solution and method for prolonging the life duration of hydrogen dissolved in the aqueous solution |
| WO2008156171A1 (en) * | 2007-06-20 | 2008-12-24 | Eureka-Lab Inc. | Method of regulating liquid properties of reducing hydrogen solution and reducing hydrogen solution composition |
| JP2012524033A (en) * | 2009-04-17 | 2012-10-11 | ディーエスエム アイピー アセッツ ビー．ブイ． | Combination of hydroxytyrosol to enhance mitochondrial function and energy production |
| WO2011108730A1 (en) * | 2010-03-04 | 2011-09-09 | 国立大学法人大阪大学 | Mononuclear metal complex, hydrogenation reduction catalyst, dehydrogenation catalyst, method for producing hydrogenation reduction product, method for producing hydrogen (h2), and method for producing dehydrogenation reaction product |
| JP2016063804A (en) * | 2013-12-27 | 2016-04-28 | 亀井 一郎 | Mitochondrial activation composition |
Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2021090926A1 (en) * | 2019-11-08 | 2021-05-14 | 学校法人北里研究所 | Agent for preventing or treating arrhythmia and device for preventing or treating arrhythmia |
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