WO2011126030A1 - 保存安定性に優れたs-アデノシル-l-メチオニン含有乾燥酵母組成物及びその製造方法 - Google Patents
保存安定性に優れたs-アデノシル-l-メチオニン含有乾燥酵母組成物及びその製造方法 Download PDFInfo
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- WO2011126030A1 WO2011126030A1 PCT/JP2011/058652 JP2011058652W WO2011126030A1 WO 2011126030 A1 WO2011126030 A1 WO 2011126030A1 JP 2011058652 W JP2011058652 W JP 2011058652W WO 2011126030 A1 WO2011126030 A1 WO 2011126030A1
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- gum
- methionine
- adenosyl
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- dry yeast
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- C—CHEMISTRY; METALLURGY
- C12—BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
- C12N—MICROORGANISMS OR ENZYMES; COMPOSITIONS THEREOF; PROPAGATING, PRESERVING, OR MAINTAINING MICROORGANISMS; MUTATION OR GENETIC ENGINEERING; CULTURE MEDIA
- C12N1/00—Microorganisms, e.g. protozoa; Compositions thereof; Processes of propagating, maintaining or preserving microorganisms or compositions thereof; Processes of preparing or isolating a composition containing a microorganism; Culture media therefor
- C12N1/14—Fungi; Culture media therefor
- C12N1/16—Yeasts; Culture media therefor
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- C—CHEMISTRY; METALLURGY
- C12—BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
- C12N—MICROORGANISMS OR ENZYMES; COMPOSITIONS THEREOF; PROPAGATING, PRESERVING, OR MAINTAINING MICROORGANISMS; MUTATION OR GENETIC ENGINEERING; CULTURE MEDIA
- C12N1/00—Microorganisms, e.g. protozoa; Compositions thereof; Processes of propagating, maintaining or preserving microorganisms or compositions thereof; Processes of preparing or isolating a composition containing a microorganism; Culture media therefor
- C12N1/04—Preserving or maintaining viable microorganisms
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- C—CHEMISTRY; METALLURGY
- C12—BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
- C12N—MICROORGANISMS OR ENZYMES; COMPOSITIONS THEREOF; PROPAGATING, PRESERVING, OR MAINTAINING MICROORGANISMS; MUTATION OR GENETIC ENGINEERING; CULTURE MEDIA
- C12N1/00—Microorganisms, e.g. protozoa; Compositions thereof; Processes of propagating, maintaining or preserving microorganisms or compositions thereof; Processes of preparing or isolating a composition containing a microorganism; Culture media therefor
- C12N1/14—Fungi; Culture media therefor
- C12N1/16—Yeasts; Culture media therefor
- C12N1/18—Baker's yeast; Brewer's yeast
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- C—CHEMISTRY; METALLURGY
- C12—BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
- C12P—FERMENTATION OR ENZYME-USING PROCESSES TO SYNTHESISE A DESIRED CHEMICAL COMPOUND OR COMPOSITION OR TO SEPARATE OPTICAL ISOMERS FROM A RACEMIC MIXTURE
- C12P19/00—Preparation of compounds containing saccharide radicals
- C12P19/26—Preparation of nitrogen-containing carbohydrates
- C12P19/28—N-glycosides
- C12P19/38—Nucleosides
- C12P19/40—Nucleosides having a condensed ring system containing a six-membered ring having two nitrogen atoms in the same ring, e.g. purine nucleosides
Definitions
- the present invention relates to a dry yeast composition excellent in storage stability containing S-adenosyl-L-methionine (hereinafter referred to as SAMe) useful as a water-soluble physiologically active substance at a high concentration, and a method for producing the same.
- SAMe S-adenosyl-L-methionine
- SAMe is widely present in the living body and plays an important role as a methyl group donor in methylation reactions by various transmethylases in the synthesis and metabolism of nucleic acids, neurotransmitters, phospholipids, hormones, proteins, etc. It is a water-soluble physiologically active substance. SAMe is found in almost all cells of the human body, acts as a cofactor in various biochemical reactions, and is metabolized by three metabolic pathways: methyl group transfer, sulfur group transfer, and aminopropyl group transfer. For example, it is a substance indispensable for maintenance of cartilage and biosynthesis of substances in the brain.
- SAMe is an important physiologically active substance, and is widely used in Western countries as a therapeutic agent for depression, liver disease, arthritis, etc., or as a health food.
- SAMe synthase methionine adenosyltransferase isolated and purified from microorganisms such as yeast
- ATP adenosine 5′-triphosphate
- L-methionine adenosine 5′-triphosphate
- SAMe synthase methionine adenosyltransferase isolated and purified from microorganisms such as yeast is used, and SAMe is enzymatically produced using adenosine 5'-triphosphate (ATP) and L-methionine as substrates.
- ATP adenosine 5'-triphosphate
- this method has advantages such as a large amount of SAMe accumulated and no need for SAMe extraction from cells, compared with the fermentation method, but the preparation of the enzyme is complicated. There are various problems such as that the activity of the enzyme to be obtained is weak, that it is necessary to remove interfering substances such as ATP-degrading enzyme, and that ATP as a substrate is extremely expensive.
- SAMe is thermally unstable and has the property of easily decomposing at room temperature, which is a major obstacle when used as pharmaceuticals and health foods.
- many attempts have been made to improve storage stability.
- the composition of SAMe obtained by the above-described production method is purified by chromatography and the like, and then the salt of SAMe is stabilized by using a salt with sulfuric acid, p-toluenesulfonic acid, or a salt with butanedisulfonic acid.
- Patent Document 1 there are many methods (for example, see Patent Document 1) or methods for stabilizing the SAMe composition (for example, see Patent Document 1) by treating the purified SAMe with additives.
- An object of the present invention is to establish a process capable of easily and easily producing a dry yeast composition having a high concentration of SAMe and having excellent storage stability.
- the present inventors have intensively studied a method for economically producing a composition containing SAMe at a high concentration and capable of being stored in a stable state for a long period of time. It was obtained by using a yeast having SAMe-producing ability and capable of being orally ingested, producing and accumulating SAMe in a high concentration in the microbial cells, and then separating the yeast cells from the culture solution by a separation means such as centrifugation. After adding a thickener to the yeast cell concentrate, it is dried to easily produce dry yeast, which is a composition containing the desired SAMe at a high concentration and excellent in storage stability. The present inventors have found that this can be done and have completed the present invention. Moreover, it discovered that the SAMe containing dry yeast composition of this invention was excellent also in bioabsorbability in addition to storage stability, and came to complete this invention.
- the present invention (1) S-adenosyl-L-methionine and a S-adenosyl-L-methionine-containing dry yeast composition containing a thickener, and (2) a yeast having the ability to produce S-adenosyl-L-methionine,
- a method for producing a dried yeast composition containing S-adenosyl-L-methionine, which is dried after adding a thickener to a yeast cell concentrate obtained from a yeast cell culture solution, I will provide a.
- the S-adenosyl-L-methinion-containing dry yeast composition of the present invention is excellent in storage stability and bioabsorbability, so it can be crushed into a powder form or other physiologically active ingredients as necessary. Or additives such as excipients, compressed into tablets to form tablet-like compositions, granulated powders, packed granulated granules and encapsulated, A composition useful as a water-soluble physiologically active substance for pharmaceuticals and health foods can be provided. In addition, it is possible to provide a method for easily producing a composition containing S-adenosyl-L-methionine at a high concentration and excellent in storage stability and a SAMe-containing dry yeast composition excellent in bioabsorbability at low cost.
- the type of yeast used in the present invention is not particularly limited as long as it has SAMe-producing ability and can be taken orally, and examples thereof include yeast belonging to the genus Saccharomyces. Of these, Saccharomyces cerevisiae is more preferred. Dry yeast contains useful components such as 5'-nucleotide, free amino acids, glutathione that has an antioxidant action and is useful for improving liver function, ⁇ -glucan that promotes immunity and intestinal regulation, and dietary fiber. Many are included and widely used as health foods.
- the carbon source used for culturing the yeast is not particularly limited as long as the yeast can assimilate, for example, carbohydrates such as glucose, sucrose, starch, and molasses, alcohols such as ethanol, acetic acid, and the like. Organic acids are mentioned.
- the nitrogen source is not particularly limited as long as the yeast to be used can be assimilated.
- the nitrogen source includes inorganic nitrogen compounds such as ammonia, nitric acid, urea, or organic nitrogen compounds such as yeast extract and malt extract. Can be mentioned.
- inorganic salts salts of phosphoric acid, potassium, sodium, magnesium, calcium, iron, zinc, manganese, cobalt, copper, molybdenum and the like are used.
- methionine, adenine, and adenosylribonucleoside which are related to the skeleton structure of SAMe can be added and cultured.
- an L-methionine-containing medium (Shiozaki S., et all, J. Biotechnology, 4, 345-354 (1986)) was used. Inoculate a medium containing sucrose, yeast extract, L-methionine, urea, glycine, potassium dihydrogen phosphate, magnesium sulfate heptahydrate, biotin, calcium chloride dihydrate, and trace metal salts Then, SAM-containing cells can be obtained by culturing aerobically while feeding a carbon source such as sucrose or / and ethanol.
- a carbon source such as sucrose or / and ethanol.
- the culture temperature and the pH of the culture solution vary depending on the type of yeast used, the culture temperature can be in the range of 20 to 35 ° C., and the culture solution pH can be in the range of pH 4 to 7.
- the culture tank is not particularly limited as long as it can be ventilated and can be stirred if necessary.
- a mechanical stirring culture tank, an air lift type culture tank, a bubble column type culture tank, or the like can be used.
- a method for supplying the culture medium a carbon source, a nitrogen source, various inorganic salts, various additives, and the like are supplied all at once or continuously or intermittently.
- a substrate such as sucrose or ethanol may be supplied to the culture tank as a mixture with other medium components, or may be supplied to the culture tank independently of the other medium components.
- the pH of the culture solution is controlled by an acid or alkali solution.
- the alkali it is desirable to control the pH using ammonia, urea, or a non-nitrogen base used as a nitrogen source, such as caustic soda or caustic potash.
- the acid an inorganic acid such as phosphoric acid, sulfuric acid, nitric acid, or an organic acid is used.
- the pH can also be controlled using inorganic salts such as phosphates, potassium salts, sodium salts, nitrates and the like.
- the separation method is not particularly limited as long as it is a method capable of efficiently separating and washing the cells, but a suitable example is an ultrafiltration device using a counter-current type yeast separator or a separation membrane.
- the amount of the thickening agent to be added is preferably in the range of 0.1 to 70 mass percent as a mass ratio with respect to the S-adenosyl-L-methionine-containing dry yeast composition, preferably 0.4 to 70 mass.
- the percentage range is more preferable, and the range of 0.7 to 70 mass percent is more preferable.
- the thickener refers to various thickeners that have a thickening action and can be added to foods, so-called gelling agents.
- a thickener that can be specifically used, (1) a microorganism-derived thickener selected from xanthan gum, gellan gum, curdlan, argin xanthan gum, pullulan, and natto fungus gum, (2) a seed-derived thickener selected from guar gum, tara gum, locust bean gum, tamarind gum, and psyllium seed gum; (3) plant-derived thickener selected from cellulose, methylcellulose, hydroxypropylcellulose, hydroxypropylmethylcellulose, carboxymethylcellulose, starch, and sodium carboxymethylate; (4) Seaweed-derived thickener selected from carrageenan, sodium alginate, alginic acid, and propylene glycol alginate, (5) A resin-derived thickener selected from gum arabic, gum tragacanth, shellac, and arabinogalactan
- a microorganism-derived thickener selected from xanthan gum, gellan gum, curdlan, argin xanthan gum, pullulan, and natto fungus gum
- a seed-derived thickener selected from guar gum, tara gum, locust bean gum, tamarind gum, and psyllium seed gum
- a resin-derived thickener selected from gum arabic, gum tragacanth, shellac, and arabinogalactan
- a shell-derived thickener selected from chitosan and chitin
- a thickener selected from pectin, mannan, hyaluronic acid, chondroitin, agar, collagen, albumin, zein, casein, and sodium caseinate More preferred.
- microorganism-derived thickeners such as xanthan gum, gellan gum, curdlan, algin xanthan gum, pullulan, and natto fungus gum, and (2) guar gum, tara gum, locust bean gum, tamarind gum, and psyllium seed gum Seed-derived thickeners are particularly preferred.
- the thickener used in the present invention is widely used in food, cosmetics and pharmaceutical applications and can be used safely.
- the yeast cell concentrate is evaporated by a drying method such as a spray drying method using a spray dryer or a freeze drying method to obtain a SAMe-containing dry yeast composition.
- a drying method such as a spray drying method using a spray dryer or a freeze drying method to obtain a SAMe-containing dry yeast composition.
- the drying conditions in the spray drying method, it is desirable to dry at an inlet temperature of 210 ° C. or lower and an outlet temperature of 110 ° C. or lower.
- the freeze-drying method it is desirable to dry at a final shelf temperature of 30 ° C. or lower.
- the SAMe-containing composition of the present invention preferably has a water content of 5.0% by mass or less from the viewpoint of storage stability.
- this dry yeast composition is crushed into a powder form, or, if necessary, additives such as other physiologically active ingredients and excipients are added to the powdered dry yeast, and then compressed into tablets to form tablets. It is also possible to coat the surface of the composition. Also, the powder can be granulated, or the powder or granulated granule can be packed and encapsulated.
- yeast Saccharomyces cerevisiae IFO2346 belonging to the genus Saccharomyces is added to an L-methionine-containing medium (Shiozaki S., et all, J. Biotechnology, 4, 345-354 (1986)). And cultured for 6 days at a culture temperature of 27-29 ° C. under aerobic aeration and stirring. As a result, a yeast cell culture solution 18 L of a cell concentration of 3.5 wt% and a SAMe content of 205 mg / g-dry yeast was obtained.
- yeast cell culture solution 18L was treated with a continuous rotary centrifuge (Hitachi HIMAC CENTRIFUGE CR10B2), and the yeast concentration was liquid yeast corresponding to 18% by mass in terms of dry matter. 3.4 kg of body concentrate was obtained.
- C Addition of thickener to yeast cell concentrate The mass ratio of xanthan gum to SAMe in the yeast concentrate is 0.02, 0.2, 2.2 to 3.4 kg of the yeast cell concentrate. 11.1 times the amount was added and stirred and mixed at room temperature for 30 minutes to obtain a yeast cell concentrate to which xanthan gum was added.
- the SAMe remaining rate was determined by a comparative quantification method using liquid chromatography after extracting SAMe from a SAMe-containing dry yeast by a known method using perchloric acid.
- the presence or absence of odor after storage was determined by a sensory test with five panelists.
- the sensory evaluation method is “ ⁇ ” when all five panelists have no off-flavors, “ ⁇ ” when one to two out of five people have off-flavors, and “three” or more out of five. The case where there was an off-flavor was marked as “x”.
- the SAMe measurement method in the present invention used liquid chromatography under the following conditions.
- Examples 5-8 The yeast cell concentrate was treated with curdlan in the same manner as in Example 1 to obtain dry powder yeast.
- Example 9 Powdered dry yeast was obtained in the same manner as in Example 1, except that guar gum was added to the yeast cell concentrate in an amount of 0.2 times the mass ratio of SAMe in the yeast concentrate.
- Example 10 Powdered dry yeast was obtained by treating in the same manner as in Example 1 except that tamarind gum was added to the yeast cell concentrate in an amount of 0.2 times the mass ratio of SAMe in the yeast concentrate.
- Example 11 Powdered dry yeast was obtained by treating in the same manner as in Example 1 except that gellan gum was added to the yeast cell concentrate in an amount of 0.2 times the mass ratio of SAMe in the yeast concentrate.
- Comparative Example 1 Powdered dry yeast was obtained in the same manner as in Example 1 except that xanthan gum was not added to the yeast cell concentrate.
- Table 3 shows the SAMe content and mass in the obtained powdered dry yeast, the results of the storage stability test under the accelerated condition of 40 ° C and RH 75% in the sealed glass container of the obtained SAMe-containing dry yeast, and the results of the sensory test. It is shown in 1.
- Comparative Example 2 Powdered dry yeast was obtained in the same manner as in Example 1 except that trehalose was added to the yeast cell concentrate in a 2.2-fold amount as a mass ratio to SAMe in the yeast concentrate.
- Table 3 shows the SAMe content and mass in the obtained powdered dry yeast, the results of the storage stability test under the accelerated condition of 40 ° C and RH 75% in the sealed glass container of the obtained SAMe-containing dry yeast, and the results of the sensory test. It is shown in 1.
- Examples 12-19 Using a 200 L culture tank, the amount of additive to the SAMe-containing yeast concentrate (SAMe content 3.7% by mass) having a solid concentration of 18.2% by mass is 1% by mass, and ⁇ -carrageenan (Example) 12), xanthan gum (Example 13), guar gum (Example 14), tamarind gum (Example 15), curdlan (Example 16), gellan gum (Example 17), alginic acid (Example 18), Ceraos ST- O2 (crystalline cellulose) (Example 19) was added, and the recovery rate after freeze-drying, the SAMe content (mass%) at 40 ° C. for 30 days, and the SAMe residual rate after 60 days were measured.
- SAMe content mass 3.7% by mass
- SAMe residual rate after 60 days were measured.
- the conditions of the detailed examples of Examples 12 to 19 are as follows.
- A Cultivation of yeast cells Culture was performed under the same conditions as in Example 1 to obtain 120 L of yeast cell culture solution of 3.5% by mass of cell concentration and 201.5 mg / g-SAMe content of dry yeast.
- B Collection of yeast cells The above yeast cell culture solution 120L is treated with a continuous rotary centrifuge (Hitachi HIMAC CENTRIFUGE CR10B2), and the yeast concentration is liquid yeast corresponding to 18% by mass in terms of dry matter. 23.4 kg of body concentrate was obtained.
- C Addition of thickener to yeast cell concentrate 23.4 kg of the above yeast cell concentrate is mixed with the thickeners of Examples 12 to 19 as a mass ratio to SAMe in the yeast concentrate.
- a 0.0-fold amount was added and stirred and mixed at room temperature for 30 minutes to obtain a yeast cell concentrate to which the thickeners of Examples 12 to 19 were added.
- (D) Production of dry yeast The yeast cell concentrate to which the thickeners of Examples 12 to 19 above were added was poured into a freeze-drying stainless steel tray of a freeze dryer (manufactured by Nippon Vacuum Technology Co., Ltd.) at -50 ° C. After freezing, it was lyophilized for 36 hours under conditions of a final shelf temperature of 25 ° C. The obtained freeze-dried yeast was further pulverized to obtain powder-dried yeast. The powder dry yeast thus obtained was packed in a sealed glass container, and a storage stability test was performed under an acceleration test condition of 40 ° C.
- Table 2 shows the results of the accelerated storage stability test at 40 ° C. and RH 75%.
- the SAMe remaining rate was measured by the above method.
- distribution condition was observed visually and evaluated.
- Table 2 summarizes the results of mixing conditions of additives, recovery rate after freeze-drying, shape, SAMe content after drying (mass%), 30 days at 40 ° C., and SAMe residual rate after 60 days.
- Comparative Example 3 Powdered dry yeast was obtained in the same manner as in Example 1 except that the culture was performed in a medium not containing L-methionine. SAMe was not contained in the obtained powder dry yeast. The following experiment was conducted using this.
- the absorptivity test was performed using the method of nonpatent literature 2 (J of Chromatography B, 863, 94-100 (2008)).
- the dose of dry yeast to rats was orally administered to rats in a state where dry yeast was dispersed in distilled water so that the dose of 300 mg / kg-rat as SAMe, and 0.5, 2,
- the blood of the rat after 3 and 5 hours was collected, and the blood was rapidly centrifuged to separate the plasma components.
- the extract of the SAMe component using perchloric acid was analyzed by high performance liquid chromatography (HPLC) with LC.
- HPLC high performance liquid chromatography
- the analysis was performed under the following conditions by -MS-MS (Liquid chromatography coupled with mass spectrometry).
- -MS-MS Liquid chromatography coupled with mass spectrometry
- LC-MS-MS Thermo Accela, LTQ orbitrap Discovery HPLC condition column: Intersil ODS-3 (4.6 mm ⁇ 150 mm) manufactured by GL Sciences Inc.
- composition of the present invention a composition containing S-adenosyl-L-methionine having excellent storage stability, and further having excellent bioabsorbability as a physiologically active substance for pharmaceuticals and health foods Can be used effectively.
- the production method of the present invention can be used as a method for easily producing a composition containing S-adenosyl-L-methionine at a high concentration and excellent in storage stability at low cost.
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Abstract
Description
(1)S-アデノシル-L-メチオニンと、増粘剤を含有するS-アデノシル-L-メチオニン含有乾燥酵母組成物、及び
(2) S-アデノシル-L-メチオニン生産能を有する酵母を用い、酵母の菌体培養液より得られる酵母菌体濃縮物に増粘剤を添加した後、乾燥するS-アデノシル-L-メチオニン含有乾燥酵母組成物の製造方法、
を提供する。
また、S-アデノシル-L-メチオニンを高濃度に含み保存安定性に優れる組成物を、さらに生体吸収性にも優れるSAMe含有乾燥酵母組成物を低コストで簡便に製造する方法を提供できる。
培地成分としては、スクロース、酵母エキス、L-メチオニン、尿素、グリシン、リン酸二水素カリウム、硫酸マグネシウム七水和物、ビオチン、塩化カルシウム二水和物、及び微量金属塩を含む培地に植菌し、スクロース又は/及びエタノール等の炭素源を流加しつつ、好気的に培養することによりSAM含有菌体を得ることができる。
培養温度及び培養液のpHは使用する酵母の種類よって異なるが、培養温度としては20~35℃の範囲を、培養液のpHとしてはpH4~7の範囲を挙げることができる。
また、菌体内のSAMe含量を高めるには、好気的に培養することが好ましい。培養槽は、通気可能で必要に応じ攪拌できるものであればよく、例えば、機械的攪拌培養槽、エアーリフト式培養槽及び気泡塔型培養槽等を利用することができる。
培地の供給方法は、炭素源、窒素源、各種無機塩類、各種添加剤等を、一括若しくは個別に連続的又は間欠的に供給する。例えば、蔗糖、エタノール等の基質は他の培地成分との混合物として培養槽に供給してもよく、また他の培地成分とは別に独立して培養槽に供給してもよい。培養液のpH制御は、酸、アルカリ溶液によって行われる。アルカリとしては窒素源として使用されるアンモニア、尿素、又は非窒素系塩基、例えば、苛性ソーダ、苛性カリ等を用いてpH制御するのが望ましい。酸としては無機酸、例えば、リン酸、硫酸、硝酸、又は有機酸が用いられる。なお、無機塩類であるリン酸塩、カリウム塩、ナトリウム塩、硝酸塩等を用いてpH制御することもできる。
具体的に使用できる増粘剤としては、(1)キサンタンガム、ジェランガム、カードラン、アルギンキサンタンガム、プルラン、及び納豆菌ガムから選択される微生物由来増粘剤、
(2)グアーガム、タラガム、ローカストビーンガム、タマリンドガム、及びサイリウムシードガムから選択される種子由来増粘剤、
(3)セルロース、メチルセルロース、ヒドロキシプロピルセルロース、ヒドロキシプロピルメチルセルロース、カルボキシメチルセルロース、デンプン、及びカルボキシメチル酸ナトリウムから選択される植物由来増粘剤、
(4)カラギーナン、アルギン酸ナトリウム、アルギン酸、及びアルギン酸プロピレングリコールエステルから選択される海藻由来増粘剤、
(5)アラビアガム、トラガントガム、シェラック、及びアラビノガラクタンから選択される樹脂由来増粘剤、
(6)キトサン、及びキチンから選択される甲殻由来増粘剤、及び
(7)ペクチン、マンナン、ヒアルロン酸、コンドロイチン、寒天、コラーゲン、アルブミン、ツェイン、カゼイン、及びカゼインナトリウム等から選ばれる増粘剤が挙げられ、これらから1種以上を選択して用いることができる。
これらのうち、(1)キサンタンガム、ジェランガム、カードラン、アルギンキサンタンガム、プルラン、及び納豆菌ガムから選択される微生物由来増粘剤、
(2)グアーガム、タラガム、ローカストビーンガム、タマリンドガム、及びサイリウムシードガムから選択される種子由来増粘剤、
(5)アラビアガム、トラガントガム、シェラック、及びアラビノガラクタンから選択される樹脂由来増粘剤、
(6)キトサン、及びキチンから選択される甲殻由来増粘剤、及び
(7)ペクチン、マンナン、ヒアルロン酸、コンドロイチン、寒天、コラーゲン、アルブミン、ツェイン、カゼイン、及びカゼインナトリウムから選ばれる増粘剤がより好ましい。
さらに、(1)キサンタンガム、ジェランガム、カードラン、アルギンキサンタンガム、プルラン、及び納豆菌ガム等の微生物由来増粘剤、及び(2)グアーガム、タラガム、ローカストビーンガム、タマリンドガム、及びサイリウムシードガム等の種子由来増粘剤が特に好ましい。
本発明で使用する増粘剤は食品、化粧品、医薬品用途で汎用されており、安全に使用することができる。
乾燥条件としては、噴霧乾燥法では、入口温度210℃以下、出口温度110℃以下にて乾燥させることが望ましい。凍結乾燥法では、最終棚温度30℃以下にて乾燥させることが望ましい。本発明のSAMe含有組成物は保存安定性の観点から、その水分含量が5.0質量%以下になるようにすることが望ましい。
また、粉体を顆粒状に造粒することや、粉体や造粒した顆粒を詰めてカプセル化することもできる。
(a)酵母菌体の培養
前述した公知の培養法に従って、L-メチオニン含有培地(Shiozaki S.,et all,J.Biotechnology,4,345-354(1986))にサッカロマイセス属に属する酵母サッカロマイセス・セレビジエIFO2346を接種し、培養温度27~29℃で好気的に通気攪拌しながら6日間培養した。その結果、菌体濃度3.5wt%,SAMe含量205mg/g-乾燥酵母の酵母菌体培養液18Lを得た。
(b)酵母菌体の集菌
上記の酵母菌体培養液18Lを連続ロータリー型遠心分離器(日立HIMAC CENTRIFUGE CR10B2)で処理し、菌濃度が乾物換算で18質量%に相当する液状の酵母菌体濃縮物3.4kgを得た。
(c)酵母菌体濃縮物への増粘剤の添加
上記の酵母菌体濃縮物3.4kgにキサンタンガムを該酵母濃縮物中のSAMeに対する質量比として0.02、0.2、2.2、11.1倍量加えて、室温にて30分間攪拌混合し、キサンタンガムを添加した酵母菌体濃縮物を得た。
(d)乾燥酵母の製造
上記のキサンタンガムを添加した酵母菌体濃縮物を凍結乾燥器(日本真空技術株式会社製)の凍結乾燥用ステンレストレーに流し込み-50℃で凍結した後、最終棚段温度25℃の条件で36時間凍結乾燥した。得られた凍結乾燥酵母をさらに粉砕することによって粉末乾燥酵母を得た。このようにして得られた粉末乾燥酵母を密閉ガラス容器中に詰め、40℃、RH75%の加速度試験条件下で保存安定性試験を行った。表1に40℃、RH75%での加速保存安定性試験結果を示した。なお、SAMe残存率は、SAMe含有乾燥酵母より過塩素酸を用いた公知の方法でSAMeを抽出し、液体クロマトグラフィーを用いた比較定量法にて実施した。保存後の臭気の有無については5名のパネラーによる官能検査にて求めた。官能検査の評価方法は、5名のパネラー全員が異臭なしとした場合を「○」、5名のうち1~2名が異臭があるとした場合を「△」、5名のうち3名以上が異臭ありとした場合を「×」とした。
本発明におけるSAMe測定法は、以下の条件の液体クロマトグラフィーを使用した。
用いられた分析条件
カラム:ナカライ(nacalai tesque) COSMOSIL 4.6φ×100mm
溶離液:0.2M KH2PO4水溶液/メタノール=95/5
流速:0.7mL/min、検出器:UV(260nm)
SAMe保持時間:約150秒
酵母菌体濃縮物にカードランを用いて、実施例1と同様に処理して、粉末乾燥酵母を得た。得られた粉末乾燥酵母中のSAMe含量、質量、及び得られたSAMe含有乾燥酵母の密閉ガラス容器中、40℃、RH75%の加速条件下での保存安定性試験の結果、官能検査の結果を表1に示す。
酵母菌体濃縮物にグアーガムを該酵母濃縮物中のSAMeに対する質量比として0.2倍量加えた以外は、実施例1と同様に処理して、粉末乾燥酵母を得た。得られた粉末乾燥酵母中のSAMe含量、質量、及び得られたSAMe含有乾燥酵母の密閉ガラス容器中、40℃、RH75%の加速条件下での保存安定性試験の結果、官能検査の結果を表1に示す。
酵母菌体濃縮物にタマリンドガムを該酵母濃縮物中のSAMeに対する質量比として0.2倍量加えた以外は、実施例1と同様に処理して、粉末乾燥酵母を得た。得られた粉末乾燥酵母中のSAMe含量、質量、及び得られたSAMe含有乾燥酵母の密閉ガラス容器中、40℃、RH75%の加速条件下での保存安定性試験の結果、官能検査の結果を表1に示す。
酵母菌体濃縮物にジェランガムを該酵母濃縮物中のSAMeに対する質量比として0.2倍量加えた以外は、実施例1と同様に処理して、粉末乾燥酵母を得た。得られた粉末乾燥酵母中のSAMe含量、質量、及び得られたSAMe含有乾燥酵母の密閉ガラス容器中、40℃、RH75%の加速条件下での保存安定性試験の結果、官能検査の結果を表1に示す。
酵母菌体濃縮物へキサンタンガムを添加しなかったこと以外は実施例1と同様に処理して、粉末乾燥酵母を得た。得られた粉末乾燥酵母中のSAMe含量、質量、得られたSAMe含有乾燥酵母の密閉ガラス容器中、40℃、RH75%の加速条件下での保存安定性試験の結果、官能検査の結果を表1に示す。
酵母菌体濃縮物にトレハロースを該酵母濃縮物中のSAMeに対する質量比として2.2倍量加えた以外は、実施例1と同様に処理して、粉末乾燥酵母を得た。得られた粉末乾燥酵母中のSAMe含量、質量、得られたSAMe含有乾燥酵母の密閉ガラス容器中、40℃、RH75%の加速条件下での保存安定性試験の結果、官能検査の結果を表1に示す。
200L培養槽を用い、固形分濃度が18.2質量%のSAMe含有酵母濃縮液(SAMe含量3.7質量%)に対する添加物の量を1質量%とし、添加物としてκ-カラギーナン(実施例12)、キサンタンガム(実施例13)、グアーガム(実施例14)、タマリンドガム(実施例15)、カードラン(実施例16)、ジェランガム(実施例17)、アルギン酸(実施例18)、セラオスST-O2(結晶セルロース)(実施例19)を添加し、凍結乾燥後の回収率、SAMe含有量(質量%)40℃で30日、60日後のSAMe残存率を測定した。
実施例12~19の詳細な実施例の条件は以下のとおりである。
(a)酵母菌体の培養
実施例1と同様の条件で培養し、菌体濃度3.5質量%、SAMe含量201.5mg/g-乾燥酵母の酵母菌体培養液120Lを得た。
(b)酵母菌体の集菌
上記の酵母菌体培養液120Lを連続ロータリー型遠心分離器(日立HIMAC CENTRIFUGE CR10B2)で処理し、菌濃度が乾物換算で18質量%に相当する液状の酵母菌体濃縮物23.4kgを得た。
(c)酵母菌体濃縮物への増粘剤の添加
上記の酵母菌体濃縮物23.4kgに上記の実施例12~19の増粘剤を該酵母濃縮物中のSAMeに対する質量比として1.0倍量加えて、室温にて30分間攪拌混合し、実施例12~19の増粘剤を添加した酵母菌体濃縮物を得た。
(d)乾燥酵母の製造
上記の実施例12~19の増粘剤を添加した酵母菌体濃縮物を凍結乾燥器(日本真空技術株式会社製)の凍結乾燥用ステンレストレーに流し込み-50℃で凍結した後、最終棚段温度25℃の条件で36時間凍結乾燥した。得られた凍結乾燥酵母をさらに粉砕することによって粉末乾燥酵母を得た。このようにして得られた粉末乾燥酵母を密閉ガラス容器中に詰め、40℃、RH75%の加速度試験条件下で保存安定性試験を行った。表2に40℃、RH75%での加速保存安定性試験の結果を示した。なお、SAMe残存率は、前記の方法で測定した。また、SAMe含有酵母濃縮液に対する添加物の混合具合については、目視により分散状況を観察して評価した。添加物の混合具合、凍結乾燥後の回収率、形状、乾燥後SAMe含有量(質量%)、40℃で30日、60日後のSAMe残存率の結果をまとめて表2に示す。
L-メチオニンを含まない培地にて培養を行った以外は、実施例1と同様に処理して、粉末乾燥酵母を得た。得られた粉末乾燥酵母中にはSAMeは含有されていなかった。これを用いて以下の実験を行った。
実施例2、6、9、10、11、比較例1、及び比較例3で得られた乾燥酵母について、文献記載の方法(非特許文献2)と同様にSD系ラット(雄 8週齢、動物数:各群n=3)を用いて、生体吸収性試験を性能評価の試験例1~5、比較性能試験の評価例1,2として行った。
吸収性試験は、非特許文献2(J of Chromatography B,863,94-100(2008))の方法を用いて行った。ラットへの乾燥酵母の投与量は、SAMeとして300mg/kg-ラットの投与量になる様に乾燥酵母を蒸留水へ分散した状態でラットに経口投与を行い、経口投与後0.5、2、3、5時間後のラットの血液を採取し、血液は速やかに遠心分離により血漿成分の分離を行い、過塩素酸を用いたSAMe成分の抽出物を、高速液体クロマトグラフィー(HPLC)で、LC-MS-MS法(Liquid chromatography coupled with mass spectrometry)により下記の条件で分析した。その結果、各乾燥酵母ともに経口投与2時間後血漿中SAMe濃度が最も高かった。各乾燥酵母の経口投与2時間後生体吸収性試験の結果を表3に示す。表3より、いずれの試験例も、増粘剤を添加した乾燥酵母の生体吸収性が、評価例1として示す添加処理を行っていない比較例1の乾燥酵母による場合よりも向上することが確認された。
LC-MS-MS法
LC-MS-MS装置:Thermo社製 Accela、LTQ orbitrap Discovery
HPLC条件
カラム:ジーエルサイエンス社製 Intersil ODS-3(4.6mm×150mm)
流速:0.5mL/min、カラムオーブン:40℃、検出器:UV(260nm)、SAMe保持時間:約145秒、注入量:10μL
溶離液: 2 mmol/Lヘプタフルオロ酪酸水溶液:アセトニトリル=30:70
MS条件
Ion Source:ESI
Ion Polarity Mode: Positive
Scan Mode Type:FTフルマス
Resolution:30000
Mass Range:m/z 360-410
本発明の製造方法は、S-アデノシル-L-メチオニンを高濃度に含み、保存安定性に優れる組成物を、低コストで簡便に製造する方法として利用できる。
Claims (7)
- S-アデノシル-L-メチオニンと、増粘剤を含有するS-アデノシル-L-メチオニン含有乾燥酵母組成物。
- 前記増粘剤が、下記の(1)~(7)のいずれかから選ばれる少なくとも1種である請求項1に記載のS-アデノシル-L-メチオニン含有乾燥酵母組成物。
(1)キサンタンガム、ジェランガム、カードラン、アルギンキサンタンガム、プルラン、及び納豆菌ガムから選択される微生物由来増粘剤、
(2)グアーガム、タラガム、ローカストビーンガム、タマリンドガム、及びサイリウムシードガムから選択される種子由来増粘剤、
(3)セルロース、メチルセルロース、ヒドロキシプロピルセルロース、ヒドロキシプロピルメチルセルロース、カルボキシメチルセルロース、デンプン、及びカルボキシメチル酸ナトリウムから選択される植物由来増粘剤、
(4)カラギーナン、アルギン酸ナトリウム、アルギン酸、及びアルギン酸プロピレングリコールエステルから選択される海藻由来増粘剤、
(5)アラビアガム、トラガントガム、シェラック、及びアラビノガラクタンから選択さ れる樹脂由来増粘剤、
(6)キトサン、及びキチンから選択される甲殻由来増粘剤、及び
(7)ペクチン、マンナン、ヒアルロン酸、コンドロイチン、寒天、コラーゲン、アルブミン、ツェイン、カゼイン、及びカゼインナトリウムから選ばれる増粘剤 - 前記増粘剤が、下記の(1)、(2)及び(5)~(7)のいずれかから選ばれる少なくとも1種である請求項2に記載のS-アデノシル-L-メチオニン含有乾燥酵母組成物。
(1)キサンタンガム、ジェランガム、カードラン、アルギンキサンタンガム、プルラン、及び納豆菌ガムから選択される微生物由来増粘剤、
(2)グアーガム、タラガム、ローカストビーンガム、タマリンドガム、及びサイリウムシードガムから選択される種子由来増粘剤、
(5)アラビアガム、トラガントガム、シェラック、及びアラビノガラクタンから選択される樹脂由来増粘剤、
(6)キトサン、及びキチンから選択される甲殻由来増粘剤、及び
(7)ペクチン、マンナン、ヒアルロン酸、コンドロイチン、寒天、コラーゲン、アルブミン、ツェイン、カゼイン、及びカゼインナトリウムから選ばれる増粘剤 - 前記増粘剤が、S-アデノシル-L-メチオニン含有乾燥酵母組成物に対して0.1~70質量%含まれてなる請求項1~3のいずれかに記載のS-アデノシル-L-メチオニン含有乾燥酵母組成物。
- 乾燥酵母が、サッカロマイセス属に属する酵母である、請求項1~4のいずれかに記載のS-アデノシル-L-メチオニン含有乾燥酵母組成物。
- 前記サッカロマイセス属に属する酵母がサッカロマイセス・セレビジエである、請求項5に記載のS-アデノシル-L-メチオニン含有乾燥酵母組成物。
- S-アデノシル-L-メチオニン生産能を有する酵母を用い、酵母の菌体培養液より得られる酵母菌体濃縮物に増粘剤を添加した後、乾燥する、ことを特徴とするS-アデノシル-L-メチオニン含有乾燥酵母組成物の製造方法。
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CN108060194A (zh) * | 2017-12-23 | 2018-05-22 | 青岛麦迪尔生物工程有限公司 | 一种通过发酵虾蟹壳制备抗氧化多肽和甲壳素的方法 |
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Also Published As
Publication number | Publication date |
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AU2011236907A1 (en) | 2012-11-01 |
AU2011236907B2 (en) | 2015-04-02 |
EP3214167A1 (en) | 2017-09-06 |
CN102858950A (zh) | 2013-01-02 |
US9404076B2 (en) | 2016-08-02 |
EP2557151A4 (en) | 2014-02-19 |
EP2557151A1 (en) | 2013-02-13 |
RU2579972C2 (ru) | 2016-04-10 |
RU2012142647A (ru) | 2014-05-20 |
KR20130079997A (ko) | 2013-07-11 |
JPWO2011126030A1 (ja) | 2013-07-11 |
TW201202416A (en) | 2012-01-16 |
US20130028878A1 (en) | 2013-01-31 |
TWI513816B (zh) | 2015-12-21 |
CA2795539A1 (en) | 2011-10-13 |
EP2557151B1 (en) | 2017-10-04 |
DK2557151T3 (en) | 2017-12-11 |
JP5974891B2 (ja) | 2016-08-23 |
NO2557151T3 (ja) | 2018-03-03 |
KR101800773B1 (ko) | 2017-11-23 |
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