WO2010140625A1 - 還元型グルタチオンの製造法 - Google Patents
還元型グルタチオンの製造法 Download PDFInfo
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- WO2010140625A1 WO2010140625A1 PCT/JP2010/059361 JP2010059361W WO2010140625A1 WO 2010140625 A1 WO2010140625 A1 WO 2010140625A1 JP 2010059361 W JP2010059361 W JP 2010059361W WO 2010140625 A1 WO2010140625 A1 WO 2010140625A1
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07K—PEPTIDES
- C07K5/00—Peptides containing up to four amino acids in a fully defined sequence; Derivatives thereof
- C07K5/02—Peptides containing up to four amino acids in a fully defined sequence; Derivatives thereof containing at least one abnormal peptide link
- C07K5/0215—Peptides containing up to four amino acids in a fully defined sequence; Derivatives thereof containing at least one abnormal peptide link containing natural amino acids, forming a peptide bond via their side chain functional group, e.g. epsilon-Lys, gamma-Glu
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- C—CHEMISTRY; METALLURGY
- C25—ELECTROLYTIC OR ELECTROPHORETIC PROCESSES; APPARATUS THEREFOR
- C25B—ELECTROLYTIC OR ELECTROPHORETIC PROCESSES FOR THE PRODUCTION OF COMPOUNDS OR NON-METALS; APPARATUS THEREFOR
- C25B3/00—Electrolytic production of organic compounds
- C25B3/20—Processes
- C25B3/25—Reduction
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- the present invention relates to a method for producing reduced glutathione by electrolytic reduction of oxidized glutathione.
- Patent Document 1 As a method for electrolytic reduction of a disulfide compound, a method using an alloy composed of two or more specific metals for the cathode is known (Patent Document 1). Also, as a method of producing L-cysteine by electrolytic reduction of L-cystine, which is a kind of disulfide compound, a cation exchange membrane was used for the diaphragm, and a mineral acid such as hydrochloric acid was added to the cathode side electrolytic cell to make it acidic. A method using an L-cystine solution is known (Patent Document 2).
- the required area of the electrode and ion exchange membrane is reduced to a practical size while suppressing the corrosion of the cathode and the decomposition of the reduced glutathione. In addition, it is required to improve the reduction efficiency.
- the present invention relates to the methods described in the following (1) to (7).
- a method for producing reduced glutathione by electrolytic reduction of oxidized glutathione using a cathode chamber and an anode chamber separated by a diaphragm a pH 2.0 to 3.0 containing a conductive agent other than acid in the solution in the cathode chamber
- the production method of the above (1), wherein the conductive agent other than the acid is a neutral salt.
- the neutral salt is sodium sulfate, sodium chloride, potassium sulfate or potassium chloride.
- reduced glutathione can be produced efficiently on an industrial scale.
- FIG. 1A is a graph showing the change with time of the residual ratio of reduced glutathione at each pH.
- FIG. 1B is a diagram showing the change over time in the amount of increase in impurities in the reduced glutathione aqueous solution at each pH.
- the vertical axis in FIG. 1A represents the residual ratio of reduced glutathione, and the horizontal axis represents time (time).
- the vertical axis represents the impurity content (g / L) in the reduced glutathione aqueous solution, and the horizontal axis represents the elapsed time (hours).
- FIG. 2 is a graph showing the relationship between the oxidized glutathione concentration of the cathode tank solution and the electrolytic reduction rate.
- the vertical axis represents the electrolytic reduction rate (g / m 2 / h), and the horizontal axis represents the oxidized glutathione concentration (g / L).
- the method of the present invention is a method for producing reduced glutathione by electrolytic reduction of oxidized glutathione using a cathode tank and an anode tank separated by a diaphragm, and a pH 2.0 to 3.0 containing a conductive agent other than acid in the cathode tank solution.
- a method for producing reduced glutathione characterized by using an oxidized glutathione aqueous solution.
- Conductive agents other than acids are substances other than acids that have the effect of lowering the pH of aqueous solutions such as inorganic acids such as hydrochloric acid and sulfuric acid, and organic acids such as acetic acid and propionic acid when added to an oxidized glutathione aqueous solution.
- the conductive agent is not particularly limited as long as it is a conductive agent that improves the conductivity of the aqueous solution.
- a conductive agent is preferably a neutral salt.
- neutral salts include inorganic salts such as sulfates, nitrates, chlorine salts and phosphates, and organic salts such as acetates and propionates.
- the salt constituting the neutral salt include metal salts such as sodium, potassium, and magnesium, and ammonium salts.
- Particularly preferable examples of the conductive agent include sodium sulfate, sodium chloride, potassium sulfate, and potassium chloride, and most preferable examples include sodium sulfate.
- An oxidized glutathione aqueous solution containing a neutral salt may be prepared by directly dissolving the neutral salt in the solution, or by mixing an acid and an alkali to form a neutralized salt in the aqueous solution. It may be prepared.
- the pH of the aqueous solution of oxidized glutathione is preferably 2.0 to 3.0, more preferably 2.5 to 2.9, because reduced glutathione produced by electrolytic reduction decomposes under strong acidity and electrolytic reduction does not proceed near neutrality. A pH of 2.8 to 2.9 is particularly preferred.
- the concentration of the conductive agent is not particularly limited as long as it is equal to or lower than the saturated concentration in the oxidized glutathione aqueous solution.
- sodium sulfate is used as the conductive agent, 0.05 to 5.0 mol / L, preferably 0.2 to 3.0 mol / L, More preferably, it is 0.4 to 1.0 mol / L.
- the conductivity of the solution can be improved without lowering the pH of the oxidized glutathione aqueous solution.
- the electrical resistance of the solution is lower than when the same current is applied to the aqueous glutathione solution, and therefore the temperature of the aqueous solution does not increase. That is, decomposition of reduced glutathione in the cathode chamber can be suppressed.
- an electrolytic glutathione aqueous solution containing a conductive agent other than an acid is placed in the cathode tank and subjected to electrolytic reduction, so that the production efficiency can be increased while suppressing decomposition of the reduced glutathione.
- the size of the electrode can be reduced, so that the equipment cost can be kept low.
- the production method of the present invention has another feature in that a supersaturated oxidized glutathione aqueous solution is used as the oxidized glutathione aqueous solution in the cathode chamber.
- Saturated solubility of oxidized glutathione in water at room temperature is 20 g / L or less, and solubilization does not increase even with salt unless the pH is greatly changed.
- oxidized glutathione once had a very high supersaturated solubility exceeding 300 g / L. This supersaturated state is stable at room temperature and takes several days to crystallize.
- the concentration of the supersaturated oxidized glutathione aqueous solution containing a conductive agent other than an acid is not limited as long as the supersaturated state can be maintained, but is 50 g / L or more, preferably 100 g / L or more, more preferably 150 g / L or more. More preferably, the concentration can be 200 g / L or more, and most preferably 300 g / L or more.
- the solution has a supersaturated oxidation of 200 g / L or more.
- Type glutathione aqueous solution the reduction rate greatly exceeds the degradation rate of reduced glutathione under strong acidity, so it is economically efficient if an electrode made of an inexpensive material that is not easily corroded under strong acidity as a cathode.
- reduced glutathione can be produced.
- the solution of the anode tank in the present invention is not particularly limited as long as it is a conductive aqueous solution, an inorganic acid solution such as hydrochloric acid and sulfuric acid, an organic acid solution such as acetic acid and propionic acid, and a solution in which a conductive agent other than an acid is dissolved.
- the concentration of inorganic acid or organic acid is low, the conductivity is poor, and when the concentration is high, the ion exchange membrane is likely to deteriorate. Therefore, it is used at a concentration of 0.5 to 3 mol / L, preferably 1 to 2 mol / L.
- the conductive agent other than the acid include the conductive agent contained in the oxidized glutathione aqueous solution in the cathode chamber described above, and preferably the same conductive agent as that contained in the oxidized glutathione aqueous solution.
- the concentration of the conductive agent in the solution in the anode vessel is preferably the same as the concentration of the conductive agent in the solution in the cathode vessel.
- concentration is 0.05 to 5.0 mol / L
- the amount is preferably 0.2 to 3.0 mol / L, more preferably 0.4 to 1.0 mol / L.
- a metal having a hydrogen overvoltage of carbon or more examples include zinc, lead, carbon, and porous carbon, and more preferably zinc. Can give.
- any metal can be used as long as it is an insoluble metal, but a metal having excellent corrosion resistance is preferable, for example, platinum-plated titanium, platinum-iridium, lead, lead Alloys, lead dioxide, and titanium oxide can be mentioned, and platinum-plated titanium is preferable.
- the membrane used in the method of the present invention may be any membrane as long as it can reduce leakage of reduced glutathione produced in the cathode cell to the anode cell, preferably an ion exchange membrane, more preferably cation exchange.
- a membrane can be mentioned, specifically, Selemion CMT (Asahi Glass Co., Ltd.) can be mentioned.
- the current density, voltage, temperature and the like are not particularly limited, but as a condition for improving the reduction efficiency while suppressing the decomposition of the produced reduced glutathione, the current density is preferably 0.1 to 30 A. / dm 2 , more preferably 0.5 to 20 A / dm 2 , more preferably 1 to 10 A / dm 2 , the voltage is preferably 1 to 20 V, more preferably 2 to 15 V, more preferably 3 to 10 V, and the temperature is preferably The temperature can be 4 to 50 ° C., more preferably 10 to 30 ° C., and still more preferably 10 to 25 ° C.
- the solution in the cathode tank containing the reduced glutathione produced is desalted by passing through an ion exchange column, and the desalted reduced glutathione aqueous solution can be used as it is for crystallization.
- ion exchange resins strong acid cation exchange resins represented by SK-116 and SK-104 (both Diaion and Mitsubishi Chemical) and weak basicity represented by WA-30 and WA-21 An ion exchange resin (both are Diaion, manufactured by Mitsubishi Chemical Corporation) can be mentioned, and the desalted reduced glutathione can be crystallized by adding a solvent or a seed crystal as appropriate after cooling and cooling.
- the amount of impurities increased due to hydrolysis was larger in the solution having a pH of 2.0 or less than that in the solution having a pH of 2.90.
- the total amount of substances other than reduced glutathione and oxidized glutathione was quantified under the following HPLC conditions, and the concentration (g / L) converted to reduced glutathione was calculated.
- HPLC condition column Nucleosil 100-5 C18 ⁇ 4.6 ⁇ 150mm Column temperature: 40 ° C Buffer solution: 10% acetonitrile solution containing 0.405% sodium 1-heptanesulfonate (adjusted to pH 2.0 with phosphoric acid) Flow rate: 1.0mL / min Detector: UV detector (wavelength 210nm)
- Electrolytic reduction of oxidized glutathione using sodium sulfate as a conductive agent About 400 g / L of oxidized glutathione aqueous solution was prepared by adding sodium hydroxide to pH 7.0, and this was passed through a cation exchange resin. By desalting, an about 350 g / L supersaturated oxidized glutathione aqueous solution was prepared. The solution was diluted and sodium sulfate was added to prepare a 310 g / L oxidized glutathione aqueous solution containing 0.75 mol / L sodium sulfate. The pH of the solution was 2.91.
- the electrolytic cell used was an anode side of 150 mL and a cathode side of 300 mL, and the bipolar cell was separated by a 50 cm 2 cation exchange membrane selemion CMT (manufactured by Asahi Glass Co., Ltd.).
- a 50 cm 2 platinum-plated titanium plate was used for the anode, and a 50 cm 2 zinc plate was used for the cathode.
- the anode tank was filled with 140 mL of a 0.50 mol / L sulfuric acid solution, and the cathode tank was filled with 280 mL of the oxidized glutathione aqueous solution prepared above.
- the electrolytic reduction reaction was performed at an electrolytic voltage of 5-6 V, an electrolytic current of 3.0 A, and room temperature for 10 hours.
- the product in the cathode chamber was quantified by HPLC under the same conditions as in Example 1, and it was confirmed that 79.7 g of reduced glutathione was produced (conversion rate: 91.8%).
- the cathode Under the above electrolytic reduction conditions, the cathode was hardly corroded, but under the above electrolytic reduction conditions, instead of the oxidized glutathione aqueous solution containing 0.75 mol / L sodium sulfate as the cathode bath solution, the pH was adjusted to 0. When the 150 g / L oxidized glutathione aqueous solution prepared in 68 was used, it was observed that zinc used for the cathode was eluted in the cathode cell solution.
- Electrolytic reduction rate when using supersaturated oxidized glutathione aqueous solution About 350 g / L supersaturated oxidized glutathione aqueous solution prepared in Example 2 was diluted to 300 g / L containing 0.75 mol / L sodium sulfate, Oxidized glutathione aqueous solutions of 200 g / L, 150 g / L and 100 g / L were prepared. The pH of each solution was 2.89.
- the electrolytic cell, cation exchange membrane, and both electrodes were the same as in Example 2.
- the anode tank was filled with 140 mL of a 0.50 mol / L sulfuric acid solution, and the cathode tank was filled with 280 mL of the oxidized glutathione aqueous solution prepared above.
- Electrolytic reduction reaction was performed at an electrolysis voltage of 5 to 7 V, an electrolysis current of 3.0 A, and room temperature.
- the product in the cathode chamber was quantified by HPLC under the same conditions as in Example 1, and the higher the concentration of the oxidized glutathione aqueous solution in the cathode chamber, the higher the electroreduction rate, especially at higher than 150 g / L. (Fig. 2).
- Example 2 Production of Reduced Glutathione Crystals
- the reduced glutathione aqueous solution obtained in Example 2 was subjected to strong acidic cation exchange resin SK-116 (H +) (manufactured by Mitsubishi Chemical Corporation), followed by weakly basic anion exchange resin WA-21 ( OH-) (Mitsubishi Chemical Co., Ltd.) was passed through to remove the coexisting salt.
- the obtained reduced glutathione-containing fraction was concentrated under reduced pressure, seed crystals were added and crystallized to obtain reduced glutathione crystals.
- the method of the present invention has made it possible to produce reduced glutathione on an industrial scale by electrolytic reduction of oxidized glutathione.
- ⁇ represents pH 0.6
- ⁇ represents pH 1.2
- ⁇ represents pH 2.0
- ⁇ represents pH 2.9 reduced glutathione aqueous solution.
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Abstract
Description
(1)隔膜で隔てられた陰極槽および陽極槽を用いた酸化型グルタチオンの電解還元による還元型グルタチオンの製造法において、陰極槽内の溶液に酸以外の導電剤を含有するpH2.0~3.0の酸化型グルタチオン水溶液を用いることを特徴とする還元型グルタチオンの製造方法。
(2)酸以外の導電剤が中性塩である上記(1)の製造方法。
(3)中性塩が硫酸ナトリウム、塩化ナトリウム、硫酸カリウムまたは塩化カリウムである上記(2)の製造方法。
(4)酸以外の導電剤の濃度が0.05mol/L以上、5.0mol/L以下である上記(1)~(3)のいずれか1つの製造方法。
(5)酸化型グルタチオン水溶液の濃度が50g/L以上である上記(1)~(4)のいずれか1つの製造方法。
(6)電解還元が電流密度0.1~30A/dm2で行われることを特徴とする上記(1)~(5)のいずれか1つの製造方法。
(7)上記(1)~(6)のいずれか1つの製造方法で製造された還元型グルタチオンをイオン交換カラムに通塔して脱塩された還元型グルタチオン水溶液を取得し、その後還元型グルタチオンを結晶化させることを特徴とする還元型グルタチオン結晶の製造方法。
酸以外の導電剤は、塩酸、硫酸などの無機酸、酢酸、プロピオン酸などの有機酸のように酸化型グルタチオン水溶液に加えたときに該水溶液のpHを下げる作用を有する酸以外の物質であり、該水溶液の電導性を向上させる導電剤であれば特に制限されない。そのような導電剤としては、好ましくは中性塩をあげることができる。中性塩としては、硫酸塩、硝酸塩、塩素塩、リン酸塩などの無機塩、酢酸塩、プロピオン酸塩などの有機塩などをあげることができる。中性塩を構成する塩としては、ナトリウム、カリウム、マグネシウムなどの金属塩およびアンモニウム塩などをあげることができる。特に好ましい導電剤としては硫酸ナトリウム、塩化ナトリウム、硫酸カリウムおよび塩化カリウムをあげることができ、最も好ましくは硫酸ナトリウムをあげることができる。
酸化型グルタチオン水溶液のpHは、強酸性下では電解還元により生成した還元型グルタチオンが分解し、中性付近では電解還元が進行しないので、pH2.0~3.0が好ましく、pH2.5~2.9がさらに好ましく、pH2.8~2.9が特に好ましい。
本発明の方法では、酸以外の導電剤を酸化型グルタチオン水溶液に加えることにより、酸化型グルタチオン水溶液のpHを下げることなく該溶液の電導性を向上させることができるので、導電剤非含有の酸化型グルタチオン水溶液に同じ電流を通電した場合に比べて溶液の電気抵抗は低く、よって水溶液の温度も高くならない。すなわち、陰極槽中での還元型グルタチオンの分解を抑えることができる。
本発明の製造方法は、陰極槽の酸化型グルタチオン水溶液として過飽和の酸化型グルタチオン水溶液を用いることをもう一つの特徴とする。
本発明における陽極槽の溶液は、導電性がある水溶液であれば特に制限はなく、塩酸、硫酸などの無機酸溶液、酢酸、プロピオン酸などの有機酸溶液、酸以外の導電剤を溶解した溶液などをあげることができる。無機酸、有機酸の濃度は、低濃度だと導電性が悪く、高濃度だとイオン交換膜が劣化し易くなるので、0.5~3mol/L、好ましくは1~2mol/Lの濃度で用いられる。酸以外の導電剤としては、上記した陰極槽内の酸化型グルタチオン水溶液に含まれる導電剤をあげることができ、好ましくは酸化型グルタチオン水溶液に含まれる導電剤と同じ導電剤をあげることができる。
本発明の方法で用いられる陰極には、水素過電圧が炭素以上の金属を用いることが好ましく、そのような金属としては例えば亜鉛、鉛および炭素、多孔性炭素をあげることができ、より好ましくは亜鉛をあげることができる。
本発明の方法で用いられる隔膜としては、陰極槽内で生成する還元型グルタチオンの陽極槽への漏出を低減できる膜であればいずれの膜でもよく、好ましくはイオン交換膜、より好ましくはカチオン交換膜をあげることができ、具体的にはセレミオンCMT(旭硝子社製)をあげることができる。
100g/Lの還元型グルタチオン水溶液(pH2.90)、および硫酸を用いてpH0.6、1.2、2.0に調整した100g/Lの還元型グルタチオン水溶液をそれぞれ作製した。
それぞれの溶液を、25℃、24~36時間保存した後、以下の条件での高速液体クロマトグラフィー(HPLC)で還元型グルタチオンの残存量を定量した。図1Aに示すように、pH2.0以下の溶液では、pH2.90の溶液に比べ還元型グルタチオンの残存率が低下することがわかった。さらに、図1Bに示すように、pH2.0以下の溶液では、pH2.90の溶液に比べ、加水分解による不純物の増加量が大きいことがわかった。なお、不純物は下記のHPLC条件で還元型グルタチオン、酸化型グルタチオン以外の物質の総量を定量し、還元型グルタチオンに換算した濃度(g/L)を算出した。
HPLC条件
カラム:Nucleosil 100-5 C18 φ4.6×150mm
カラム温度:40℃
緩衝液:0.405%の1-ヘプタンスルホン酸ナトリウムを含む、10%アセトニトリル溶液(燐酸でpH2.0に調整)
流速:1.0mL/min
検出器:UV検出器(波長210nm)
水酸化ナトリウムを加えてpHを7.0にすることで約400g/Lの酸化型グルタチオン水溶液を調製し、これをカチオン交換樹脂に通塔して脱塩することで約350g/Lの過飽和の酸化型グルタチオン水溶液を作製した。該溶液を希釈するとともに硫酸ナトリウムを加え、0.75mol/Lの硫酸ナトリウムを含む310g/Lの酸化型グルタチオン水溶液を作製した。該溶液のpHは2.91であった。
電解電圧5~6V、電解電流3.0A、室温下で10時間、電解還元反応を行った。実施例1と同条件のHPLCで陰極槽内の生成物を定量し、79.7gの還元型グルタチオンが生成していることを確認した(転換率91.8%)。
実施例2で調整した約350g/Lの過飽和の酸化型グルタチオン水溶液を希釈して、0.75mol/Lの硫酸ナトリウムを含む、300g/L、200g/L、150g/Lおよび100g/Lの酸化型グルタチオン水溶液を作製した。それぞれの溶液のpHは、いずれも2.89であった。
電解槽、カチオン交換膜、および両極は実施例2と同じものを用いた。陽極槽には0.50mol/Lの硫酸溶液140mL、陰極槽には上記で作製した酸化型グルタチオン水溶液をそれぞれ280mL入れた。
実施例2で得られた還元型グルタチオン水溶液を、強酸性陽イオン交換樹脂SK-116(H+)(三菱化学社製)、次いで弱塩基性陰イオン交換樹脂WA-21(OH-)(三菱化学社製)に通過させることで、共存する塩を除去した。得られた還元型グルタチオン含有画分を減圧濃縮し、種晶を添加して晶析させることにより、還元型グルタチオンの結晶を取得した。
Claims (7)
- 隔膜で隔てられた陰極槽および陽極槽を用いた酸化型グルタチオンの電解還元による還元型グルタチオンの製造法において、陰極槽内の溶液に酸以外の導電剤を含有するpH2.0~3.0の酸化型グルタチオン水溶液を用いることを特徴とする還元型グルタチオンの製造方法。
- 酸以外の導電剤が中性塩である請求項1記載の製造方法。
- 中性塩が硫酸ナトリウム、塩化ナトリウム、硫酸カリウムまたは塩化カリウムである請求項2記載の製造方法。
- 酸以外の導電剤の濃度が0.05mol/L以上、5.0mol/L以下である請求項1~3記載のいずれか1項に記載の製造方法。
- 酸化型グルタチオン水溶液の濃度が50g/L以上である請求項1~4のいずれか1項に記載の製造方法。
- 電解還元が電流密度0.1~30A/dm2で行われることを特徴とする請求項1~5のいずれか1項に記載の製造方法。
- 請求項1~6のいずれか1項に記載の製造方法で製造された還元型グルタチオンをイオン交換カラムに通塔して脱塩された還元型グルタチオン水溶液を取得し、その後還元型グルタチオンを結晶化させることを特徴とする還元型グルタチオン結晶の製造方法。
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JP2011518476A JP5654457B2 (ja) | 2009-06-03 | 2010-06-02 | 還元型グルタチオンの製造法 |
EP10783407.9A EP2439312B1 (en) | 2009-06-03 | 2010-06-02 | Process for production of reduced glutathione |
US13/375,630 US9249517B2 (en) | 2009-06-03 | 2010-06-02 | Process for production of reduced glutathione |
CN201080034332.1A CN102803567B (zh) | 2009-06-03 | 2010-06-02 | 制造还原型谷胱甘肽的方法 |
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Cited By (4)
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WO2012137824A1 (ja) | 2011-04-06 | 2012-10-11 | 協和発酵バイオ株式会社 | 還元型グルタチオンの製造法 |
WO2014133129A1 (ja) | 2013-02-28 | 2014-09-04 | 協和発酵バイオ株式会社 | 還元型グルタチオンの製造法 |
CN106526004A (zh) * | 2016-10-14 | 2017-03-22 | 安琪酵母股份有限公司 | 一种富含谷胱甘肽酵母抽提物中氧化型谷胱甘肽杂质的检测方法 |
WO2017159555A1 (ja) | 2016-03-17 | 2017-09-21 | 協和発酵バイオ株式会社 | 還元型グルタチオンの結晶及びその製造方法 |
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US10640532B2 (en) * | 2015-03-31 | 2020-05-05 | University Public Corporation Osaka | Crystal of reduced glutathione |
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Cited By (9)
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WO2012137824A1 (ja) | 2011-04-06 | 2012-10-11 | 協和発酵バイオ株式会社 | 還元型グルタチオンの製造法 |
CN103459409A (zh) * | 2011-04-06 | 2013-12-18 | 协和发酵生化株式会社 | 制造还原型谷胱甘肽的方法 |
US9028669B2 (en) | 2011-04-06 | 2015-05-12 | Kyowa Hakko Bio Co., Ltd. | Process for producing reduced glutathione |
CN103459409B (zh) * | 2011-04-06 | 2015-11-25 | 协和发酵生化株式会社 | 制造还原型谷胱甘肽的方法 |
JP5985467B2 (ja) * | 2011-04-06 | 2016-09-06 | 協和発酵バイオ株式会社 | 還元型グルタチオンの製造法 |
WO2014133129A1 (ja) | 2013-02-28 | 2014-09-04 | 協和発酵バイオ株式会社 | 還元型グルタチオンの製造法 |
US10094031B2 (en) | 2013-02-28 | 2018-10-09 | Kyowa Hakko Bio Co., Ltd. | Method for manufacturing reduced glutathione |
WO2017159555A1 (ja) | 2016-03-17 | 2017-09-21 | 協和発酵バイオ株式会社 | 還元型グルタチオンの結晶及びその製造方法 |
CN106526004A (zh) * | 2016-10-14 | 2017-03-22 | 安琪酵母股份有限公司 | 一种富含谷胱甘肽酵母抽提物中氧化型谷胱甘肽杂质的检测方法 |
Also Published As
Publication number | Publication date |
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US9249517B2 (en) | 2016-02-02 |
EP2439312B1 (en) | 2017-08-09 |
EP2439312A4 (en) | 2013-02-13 |
CN102803567B (zh) | 2015-06-03 |
JP5654457B2 (ja) | 2015-01-14 |
US20120118756A1 (en) | 2012-05-17 |
CN102803567A (zh) | 2012-11-28 |
EP2439312A1 (en) | 2012-04-11 |
JPWO2010140625A1 (ja) | 2012-11-22 |
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