WO2013080265A1 - Stabilization of s-adenosylmethionine with acid sodium metaphosphate - Google Patents
Stabilization of s-adenosylmethionine with acid sodium metaphosphate Download PDFInfo
- Publication number
- WO2013080265A1 WO2013080265A1 PCT/JP2011/006780 JP2011006780W WO2013080265A1 WO 2013080265 A1 WO2013080265 A1 WO 2013080265A1 JP 2011006780 W JP2011006780 W JP 2011006780W WO 2013080265 A1 WO2013080265 A1 WO 2013080265A1
- Authority
- WO
- WIPO (PCT)
- Prior art keywords
- adenosylmethionine
- sodium metaphosphate
- present
- acidic sodium
- concentration
- Prior art date
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- MOMKYJPSVWEWPM-UHFFFAOYSA-N 4-(chloromethyl)-2-(4-methylphenyl)-1,3-thiazole Chemical compound C1=CC(C)=CC=C1C1=NC(CCl)=CS1 MOMKYJPSVWEWPM-UHFFFAOYSA-N 0.000 title claims abstract description 117
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Classifications
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- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/185—Acids; Anhydrides, halides or salts thereof, e.g. sulfur acids, imidic, hydrazonic or hydroximic acids
- A61K31/19—Carboxylic acids, e.g. valproic acid
- A61K31/195—Carboxylic acids, e.g. valproic acid having an amino group
- A61K31/197—Carboxylic acids, e.g. valproic acid having an amino group the amino and the carboxyl groups being attached to the same acyclic carbon chain, e.g. gamma-aminobutyric acid [GABA], beta-alanine, epsilon-aminocaproic acid or pantothenic acid
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- A—HUMAN NECESSITIES
- A23—FOODS OR FOODSTUFFS; TREATMENT THEREOF, NOT COVERED BY OTHER CLASSES
- A23L—FOODS, FOODSTUFFS, OR NON-ALCOHOLIC BEVERAGES, NOT COVERED BY SUBCLASSES A21D OR A23B-A23J; THEIR PREPARATION OR TREATMENT, e.g. COOKING, MODIFICATION OF NUTRITIVE QUALITIES, PHYSICAL TREATMENT; PRESERVATION OF FOODS OR FOODSTUFFS, IN GENERAL
- A23L33/00—Modifying nutritive qualities of foods; Dietetic products; Preparation or treatment thereof
- A23L33/10—Modifying nutritive qualities of foods; Dietetic products; Preparation or treatment thereof using additives
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- A—HUMAN NECESSITIES
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- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
- A61K47/02—Inorganic compounds
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- A—HUMAN NECESSITIES
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- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
- A61P1/16—Drugs for disorders of the alimentary tract or the digestive system for liver or gallbladder disorders, e.g. hepatoprotective agents, cholagogues, litholytics
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- A61P19/02—Drugs for skeletal disorders for joint disorders, e.g. arthritis, arthrosis
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- A—HUMAN NECESSITIES
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- A—HUMAN NECESSITIES
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- A—HUMAN NECESSITIES
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- A61P25/00—Drugs for disorders of the nervous system
- A61P25/28—Drugs for disorders of the nervous system for treating neurodegenerative disorders of the central nervous system, e.g. nootropic agents, cognition enhancers, drugs for treating Alzheimer's disease or other forms of dementia
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- A61P31/12—Antivirals
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Definitions
- the present invention relates to stabilization of S-adenosylmethionine with acidic sodium metaphosphate.
- the present invention particularly relates to a edible composition comprising S-adenosylmethionine and acidic sodium metaphosphate.
- the invention also relates to a process for the production of stabilized S-adenosylmethionine.
- S-adenosylmethionine is present throughout the body and is a physiologically involved in many biological reactions as a methyl group donor or enzyme activator in the synthesis and metabolism of hormones, neurotransmitters, phospholipids, and proteins.
- a compound. S-adenosylmethionine is metabolized by three metabolic pathways: methyl group transfer, sulfur group transfer, and aminopropyl group transfer.
- S-adenosylmethionine has been reported to have useful effects on liver disorders such as cirrhosis, depression, arthritis, osteoarthritis, cartilage protection, Alzheimer's disease, peripheral neuropathy caused by HIV infection, or myelopathy. ing.
- Patent Document 1 stabilization with polyanions (for example, sodium hexametaphosphate)
- Patent Document 2 stabilization with phosphate compounds
- Patent Document 3 S-adenosylmethionine salts such as sulfate and p-toluenesulfonate Is suspended in an alcohol solvent
- Patent Document 4 S-adenosylmethionine salts such as sulfate and p-toluenesulfonate Is suspended in an alcohol solvent
- Patent Document 4 stabilized by an organic carboxylic acid and / or a compound having a chelate-forming ability
- Patent Document 5 has been reported.
- the inventors have unexpectedly discovered that by using acidic sodium metaphosphate, significant stabilization of S-adenosylmethionine can be achieved compared to the previously known stabilization by sodium metaphosphate.
- the present invention has been completed. It has not been known in the past that superior stabilization of S-adenosylmethionine is achieved by using acidic sodium metaphosphate compared to using sodium metaphosphate. Furthermore, as described in Examples 1 and 2 below, when sodium metaphosphate was used for stabilizing S-adenosylmethionine under acidic conditions, no significant stabilizing effect was observed. Considering these facts, it is unexpected that a remarkable stabilization effect can be obtained by using acidic sodium metaphosphate instead of sodium metaphosphate.
- the present invention provides a food-drinking composition comprising S-adenosylmethionine and acidic sodium metaphosphate.
- the composition of the present invention contains the acidic sodium metaphosphate at a concentration of 2.5 times or more the S-adenosylmethionine.
- composition of the present invention contains the acidic sodium metaphosphate at a concentration of 2.5 to 10 times that of the S-adenosylmethionine.
- composition of the present invention contains the acidic sodium metaphosphate at a concentration of 2.5 to 7.5 times that of the S-adenosylmethionine.
- composition of the present invention contains the acidic sodium metaphosphate at a concentration of 5 to 7.5 times the S-adenosylmethionine.
- the present invention provides a pharmaceutical composition comprising S-adenosylmethionine and sodium acid metaphosphate.
- the pharmaceutical composition of the present invention contains the acidic sodium metaphosphate at a concentration of 2.5 times or more the S-adenosylmethionine.
- the pharmaceutical composition of the present invention contains the acidic sodium metaphosphate at a concentration of 2.5 to 10 times that of the S-adenosylmethionine.
- the pharmaceutical composition of the present invention contains the acidic sodium metaphosphate at a concentration of 2.5 to 7.5 times that of the S-adenosylmethionine.
- the pharmaceutical composition of the present invention comprises the acidic sodium metaphosphate at a concentration of 5 to 7.5 times the amount of the S-adenosylmethionine.
- the pharmaceutical composition of the present invention is for the treatment of depression or arthritis.
- the present invention provides a method for producing a stable S-adenosylmethionine, which comprises a step of adding sodium acid metaphosphate to a composition containing the S-adenosylmethionine. provide.
- the acidic sodium metaphosphate is added at a concentration of 2.5 times or more the S-adenosylmethionine.
- the acidic sodium metaphosphate is added at a concentration of 2.5 to 10 times that of the S-adenosylmethionine.
- the acidic sodium metaphosphate is added at a concentration of 2.5 to 7.5 times that of the S-adenosylmethionine.
- the acidic sodium metaphosphate is added at a concentration of 5 to 7.5 times the S-adenosylmethionine.
- the production method of the present invention further includes a step of drying a mixture containing the S-adenosylmethionine and the acidic sodium metaphosphate.
- the present invention provides a method for stabilizing S-adenosylmethionine comprising the step of adding sodium acid metaphosphate to a composition comprising the S-adenosylmethionine.
- the acidic sodium metaphosphate is added at a concentration of 2.5 times or more the S-adenosylmethionine.
- the acidic sodium metaphosphate is added at a concentration of 2.5 to 10 times that of the S-adenosylmethionine.
- the acidic sodium metaphosphate is added at a concentration of 2.5 to 7.5 times that of the S-adenosylmethionine.
- the acidic sodium metaphosphate is added at a concentration of 5 to 7.5 times the S-adenosylmethionine.
- a new method for stabilizing S-adenosylmethionine is provided.
- S-adenosylmethionine having an excellent effect as a health food, a pharmaceutical composition, a dietary supplement or the like can be supplied to consumers in a more stable state.
- FIG. 1 shows sodium pyrophosphate, sodium polyphosphate, sodium metaphosphate, sodium pyrophosphate under acidic conditions, sodium polyphosphate under acidic conditions, and sodium metaphosphate under acidic conditions as stabilizers.
- -A graph showing the residual rate (%) of S-adenosylmethionine with respect to the number of days in an accelerated tester when added to adenosylmethionine.
- the vertical axis represents the residual rate (%) of S-adenosylmethionine
- the horizontal axis represents the number of days (days) in the acceleration tester.
- FIG. 2 shows in an accelerated test machine when 10-fold, 7.5-fold, 5-fold and 2.5-fold sodium sodium metaphosphate was added to S-adenosylmethionine as a stabilizer, respectively.
- Is a graph showing the residual rate (%) of S-adenosylmethionine against the number of days.
- the vertical axis represents the residual rate (%) of S-adenosylmethionine, and the horizontal axis represents the number of days (days) in the acceleration tester.
- FIG. 3 shows “A. Sodium acidic hexametaphosphate manufactured by Rin Kagaku Co., Ltd. (Toyama, Japan)”, “B. New Fcillin Sun F manufactured by F.C. Chemicals Co., Ltd.
- FIG. 4 shows the acidity of “A. Phosphorus Chemical Industry Co., Ltd. (Toyama, Japan), acid sodium hexametaphosphate, lot (11.05.21)”, “B. Phosphorus Chemical Industry Co., Ltd. (Toyama, Japan).
- the present invention provides a food-drinking composition and a pharmaceutical composition comprising S-adenosylmethionine and acidic sodium metaphosphate.
- acidic sodium metaphosphate it has not been conventionally known that excellent stabilization of S-adenosylmethionine is achieved as compared with the case where sodium metaphosphate is used.
- sodium metaphosphate when sodium metaphosphate was used for stabilizing S-adenosylmethionine under acidic conditions, no significant stabilizing effect was observed. Considering these facts, it is unexpected that a remarkable stabilization effect can be obtained by using acidic sodium metaphosphate instead of sodium metaphosphate.
- S-adenosylmethionine is a substance having an average molecular weight of 399.447, also referred to as “AdoMet”.
- the chemical formula of S-adenosylmethionine is as follows.
- acidic sodium metaphosphate is also referred to as acidic sodium hexametaphosphate, which is a polymer acidic condensed phosphorus obtained by melting a reaction product of phosphoric acid and less than an equimolar alkali and dehydrating and condensing it.
- An acid salt mixture having the general formula ⁇ Na x H y (PO 3 ) x + y ⁇ n (x is an arbitrary number of 1 or more, y is an arbitrary number of 1 or more, and n is an arbitrary number of 2 or more The pH of which is 2.2 or less.
- the acidic sodium metaphosphate in the present invention include, but are not limited to, acidic sodium metaphosphate for food additives, acidic sodium metaphosphate for quasi-drug raw materials, and / or industrial acidic sodium metaphosphate.
- the pH of acidic sodium metaphosphate refers to the pH in a 1 w / v% solution of acidic sodium metaphosphate.
- the pH measurement can be performed by any method known in the art.
- the acidic sodium metaphosphate of the present invention can be defined as follows.
- -Property This product is a white fibrous crystal or powder or a piece or lump on a non-white glass.
- -Confirmation test (1) This product exhibits a sodium salt reaction.
- the “concentration of X-fold amount of S-adenosylmethionine” refers to the concentration (w / v) of S-adenosylmethionine in a composition. , Meaning that the concentration (w / v) of that particular substance is X times.
- “containing acidic sodium metaphosphate at a concentration 5 times that of S-adenosylmethionine” means that acidic sodium metaphosphate is 5 times the concentration (w / v) of S-adenosylmethionine. In the composition (w / v).
- the “degree of polymerization” of acidic sodium metaphosphate refers to the average degree of polymerization (number average degree of polymerization) per molecule of acidic sodium metaphosphate.
- stabilization of S-adenosylmethionine refers to an effect of suppressing the degradation of unstable S-adenosylmethionine. More specifically, “stabilization” of S-adenosylmethionine in the present specification means that the residual amount of S-adenosylmethionine is significantly increased after a certain period of time as compared to untreated one. Say.
- a composition for eating and drinking refers to a composition used for eating and drinking, and examples thereof include, but are not limited to, health foods, dietary supplements, and supplements.
- the edible composition of the present invention refers to any product containing stabilized S-adenosylmethionine.
- the composition for eating and drinking according to the present invention typically contains S-adenosylmethionine for liver disorders such as cirrhosis, depression, arthritis, osteoarthritis, cartilage protection, Alzheimer's disease, peripheral neuropathy caused by HIV infection, myelopathy and the like. Displayed useful effects for sale.
- the food and drink composition of the present invention may be a food and drink supplement.
- the “health food” or “nutritional supplement” refers to a food containing a component necessary for the body, or a component useful for maintenance / promotion of health and having a physiological function.
- this component is S-adenosylmethionine, but other examples include vitamins, minerals, amino acids, coenzyme Q10, L-carnitine, brewer's yeast, ginseng extract and the like.
- the terms “nutritional supplement” and “health food” are used interchangeably and are not particularly strictly distinguished.
- the “food supplement” refers to any substance that can be added to any food and drink and that can impart favorable characteristics to the food or drink.
- the food and drink supplement of the present invention refers to any product containing stabilized S-adenosylmethionine.
- Preferred properties of the food and drink supplement of the present invention include, for example, effects on liver disorders such as cirrhosis, depression, arthritis, osteoarthritis, cartilage protection, Alzheimer's disease, peripheral neuropathy caused by HIV infection, or myelopathy. However, it is not limited to these.
- the composition of the present invention has a longer period of time (eg, 1 month, 2 months, 3 months, 4 months, 5 months, 6 months, compared to a composition comprising conventional S-adenosylmethionine.
- a composition comprising conventional S-adenosylmethionine about 60% or more, about 65% or more, about 70% or more, about 75% or more, about 80% or more, about 85% of S-adenosylmethionine immediately after preparation. More than about 90%, about 95% or more, or about 100% of S-adenosylmethionine.
- the composition of the present invention comprises about 80% or more of S-adenosylmethionine as prepared immediately after about 30 days in an accelerated tester, preferably about 40% in an accelerated tester.
- the composition of the present invention may be a powder obtained by drying a mixture containing S-adenosylmethionine and sodium acid metaphosphate. This drying can be performed, for example, by freeze drying or spray drying. For example, drying in the present invention can be accomplished by lyophilization for about 3 days or longer. Drying in the present invention can also be accomplished by spray drying until the desired amount of pulverization is achieved at an inlet temperature of 120-230 ° C and an outlet temperature of 100 ° C-70 ° C.
- composition for eating and drinking of the present invention has a useful effect on liver disorders such as cirrhosis, depression, arthritis, osteoarthritis, cartilage protection, Alzheimer's disease, peripheral neuropathy caused by HIV infection or myelopathy. Can do.
- the composition for eating and drinking of the present invention can be a food and drink supplement.
- the composition of the present invention may be a composition for eating and drinking (including nutritional supplements and health foods).
- the food and drink composition of the present invention includes health foods (specific health foods, functional nutrition foods), nutritional supplements (supplements), food additives, food supplements, and the like.
- the food and beverage composition of the present invention is a powder obtained by drying a mixture of S-adenosylmethionine and acidic sodium metaphosphate.
- the edible composition of the present invention may contain a yeast that produces S-adenosylmethionine.
- the powdered food and beverage composition of the present invention may be ingested by being added to other foods as a food additive or food supplement, or the powdered food and beverage composition of the present invention itself is a health food or It may be taken alone as a dietary supplement (supplement) or the like.
- composition of the present invention may be processed into pellets, tablets, granules, etc. together with excipients such as dextrin, lactose, starch and the like, fragrances, pigments, etc., as necessary, and coated with gelatin or the like to be processed into capsules. May be.
- excipients such as dextrin, lactose, starch and the like, fragrances, pigments, etc., as necessary, and coated with gelatin or the like to be processed into capsules. May be.
- the compositions of the present invention are particularly suitable for use as health foods or dietary supplements.
- the edible composition of the present invention comprises about 3 g or more S-adenosylmethionine per 100 g.
- the amount of S-adenosylmethionine in the composition for eating and drinking according to the present invention is difficult to define uniformly depending on the type and condition of the food, but the S-adenosylmethionine content is 10 to 5000 mg / meal, preferably 100 to 1000 mg / meal, about 10 to 100% (preferably 30 to 100%, more preferably 50 to 100%, even more preferably 80 to 100%) in the case of supplements, beverages or general foods Etc., it may be about 0.01% or less.
- composition for eating and drinking of the present invention is blended with excipients or additives usually used in foods, tablets, tablets, pills, granules, powders, powders, capsules, wettable powders, emulsions, liquids. , Extract, or elixir.
- Common excipients used in food include syrup, gum arabic, sucrose, lactose, powdered reduced maltose, cellulose sugar, mannitol, maltitol, dextran, starches, gelatin, sorbit, tragacanth, polyvinylpyrrolidone Agents; sucrose fatty acid esters, glycerin fatty acid esters, magnesium stearate, calcium stearate, talc, polyethylene glycol, etc .; disintegrants such as potato starch; wetting agents such as sodium lauryl sulfate.
- additives include fragrances, buffers, thickeners, colorants, stabilizers, emulsifiers, dispersants, suspending agents, preservatives, and the like.
- composition of the present invention may be a pharmaceutical composition (including veterinary drugs).
- the pharmaceutical preparation of the composition of the present invention may be an oral administration preparation or a parenteral administration preparation.
- the pharmaceutical composition of the present invention may be a solid preparation or a liquid preparation.
- compositions of the present invention comprises about 3 g or more of S-adenosylmethionine per 100 g.
- a solid preparation can be prepared by blending a pharmaceutically acceptable carrier or additive with the active ingredient S-adenosylmethionine of the present invention and sodium acid metaphosphate.
- a pharmaceutically acceptable carrier or additive such as sucrose, lactose, glucose, starch, mannitol; binders such as gum arabic, gelatin, crystalline cellulose, hydroxypropylcellulose, methylcellulose; disintegrants such as carmellose, starch; anhydrous citric acid Stabilizers such as sodium laurate, glycerol, and the like can be formulated for the formulation of the pharmaceutical composition of the present invention.
- the pharmaceutical composition of the present invention may be coated or encapsulated with gelatin, sucrose, gum arabic, carnauba wax and the like.
- the liquid preparation can be prepared by, for example, dissolving or dispersing the active ingredient S-adenosylmethionine of the present invention and acidic sodium metaphosphate in water, ethanol, glycerin, syrup, or a mixture thereof.
- the pharmaceutical composition of the present invention may further contain additives such as sweeteners, preservatives, demulcents, lubricants, diluents, buffers, or coloring agents.
- parenteral preparation can be any parenteral preparation known to those skilled in the art.
- parenteral preparations for the pharmaceutical composition of the present invention include, but are not limited to, creams, sprays, gels, ointments, salves and the like.
- Pharmaceutical compositions comprising S-adenosylmethionine of the present invention and acidic sodium metaphosphate can also be injected directly into bandages, gauze, or patches (eg, soaked and dried), which are then topically applied. Can be applied.
- the effective amount and method of administration of the pharmaceutical composition of the present invention can vary depending on the method of administration, the condition being treated and the severity of the condition being treated.
- the ordinary physician or veterinarian can readily determine the effective amount and method of administration of the pharmaceutical composition of the present invention.
- Sodium metaphosphate is a general term for a condensed phosphate obtained by melting an equimolar reaction product of phosphoric acid (for example, P 2 O 5 ) and an alkali (for example, caustic soda or sodium carbonate) at a high temperature and subjecting it to dehydration condensation. In terms of molecular structure, it is not a single substance but a mixture of neutral condensed phosphates containing cyclic structures and long-chain structures.
- acidic sodium metaphosphate is obtained by melting a reaction product of phosphoric acid (for example, P 2 O 5 ) and less than an equivalent amount of alkali (for example, caustic soda or sodium carbonate) and dehydrating and condensing it. It is a mixture of acidic condensed phosphates of macromolecules, and different compositions can be obtained depending on the production conditions such as the molar ratio of raw materials and reaction temperature. It is characterized in that it contains a network that is not found in sex metaphosphate.
- Both the sodium metaphosphate and acidic sodium metaphosphate can be produced by changing the charging ratio of phosphoric acid (for example, P 2 O 5 ) and alkali (for example, caustic soda or sodium carbonate), Such manufacturing methods are well known to those skilled in the art.
- Both sodium metaphosphate and acidic sodium metaphosphate are food additives used as water retention agents or sequestering agents. Acidic sodium metaphosphate is often used when it is desired to make the final product more acidic, but no other difference in use and effectiveness in these two additives has been known.
- acidic sodium metaphosphate is represented by the formula: ⁇ Na x H y (PO 3 ) x + y ⁇ n (x is an arbitrary number of 1 or more, y is an arbitrary number of 1 or more, and n is It is an arbitrary number of 2 or more).
- the pH of the acidic sodium metaphosphate used in the present invention is 2.2 or less.
- the acidic sodium metaphosphate used in the present invention is represented by the formula: ⁇ Na x H y (PO 3 ) x + y ⁇ n , where x and y are each a pH of acidic sodium metaphosphate. The number is 2.2 or less.
- the number average polymerization degree of acidic sodium metaphosphate used in the present invention is an arbitrary number of 2 or more, more preferably 10 to 300, still more preferably 10 to 23, typically Is 14.
- Acidic sodium metaphosphate is manufactured and sold by a number of manufacturers.
- Commercially available acidic sodium metaphosphates include sodium acidic hexametaphosphate manufactured by Phosphorus Chemical Co., Ltd. (Toyama, Japan), New Fcillin Sun F manufactured by FC Chemical Co., Ltd. (Osaka, Japan), Organo Food Tech Co., Ltd. Polylin Sun 1-G manufactured by (Saitama, Japan), Muscorin F-2 manufactured by Taiyo Chemical Co., Ltd. (Tokyo, Japan), Ultraporin manufactured by Taihei Chemical Industrial Co., Ltd. (Osaka, Japan), Ueno Pharmaceutical Co., Ltd. ( Examples include, but are not limited to, Tallinsan U (registered trademark) manufactured by Osaka, Japan and Ultrapolyphos manufactured by Polyphos Chemical Laboratory Co., Ltd. (Osaka, Japan).
- S-adenosylmethionine alleviates liver damage (eg, reduces mortality due to cirrhosis) (eg, Lieber CS. Role of S-adenosyl-L-methionine in the treatment of liver diseases. J Hepatol). 1999; 30: 1155-9; Williams R, Lieber CS. The role of SAMe in the treatment of liver disease. Drugs 1990; 40 (suppl): 1-2, Mato JM, eJaF.
- S-Adenylosyllineine in alcoholic liver cirrhosis a random Ized, placebo-controlled, double-blind, multicenter clinical trial. See J Hepatol 1999; 30: 1081-9, etc.), have a therapeutic effect on depression (eg, Janicak PG, M , Et al.S-Adenosylmethionine: a literature review and premier report report.Ala J Med Sci 1988; 25: 306-13; in liv . Er dysfunction and affective disorders in relation to its physiological role in cell metabolism Drugs 1989; 38:..
- depression typically refers to psychotic depression.
- the composition of the present invention is produced by culturing yeast having the ability to produce S-adenosylmethionine, producing S-adenosylmethionine, and adding acidic sodium metaphosphate to the yeast culture medium. Is done.
- This yeast is preferably the yeast Saccharomyces cerevisiae K-7 strain (Sake Yeast Association No. 7).
- the addition of acidic sodium metaphosphate to the yeast culture medium may be performed during the culture of the yeast or may be performed after the culture.
- the culture solution is removed to obtain a yeast cell concentrate, and sodium metaphosphate is added to the concentrate.
- This yeast cell concentrate is obtained by centrifuging the culture (for example, 8,000 rpm), removing the supernatant, collecting the cells, and adding an appropriate amount of the supernatant removed to the collected cells, It can be prepared by preparing a bacterial cell concentrate.
- the composition of the present invention purifies S-adenosylmethionine produced by or produced in yeast as described above and against the purified S-adenosylmethionine.
- it can also be produced by adding acidic sodium metaphosphate to chemically synthesized S-adenosylmethionine.
- Methods for purifying S-adenosylmethionine are well known in the art. Purification of S-adenosylmethionine in the present invention can be accomplished by any method that increases the concentration of S-adenosylmethionine.
- the purification of S-adenosylmethionine in the present invention is achieved by concentrating and crystallizing an extract obtained by freezing and thawing yeast cells that produced S-adenosylmethionine. obtain.
- Concentration of the S-adenosylmethionine extract can be performed by methods well known to those skilled in the art that can achieve enrichment of S-adenosylmethionine. Examples of the concentration method include, but are not limited to, a combination of adsorption by a synthetic resin or cation exchange resin and concentration by reverse dialysis.
- Adsorbents that can be used for concentration of S-adenosylmethionine include, but are not limited to, synthetic resins (eg, synthetic resin Sepabeads SP-200 (Mitsubishi Chemical Corporation, Tokyo, Japan)).
- synthetic resins eg, synthetic resin Sepabeads SP-200 (Mitsubishi Chemical Corporation, Tokyo, Japan)
- ion exchange resins that can be used for the concentration of S-adenosylmethionine include weakly acidic cation exchange resins (for example, Amberlite IRC-50 (Organo Corporation, Tokyo, Japan)). It is not limited.
- Reverse dialysis for concentration of S-adenosylmethionine includes dialysis using a reverse osmosis membrane (for example, reverse osmosis Reverse Osmosis (RO): product name Romenbra (Toray Industries, Inc., Tokyo, Japan)). It is not limited to this. Crystallization of the S-adenosylmethionine concentrate can be performed by using, for example, an acetone-methanol solvent, but is not limited thereto.
- RO reverse osmosis Reverse Osmosis
- the mixture after adding acidic sodium metaphosphate to a concentrate containing yeast that produced S-adenosylmethionine, may be dried.
- the drying method include, but are not limited to, freeze drying, spray drying, and reduced pressure drying.
- freeze-drying is preferred.
- the mixture can be dried at ⁇ 80 ° C. overnight and lyophilized for 72 h.
- the carbon source used when 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, etc.
- the organic acid is mentioned.
- the nitrogen source is not particularly limited as long as the yeast to be used can assimilate, and includes, for example, 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 can be used.
- methionine, adenine, and adenosylribonucleoside constituting the skeleton of S-adenosylmethionine can be added and cultured.
- the cultivation of S-adenosylmethionine-producing yeast in the present invention can be carried out under either anaerobic conditions or aerobic conditions, but aerobic conditions are preferred in order to efficiently grow yeast cells.
- the culture temperature of the S-adenosylmethionine-producing yeast in the present invention is an arbitrary temperature within the range in which the yeast can grow, but is preferably cultured in the range of 15 to 40 ° C, more preferably in the range of 25 to 35 ° C. .
- the pH during the culture of the S-adenosylmethionine-producing yeast in the present invention is an arbitrary pH within the range in which the yeast can grow, but the culture in the range of pH 3.5 to 8.0 is preferable, and pH 4.0 to A range of 6.5 is more preferred.
- the culture method and culture conditions for S-adenosylmethionine-producing yeast in the present invention can be appropriately determined by those skilled in the art according to general yeast culture methods or culture conditions.
- the yeast is a 5 L jar fermenter (feed medium amount: 3 L), the culture temperature is 28 ° C., the stirring speed is 500 rpm, the culture time is 36-48 h, the aeration rate is 0.5 VVM, the medium composition (w / 100 mL): cultured under conditions of 5% glucose, 0.75% yeast extract, 2.0% peptone, and 0.15% methionine.
- Example 1 Examination of stabilization effect of various phosphate compounds and influence of acid treatment
- Example 2 Examination of stabilization effect of various phosphate compounds and influence of acid treatment
- the stabilizing effect of sodium polyphosphate and sodium metaphosphate which have been conventionally known to stabilize S-adenosylmethionine, was confirmed.
- yeast Saccharomyces cerevisiae K-7 strain (Sake Yeast Association No. 7), 5 L jar fermenter (feeding medium amount: 3 L), culture temperature 28 ° C., stirring speed 500 rpm, culture time 36-48 h, aeration rate 0. 5 VVM, medium composition (w / 100 mL): cultured with glucose 5%, yeast extract 0.75%, peptone 2.0%, methionine 0.15%. The culture was centrifuged (8,000 rpm), the supernatant was removed, and the cells were collected. An appropriate amount of the supernatant liquid removed from the recovered cells was added to prepare a cell concentrate.
- the concentration of S-adenosylmethionine in the concentrate was measured and sodium pyrophosphate (Na 4 P 2 O 7 : tetrasodium pyrophosphate (crystal / anhydrous) manufactured by Taiyo Chemical Co., Ltd., Tokyo, Japan), polyphosphorus Sodium phosphate (Na 5 P 3 O 10 : sodium tripolyphosphate manufactured by Taiyo Chemical Co., Ltd., Tokyo, Japan) and sodium metaphosphate ((NaPO 3 ) n : Taiyo Chemical Co., Ltd. (Tokyo, Japan) Sodium hexametaphosphate) was added to the cell concentrate so as to be 4 times the amount of S-adenosylmethionine.
- sodium pyrophosphate Na 4 P 2 O 7 : tetrasodium pyrophosphate (crystal / anhydrous) manufactured by Taiyo Chemical Co., Ltd., Tokyo, Japan
- polyphosphorus Sodium phosphate Na 5 P 3
- the prepared sample was frozen at ⁇ 80 ° C. overnight. Lyophilization was performed for 72 hours to prepare yeast powder.
- the yeast powder was packed in an aluminum pouch and stored in an acceleration tester (Advantec, model THE051FA) (40 ° C., humidity 75%).
- One day storage of the accelerated testing machine under these conditions corresponds to six days of room temperature storage.
- Yeast powder was sampled regularly and S-adenosylmethionine was extracted using perchloric acid. Specifically, 1 mL of 10% perchloric acid was added to 0.02 g of yeast powder, extraction was performed for 1 hour, and the supernatant (extract) was collected by centrifugation (10,000 rpm, 10 minutes).
- composition containing the above S-adenosylmethionine and sodium pyrophosphate, sodium polyphosphate, or sodium metaphosphate exhibits alkalinity.
- stabilization of S-adenosylmethionine with sodium pyrophosphate, sodium polyphosphate, or sodium metaphosphate was carried out under acidic conditions. We verified the degree of.
- the acid treatment was performed by adding various phosphoric acid compounds in 4 times the amount of S-adenosylmethionine and then adjusting the pH to 1 with 78% sulfuric acid.
- yeast Saccharomyces cerevisiae K-7 strain (Sake Yeast Association No. 7), a 5 L jar fermenter (feeding medium amount: 3 L), a culture temperature of 28 ° C., a stirring speed of 500 rpm, and a culture time of 36 to 48 h.
- Aeration rate 0.5 VVM, medium composition (w / 100 mL): Glucose 5%, yeast extract 0.75%, peptone 2.0%, methionine 0.15%.
- the culture was centrifuged (8,000 rpm), the supernatant was removed, and the cells were collected. An appropriate amount of the supernatant liquid removed from the recovered cells was added to prepare a cell concentrate.
- the concentration of S-adenosylmethionine in the concentrate was measured and sodium pyrophosphate (Na 4 P 2 O 7 : tetrasodium pyrophosphate (crystal / anhydrous) manufactured by Taiyo Chemical Co., Ltd., Tokyo, Japan), polyphosphorus Sodium phosphate (Na 5 P 3 O 10 : sodium tripolyphosphate manufactured by Taiyo Chemical Co., Ltd., Tokyo, Japan) and sodium metaphosphate ((NaPO 3 ) n : Taiyo Chemical Industries, Ltd. (Tokyo, Japan) Sodium hexametaphosphate) was added to the cell concentrate so as to be 4 times the amount of S-adenosylmethionine.
- sodium pyrophosphate Na 4 P 2 O 7 : tetrasodium pyrophosphate (crystal / anhydrous) manufactured by Taiyo Chemical Co., Ltd., Tokyo, Japan
- polyphosphorus Sodium phosphate Na 5 P 3 O
- sodium pyrophosphate, sodium polyphosphate, and sodium metaphosphate provide a certain stabilizing effect compared to no addition, but they are insufficient and due to these substances under acidic conditions It was demonstrated that no significant improvement in stability was observed with stabilization.
- yeast Saccharomyces cerevisiae K-7 strain (Sake Yeast Association No. 7), 5 L jar fermenter (feeding medium amount: 3 L), culture temperature 28 ° C., stirring speed 500 rpm, culture time 36-48 h, aeration rate 0. 5 VVM, medium composition (w / 100 mL): cultured with glucose 5%, yeast extract 0.75%, peptone 2.0%, methionine 0.15%. The culture was centrifuged (8,000 rpm), the supernatant was removed, and the cells were collected. An appropriate amount of the supernatant liquid removed from the recovered cells was added to prepare a cell concentrate.
- the concentration of S-adenosylmethionine in the concentrate was measured, and sodium acid metaphosphate ( ⁇ Na x H y (PO 3 ) x + y ⁇ n (acid sodium hexametaphosphate manufactured by Rin Chemical Industry Co., Ltd., Toyama, Japan)) , S-adenosylmethionine 2.5 times, 5 times, 7.5 times, and 10 times the amount were added to the cell concentrate.
- the yeast powder was packed in an aluminum pouch and stored in an accelerated tester (Advantec, model THE051FA) (40 ° C., 75% humidity).
- One day storage of the accelerated test machine under these conditions corresponds to 6 days of storage at room temperature, sampling yeast powder on a regular basis, and extracting S-adenosylmethionine using perchloric acid. Specifically, 1 mL of 10% perchloric acid was added to 0.02 g of yeast powder, extraction was performed for 1 hour, and the supernatant (extract) was collected by centrifugation (10,000 rpm, 10 minutes). For the measurement of S-adenosylmethionine, UPLC (Waters, model TUV) was used, and the extract was analyzed by a gradient of 0.1% formic acid + 5 mM sodium nonanesulfonate and acetonitrile, and the results are shown in Table 3 below. The results are shown in Fig. 2. Note that the results are shown as relative values, with the value at the time of preparation of each sample being 100%.
- Example 3 S-adenosylmethionine stabilization effect by various acidic sodium metaphosphate products
- the difference in S-adenosylmethionine stabilization effect was examined for various acidic sodium metaphosphate products from different manufacturers.
- yeast Saccharomyces cerevisiae K-7 strain (Sake Yeast Association No. 7), 5 L jar fermenter (feeding medium amount: 3 L), culture temperature 28 ° C., stirring speed 500 rpm, culture time 36-48 h, aeration rate 0. 5 VVM, medium composition (w / 100 mL): cultured with glucose 5%, yeast extract 0.75%, peptone 2.0%, methionine 0.15%. The culture was centrifuged (8,000 rpm), the supernatant was removed, and the cells were collected. An appropriate amount of the supernatant liquid removed from the recovered cells was added to prepare a cell concentrate.
- the concentration of S-adenosylmethionine in the concentrate was measured, and sodium acid hexametaphosphate manufactured by Phosphorus Chemical Industries, Ltd. (Toyama, Japan), New Fcillin Sun F, Organofood manufactured by FC Chemical Co., Ltd. (Osaka, Japan) Polyrinsan 1-G manufactured by Tech Co., Ltd. (Saitama, Japan), Muscorin F-2 manufactured by Taiyo Chemical Co., Ltd. (Tokyo, Japan), Ultraporin manufactured by Taihei Chemical Industrial Co., Ltd. (Osaka, Japan), Ueno Pharmaceutical Tallinsan U (registered trademark) manufactured by Osaka Co., Ltd.
- This yeast powder was packed in an aluminum pouch and stored in an accelerated tester (Advantec, model THE051FA) (40 ° C., humidity 75%).
- One day storage of the accelerated testing machine under these conditions corresponds to six days of room temperature storage.
- Yeast powder was sampled regularly and S-adenosylmethionine was extracted using perchloric acid. Specifically, 1 mL of 10% perchloric acid was added to 0.02 g of yeast powder, extraction was performed for 1 hour, and the supernatant (extract) was collected by centrifugation (10,000 rpm, 10 minutes).
- Example 4 Difference in S-adenosylmethionine stabilizing effect between lots of acidic sodium metaphosphate product
- the difference in S-adenosylmethionine stabilizing effect between lots of acidic sodium metaphosphate products was examined.
- yeast Saccharomyces cerevisiae K-7 strain (Sake Yeast Association No. 7), 5 L jar fermenter (feeding medium amount: 3 L), culture temperature 28 ° C., stirring speed 500 rpm, culture time 36-48 h, aeration rate 0. 5 VVM, medium composition (w / 100 mL): cultured with glucose 5%, yeast extract 0.75%, peptone 2.0%, methionine 0.15%. The culture was centrifuged (8,000 rpm), the supernatant was removed, and the cells were collected. An appropriate amount of the supernatant liquid removed from the recovered cells was added to prepare a cell concentrate.
- the concentration of S-adenosylmethionine in the concentrate was measured, and the acid sodium sodium metametaphosphate, lot “11.05.21” or “11.08.21” manufactured by Rin Kagaku Kogyo Co., Ltd. (Toyama, Japan)
- the lotin “1” or “2” of Mascoline F-2 manufactured by Chemical Industry Co., Ltd. (Tokyo, Japan) was added to the cell concentrate so as to be 4 times the amount of S-adenosylmethionine.
- Four prepared samples were frozen overnight at -80 ° C. Lyophilization was performed for 72 hours to prepare yeast powder. This yeast powder was packed in an aluminum pouch and stored in an accelerated tester (Advantec, model THE051FA) (40 ° C., humidity 75%).
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Abstract
A novel method for the stabilization of S-adenosylmethionine is provided. The present invention provides a composition to eat or drink, said composition containing both S-adenosylmethionine and acid sodium metaphosphate. The present invention also provides a process for preparing stable S-adenosylmethionine, said process including a step of adding acid sodium metaphosphate to a composition that contains S-adenosylmethionine. The present invention further provides a method for the stabilization of S-adenosylmethionine, said method including a step of adding acid sodium metaphosphate to a composition that contains S-adenosylmethionine.
Description
本発明は、酸性メタリン酸ナトリウムによるＳ－アデノシルメチオニンの安定化に関する。本発明は特に、Ｓ－アデノシルメチオニンと酸性メタリン酸ナトリウムとを含む飲食用組成物に関する。本発明はまた、安定化されたＳ－アデノシルメチオニンの製造方法に関する。
The present invention relates to stabilization of S-adenosylmethionine with acidic sodium metaphosphate. The present invention particularly relates to a edible composition comprising S-adenosylmethionine and acidic sodium metaphosphate. The invention also relates to a process for the production of stabilized S-adenosylmethionine.
Ｓ－アデノシルメチオニンは生体組織全体に存在し、ホルモン、神経伝達物質、リン脂質、およびタンパク質の合成および代謝における、メチル基供与体または酵素活性化因子として、数多くの生物反応に関与する生理学的化合物である。Ｓ－アデノシルメチオニンは、メチル基転移、硫黄基転移、およびアミノプロピル基転移の３つの代謝経路により代謝される。
S-adenosylmethionine is present throughout the body and is a physiologically involved in many biological reactions as a methyl group donor or enzyme activator in the synthesis and metabolism of hormones, neurotransmitters, phospholipids, and proteins. A compound. S-adenosylmethionine is metabolized by three metabolic pathways: methyl group transfer, sulfur group transfer, and aminopropyl group transfer.
Ｓ－アデノシルメチオニンは、肝硬変などの肝障害、鬱病、関節炎、骨関節症、軟骨保護、アルツハイマー病、ＨＩＶ感染による末梢神経障害または脊髄症等に対して、有用な効果を有することが報告されている。
S-adenosylmethionine has been reported to have useful effects on liver disorders such as cirrhosis, depression, arthritis, osteoarthritis, cartilage protection, Alzheimer's disease, peripheral neuropathy caused by HIV infection, or myelopathy. ing.
しかしながら、Ｓ－アデノシルメチオニンは化学的に不安定な物質であり、常温においても急速に分解が進むため、医薬品やサプリメントとして使用する際の大きな障害となっている。これまでに、ポリアニオン（例えば、ヘキサメタリン酸ナトリウム）による安定化（特許文献１）、リン酸化合物による安定化（特許文献２）、硫酸塩やｐ－トルエンスルホン酸塩などのＳ－アデノシルメチオニン塩をアルコール溶媒中に懸濁することによる安定化（特許文献３）、および、有機カルボン酸および／またはキレート形成能を有する化合物による安定化（特許文献４）、フィチン酸およびシクロデキストリンによる安定化（特許文献５）などが報告されている。
However, since S-adenosylmethionine is a chemically unstable substance and rapidly decomposes even at room temperature, it is a major obstacle when used as a pharmaceutical or a supplement. Up to now, stabilization with polyanions (for example, sodium hexametaphosphate) (Patent Document 1), stabilization with phosphate compounds (Patent Document 2), S-adenosylmethionine salts such as sulfate and p-toluenesulfonate Is suspended in an alcohol solvent (Patent Document 3), and is stabilized by an organic carboxylic acid and / or a compound having a chelate-forming ability (Patent Document 4), stabilized by phytic acid and cyclodextrin ( Patent document 5) has been reported.
本発明者らは、酸性メタリン酸ナトリウムを用いることにより、従来知られていたメタリン酸ナトリウムによる安定化と比べて、Ｓ－アデノシルメチオニンの顕著な安定化が達成されることを予想外に発見し、本発明を完成させた。酸性メタリン酸ナトリウムを用いることによってメタリン酸ナトリウムを用いる場合と比較してＳ－アデノシルメチオニンの優れた安定化が達成されることは従来知られていなかった。さらに、以下の実施例１および２に記載されるように、酸性条件下でメタリン酸ナトリウムをＳ－アデノシルメチオニンの安定化に用いた場合には、顕著な安定化効果は見られなかった。これらのことを考慮すると、メタリン酸ナトリウムの代わりに酸性メタリン酸ナトリウムを用いることにより顕著な安定化効果が得られることは予想外である。
The inventors have unexpectedly discovered that by using acidic sodium metaphosphate, significant stabilization of S-adenosylmethionine can be achieved compared to the previously known stabilization by sodium metaphosphate. The present invention has been completed. It has not been known in the past that superior stabilization of S-adenosylmethionine is achieved by using acidic sodium metaphosphate compared to using sodium metaphosphate. Furthermore, as described in Examples 1 and 2 below, when sodium metaphosphate was used for stabilizing S-adenosylmethionine under acidic conditions, no significant stabilizing effect was observed. Considering these facts, it is unexpected that a remarkable stabilization effect can be obtained by using acidic sodium metaphosphate instead of sodium metaphosphate.
１つの局面において、本発明は、Ｓ－アデノシルメチオニンと酸性メタリン酸ナトリウムとを含む、飲食用組成物を提供する。
In one aspect, the present invention provides a food-drinking composition comprising S-adenosylmethionine and acidic sodium metaphosphate.
１つの実施形態において、本発明の組成物は、上記酸性メタリン酸ナトリウムを、上記Ｓ－アデノシルメチオニンの２．５倍量以上の濃度で含む。
In one embodiment, the composition of the present invention contains the acidic sodium metaphosphate at a concentration of 2.5 times or more the S-adenosylmethionine.
別の実施形態において、本発明の組成物は、上記酸性メタリン酸ナトリウムを、上記Ｓ－アデノシルメチオニンの２．５倍量～１０倍量の濃度で含む。
In another embodiment, the composition of the present invention contains the acidic sodium metaphosphate at a concentration of 2.5 to 10 times that of the S-adenosylmethionine.
別の実施形態において、本発明の組成物は、上記酸性メタリン酸ナトリウムを、上記Ｓ－アデノシルメチオニンの２．５倍量～７．５倍量の濃度で含む。
In another embodiment, the composition of the present invention contains the acidic sodium metaphosphate at a concentration of 2.5 to 7.5 times that of the S-adenosylmethionine.
別の実施形態において、本発明の組成物は、上記酸性メタリン酸ナトリウムを、上記Ｓ－アデノシルメチオニンの５～７．５倍量の濃度で含む。
In another embodiment, the composition of the present invention contains the acidic sodium metaphosphate at a concentration of 5 to 7.5 times the S-adenosylmethionine.
別の局面において、本発明は、Ｓ－アデノシルメチオニンと酸性メタリン酸ナトリウムとを含む、医薬組成物を提供する。
In another aspect, the present invention provides a pharmaceutical composition comprising S-adenosylmethionine and sodium acid metaphosphate.
１つの実施形態において、本発明の医薬組成物は、上記酸性メタリン酸ナトリウムを、上記Ｓ－アデノシルメチオニンの２．５倍量以上の濃度で含む。
In one embodiment, the pharmaceutical composition of the present invention contains the acidic sodium metaphosphate at a concentration of 2.5 times or more the S-adenosylmethionine.
別の実施形態において、本発明の医薬組成物は、上記酸性メタリン酸ナトリウムを、上記Ｓ－アデノシルメチオニンの２．５倍量～１０倍量の濃度で含む。
In another embodiment, the pharmaceutical composition of the present invention contains the acidic sodium metaphosphate at a concentration of 2.5 to 10 times that of the S-adenosylmethionine.
別の実施形態において、本発明の医薬組成物は、上記酸性メタリン酸ナトリウムを、上記Ｓ－アデノシルメチオニンの２．５倍量～７．５倍量の濃度で含む。
In another embodiment, the pharmaceutical composition of the present invention contains the acidic sodium metaphosphate at a concentration of 2.5 to 7.5 times that of the S-adenosylmethionine.
別の実施形態において、本発明の医薬組成物は、上記酸性メタリン酸ナトリウムを、上記Ｓ－アデノシルメチオニンの５～７．５倍量の濃度で含む。
In another embodiment, the pharmaceutical composition of the present invention comprises the acidic sodium metaphosphate at a concentration of 5 to 7.5 times the amount of the S-adenosylmethionine.
別の実施形態において、本発明の医薬組成物は、鬱病または関節炎の治療のためのものである。
In another embodiment, the pharmaceutical composition of the present invention is for the treatment of depression or arthritis.
別の局面において、本発明は、安定なＳ－アデノシルメチオニンの製造方法であって、該Ｓ－アデノシルメチオニンを含む組成物に、酸性メタリン酸ナトリウムを添加する工程を包含する、製造方法を提供する。
In another aspect, the present invention provides a method for producing a stable S-adenosylmethionine, which comprises a step of adding sodium acid metaphosphate to a composition containing the S-adenosylmethionine. provide.
１つの実施形態において、上記方法において、上記酸性メタリン酸ナトリウムは、上記Ｓ－アデノシルメチオニンの２．５倍量以上の濃度で添加される。
In one embodiment, in the above method, the acidic sodium metaphosphate is added at a concentration of 2.5 times or more the S-adenosylmethionine.
別の実施形態において、上記方法において、上記酸性メタリン酸ナトリウムは、上記Ｓ－アデノシルメチオニンの２．５倍量～１０倍量の濃度で添加される。
In another embodiment, in the above method, the acidic sodium metaphosphate is added at a concentration of 2.5 to 10 times that of the S-adenosylmethionine.
別の実施形態において、上記方法において、上記酸性メタリン酸ナトリウムは、上記Ｓ－アデノシルメチオニンの２．５倍量～７．５倍量の濃度で添加される。
In another embodiment, in the above method, the acidic sodium metaphosphate is added at a concentration of 2.5 to 7.5 times that of the S-adenosylmethionine.
別の実施形態において、上記方法において、上記酸性メタリン酸ナトリウムは、上記Ｓ－アデノシルメチオニンの５～７．５倍量の濃度で添加される。
In another embodiment, in the above method, the acidic sodium metaphosphate is added at a concentration of 5 to 7.5 times the S-adenosylmethionine.
別の実施形態において、本発明の製造方法は、上記Ｓ－アデノシルメチオニンと上記酸性メタリン酸ナトリウムとを含む混合物を乾燥する工程をさらに包含する。
In another embodiment, the production method of the present invention further includes a step of drying a mixture containing the S-adenosylmethionine and the acidic sodium metaphosphate.
別の局面において、本発明は、Ｓ－アデノシルメチオニンの安定化法であって、該Ｓ－アデノシルメチオニンを含む組成物に、酸性メタリン酸ナトリウムを添加する工程を包含する、方法を提供する。
In another aspect, the present invention provides a method for stabilizing S-adenosylmethionine comprising the step of adding sodium acid metaphosphate to a composition comprising the S-adenosylmethionine. .
１つの実施形態において、上記方法において、上記酸性メタリン酸ナトリウムは、上記Ｓ－アデノシルメチオニンの２．５倍量以上の濃度で添加される。
In one embodiment, in the above method, the acidic sodium metaphosphate is added at a concentration of 2.5 times or more the S-adenosylmethionine.
別の実施形態において、上記方法において、上記酸性メタリン酸ナトリウムは、上記Ｓ－アデノシルメチオニンの２．５倍量～１０倍量の濃度で添加される。
In another embodiment, in the above method, the acidic sodium metaphosphate is added at a concentration of 2.5 to 10 times that of the S-adenosylmethionine.
別の実施形態において、上記方法において、上記酸性メタリン酸ナトリウムは、上記Ｓ－アデノシルメチオニンの２．５倍量～７．５倍量の濃度で添加される。
In another embodiment, in the above method, the acidic sodium metaphosphate is added at a concentration of 2.5 to 7.5 times that of the S-adenosylmethionine.
別の実施形態において、上記方法において、上記酸性メタリン酸ナトリウムは、上記Ｓ－アデノシルメチオニンの５～７．５倍量の濃度で添加される。
In another embodiment, in the above method, the acidic sodium metaphosphate is added at a concentration of 5 to 7.5 times the S-adenosylmethionine.
Ｓ－アデノシルメチオニンの新規安定化法が提供される。本発明により、健康食品、医薬組成物、栄養補助食品等として優れた効能を有するＳ－アデノシルメチオニンを、より安定な状態で消費者に供給することが可能になる。
A new method for stabilizing S-adenosylmethionine is provided. According to the present invention, S-adenosylmethionine having an excellent effect as a health food, a pharmaceutical composition, a dietary supplement or the like can be supplied to consumers in a more stable state.
以下に本発明を、必要に応じて、添付の図面を参照して例示の実施例により説明する。本明細書の全体にわたり、単数形の表現は、特に言及しない限り、その複数形の概念をも含むことが理解されるべきである。また、本明細書において使用される用語は、特に言及しない限り、当該分野で通常用いられる意味で用いられることが理解されるべきである。したがって、他に定義されない限り、本明細書中で使用される全ての専門用語および科学技術用語は、本発明の属する分野の当業者によって一般的に理解されるのと同じ意味を有する。矛盾する場合、本明細書（定義を含めて）が優先する。
Hereinafter, the present invention will be described by way of example with reference to the accompanying drawings as necessary. Throughout this specification, it should be understood that the singular forms also include the plural concept unless specifically stated otherwise. In addition, it is to be understood that the terms used in the present specification are used in the meaning normally used in the art unless otherwise specified. Thus, unless defined otherwise, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this invention belongs. In case of conflict, the present specification, including definitions, will control.
以下に提供される実施形態は、本発明のよりよい理解のために提供されるものであり、本発明の範囲は以下の記載に限定されるべきではない。本明細書中の記載を参酌して、本発明の範囲内で適宜改変を行なうことができることは、当業者に明らかである。
The embodiments provided below are provided for a better understanding of the present invention, and the scope of the present invention should not be limited to the following description. It will be apparent to those skilled in the art that appropriate modifications can be made within the scope of the present invention with reference to the description in the present specification.
本発明は、Ｓ－アデノシルメチオニンと酸性メタリン酸ナトリウムとを含む、飲食用組成物、および医薬組成物を提供する。酸性メタリン酸ナトリウムを用いる場合、メタリン酸ナトリウムを用いる場合と比較して、Ｓ－アデノシルメチオニンの優れた安定化が達成されることは従来知られていなかった。さらに、以下の実施例１および２に記載されるように、酸性条件下でメタリン酸ナトリウムをＳ－アデノシルメチオニンの安定化に用いた場合には、顕著な安定化効果は見られなかった。これらのことを考慮すると、メタリン酸ナトリウムの代わりに酸性メタリン酸ナトリウムを用いることにより顕著な安定化効果が得られることは予想外である。
The present invention provides a food-drinking composition and a pharmaceutical composition comprising S-adenosylmethionine and acidic sodium metaphosphate. In the case where acidic sodium metaphosphate is used, it has not been conventionally known that excellent stabilization of S-adenosylmethionine is achieved as compared with the case where sodium metaphosphate is used. Furthermore, as described in Examples 1 and 2 below, when sodium metaphosphate was used for stabilizing S-adenosylmethionine under acidic conditions, no significant stabilizing effect was observed. Considering these facts, it is unexpected that a remarkable stabilization effect can be obtained by using acidic sodium metaphosphate instead of sodium metaphosphate.
（定義）
本明細書において、「Ｓ－アデノシルメチオニン」とは「ＡｄｏＭｅｔ」とも表記される平均分子量３９９．４４７の物質である。Ｓ－アデノシルメチオニンの化学式は、以下の通りである。 (Definition)
In the present specification, “S-adenosylmethionine” is a substance having an average molecular weight of 399.447, also referred to as “AdoMet”. The chemical formula of S-adenosylmethionine is as follows.
本明細書において、「Ｓ－アデノシルメチオニン」とは「ＡｄｏＭｅｔ」とも表記される平均分子量３９９．４４７の物質である。Ｓ－アデノシルメチオニンの化学式は、以下の通りである。 (Definition)
In the present specification, “S-adenosylmethionine” is a substance having an average molecular weight of 399.447, also referred to as “AdoMet”. The chemical formula of S-adenosylmethionine is as follows.
本明細書において、「酸性メタリン酸ナトリウム」とは、酸性ヘキサメタリン酸ナトリウムともいわれ、リン酸と当モル未満のアルカリとの反応生成物を熔融し、脱水縮合して得られる高分子の酸性縮合リン酸塩混合物であって、一般式｛ＮａｘＨｙ（ＰＯ３）ｘ＋ｙ｝ｎ（ｘは１以上の任意の数であり、ｙは１以上の任意の数であり、ｎは２以上の任意の数である）を有する、ｐＨが２．２以下のものをいう。本発明における酸性メタリン酸ナトリウムは、食品添加物用酸性メタリン酸ナトリウム、医薬部外品原料用酸性メタリン酸ナトリウム、および／または工業用酸性メタリン酸ナトリウムが挙げられるが、これらに限定されない。
In the present specification, “acidic sodium metaphosphate” is also referred to as acidic sodium hexametaphosphate, which is a polymer acidic condensed phosphorus obtained by melting a reaction product of phosphoric acid and less than an equimolar alkali and dehydrating and condensing it. An acid salt mixture having the general formula {Na x H y (PO 3 ) x + y } n (x is an arbitrary number of 1 or more, y is an arbitrary number of 1 or more, and n is an arbitrary number of 2 or more The pH of which is 2.2 or less. Examples of the acidic sodium metaphosphate in the present invention include, but are not limited to, acidic sodium metaphosphate for food additives, acidic sodium metaphosphate for quasi-drug raw materials, and / or industrial acidic sodium metaphosphate.
本明細書において、酸性メタリン酸ナトリウムのｐＨとは、酸性メタリン酸ナトリウムの１ｗ／ｖ％溶液でのｐＨをいう。ｐＨ測定は、当該分野において周知の任意の方法によって行われ得る。
In this specification, the pH of acidic sodium metaphosphate refers to the pH in a 1 w / v% solution of acidic sodium metaphosphate. The pH measurement can be performed by any method known in the art.
本発明の酸性メタリン酸ナトリウムは、以下のように規定され得る。
・含量：本品（酸性メタリン酸ナトリウム）を乾燥したものは、五酸化リン（Ｐ２Ｏ５＝１４１．９４）として６０．０％～８３．０％を含む。
・性状：本品は、白色の繊維状の結晶もしくは粉末または無～白色のガラス上の片もしくは塊である。
・確認試験
（１）本品は、ナトリウム塩の反応を呈する。
・純度試験
（１）液状 無色、わずかに微濁（粉末１．０ｇ、水２０ｍｌ）
（２）塩化物 Ｃｌとして０．２１％以下（粉末０．１０ｇ、比較液０．０１Ｎ塩酸０．６０ｍｌ）
（３）正リン酸塩 本品の粉末１．０ｇを量り、硝酸銀溶液（１→５０）２～３滴を加えるとき、著しい黄色を呈さない。なお、「１→５０」とは、硝酸銀溶液（０．１ｍｏｌ/Ｌ）１ｍＬを５０ｍＬに希釈することを意味する。
（４）硫酸塩ＳＯ４として０．０４８％以下。
（５）重金属 Ｐｂとして２０μｇ以下。
（６）ヒ素Ａｓ２Ｏ３として４．０μｇ／ｇ以下。
・乾燥減量 ５．０％以下。 The acidic sodium metaphosphate of the present invention can be defined as follows.
-Content: The dried product (sodium acid metaphosphate) contains 60.0% to 83.0% as phosphorus pentoxide (P 2 O 5 = 141.94).
-Property: This product is a white fibrous crystal or powder or a piece or lump on a non-white glass.
-Confirmation test (1) This product exhibits a sodium salt reaction.
・ Purity test (1) Liquid colorless, slightly turbid (powder 1.0 g,water 20 ml)
(2) Chloride Less than 0.21% as Cl (powder 0.10 g, comparative solution 0.01 N hydrochloric acid 0.60 ml)
(3) Regular phosphate When 1.0g of the powder of this product is weighed and 2-3 drops of silver nitrate solution (1 → 50) is added, it does not show a remarkable yellow color. “1 → 50” means that 1 mL of a silver nitrate solution (0.1 mol / L) is diluted to 50 mL.
(4) less 0.048% as the sulphate SO 4.
(5) Heavy metal Pb is 20 μg or less.
(6) Arsenic As 2 O 3 is 4.0 μg / g or less.
-Loss on drying 5.0% or less.
・含量：本品（酸性メタリン酸ナトリウム）を乾燥したものは、五酸化リン（Ｐ２Ｏ５＝１４１．９４）として６０．０％～８３．０％を含む。
・性状：本品は、白色の繊維状の結晶もしくは粉末または無～白色のガラス上の片もしくは塊である。
・確認試験
（１）本品は、ナトリウム塩の反応を呈する。
・純度試験
（１）液状 無色、わずかに微濁（粉末１．０ｇ、水２０ｍｌ）
（２）塩化物 Ｃｌとして０．２１％以下（粉末０．１０ｇ、比較液０．０１Ｎ塩酸０．６０ｍｌ）
（３）正リン酸塩 本品の粉末１．０ｇを量り、硝酸銀溶液（１→５０）２～３滴を加えるとき、著しい黄色を呈さない。なお、「１→５０」とは、硝酸銀溶液（０．１ｍｏｌ/Ｌ）１ｍＬを５０ｍＬに希釈することを意味する。
（４）硫酸塩ＳＯ４として０．０４８％以下。
（５）重金属 Ｐｂとして２０μｇ以下。
（６）ヒ素Ａｓ２Ｏ３として４．０μｇ／ｇ以下。
・乾燥減量 ５．０％以下。 The acidic sodium metaphosphate of the present invention can be defined as follows.
-Content: The dried product (sodium acid metaphosphate) contains 60.0% to 83.0% as phosphorus pentoxide (P 2 O 5 = 141.94).
-Property: This product is a white fibrous crystal or powder or a piece or lump on a non-white glass.
-Confirmation test (1) This product exhibits a sodium salt reaction.
・ Purity test (1) Liquid colorless, slightly turbid (powder 1.0 g,
(2) Chloride Less than 0.21% as Cl (powder 0.10 g, comparative solution 0.01 N hydrochloric acid 0.60 ml)
(3) Regular phosphate When 1.0g of the powder of this product is weighed and 2-3 drops of silver nitrate solution (1 → 50) is added, it does not show a remarkable yellow color. “1 → 50” means that 1 mL of a silver nitrate solution (0.1 mol / L) is diluted to 50 mL.
(4) less 0.048% as the sulphate SO 4.
(5) Heavy metal Pb is 20 μg or less.
(6) Arsenic As 2 O 3 is 4.0 μg / g or less.
-Loss on drying 5.0% or less.
上記規格は、食品添加物公定書第８版における、メタリン酸ナトリウムの項において規定されている。
The above standards are defined in the section of sodium metaphosphate in the 8th edition of the Food Additives Official Document.
本明細書においてある特定の物質の濃度を示す場合、「Ｓ－アデノシルメチオニンのＸ倍量の濃度」とは、ある組成物中のＳ－アデノシルメチオニンの濃度（ｗ／ｖ）に対して、その特定の物質の濃度（ｗ／ｖ）がＸ倍であることを意味する。例えば、ある組成物において「酸性メタリン酸ナトリウムをＳ－アデノシルメチオニンの５倍量の濃度で含む」という場合、酸性メタリン酸ナトリウムは、Ｓ－アデノシルメチオニンの濃度（ｗ／ｖ）の５倍の濃度（ｗ／ｖ）でその組成物中に含まれる。
In the present specification, when the concentration of a specific substance is indicated, the “concentration of X-fold amount of S-adenosylmethionine” refers to the concentration (w / v) of S-adenosylmethionine in a composition. , Meaning that the concentration (w / v) of that particular substance is X times. For example, in a certain composition, “containing acidic sodium metaphosphate at a concentration 5 times that of S-adenosylmethionine” means that acidic sodium metaphosphate is 5 times the concentration (w / v) of S-adenosylmethionine. In the composition (w / v).
本明細書において、酸性メタリン酸ナトリウムの「重合度」とは、酸性メタリン酸ナトリウムの１分子当たりの平均重合度（数平均重合度）をいう。
In the present specification, the “degree of polymerization” of acidic sodium metaphosphate refers to the average degree of polymerization (number average degree of polymerization) per molecule of acidic sodium metaphosphate.
本明細書において、Ｓ－アデノシルメチオニンの「安定化」とは、不安定であるＳ－アデノシルメチオニンの分解を抑制する効果をいう。より具体的には、本明細書におけるＳ－アデノシルメチオニンの「安定化」とは、一定時間経過後に未処理のものと比較してＳ－アデノシルメチオニンの残存量が有意に増加することをいう。
In this specification, “stabilization” of S-adenosylmethionine refers to an effect of suppressing the degradation of unstable S-adenosylmethionine. More specifically, “stabilization” of S-adenosylmethionine in the present specification means that the residual amount of S-adenosylmethionine is significantly increased after a certain period of time as compared to untreated one. Say.
本明細書において、「飲食用組成物」とは、飲食に供される組成物をいい、例えば、健康食品、栄養補助食品またはサプリメントが挙げられるが、これらに限定されない。本発明の飲食用組成物は、安定化されたＳ－アデノシルメチオニンを含む任意の製品をいう。本発明の飲食用組成物は、代表的に、肝硬変などの肝障害、鬱病、関節炎、骨関節症、軟骨保護、アルツハイマー病、ＨＩＶ感染による末梢神経障害または脊髄症等に対する、Ｓ－アデノシルメチオニンの有用な効果を表示して販売される。本発明の飲食用組成物は、飲食用補填物であってもよい。
In this specification, “a composition for eating and drinking” refers to a composition used for eating and drinking, and examples thereof include, but are not limited to, health foods, dietary supplements, and supplements. The edible composition of the present invention refers to any product containing stabilized S-adenosylmethionine. The composition for eating and drinking according to the present invention typically contains S-adenosylmethionine for liver disorders such as cirrhosis, depression, arthritis, osteoarthritis, cartilage protection, Alzheimer's disease, peripheral neuropathy caused by HIV infection, myelopathy and the like. Displayed useful effects for sale. The food and drink composition of the present invention may be a food and drink supplement.
本発明における「健康食品」または「栄養補助食品」とは、身体に必要な栄養となる成分、または健康の維持・増進に役立つ成分であって、生理機能を有する成分を含有する食品をいう。本発明においては、この成分はＳ－アデノシルメチオニンであるが、他の例としては、例えば、ビタミン、ミネラル、アミノ酸、コエンザイムＱ１０、Ｌ－カルニチン、ビール酵母や朝鮮人参エキス等が挙げられる。本発明において「栄養補助食品」と「健康食品」の用語は交換可能に使用され、特に厳密に区別されるものではない。
In the present invention, the “health food” or “nutritional supplement” refers to a food containing a component necessary for the body, or a component useful for maintenance / promotion of health and having a physiological function. In the present invention, this component is S-adenosylmethionine, but other examples include vitamins, minerals, amino acids, coenzyme Q10, L-carnitine, brewer's yeast, ginseng extract and the like. In the present invention, the terms “nutritional supplement” and “health food” are used interchangeably and are not particularly strictly distinguished.
本明細書において、「飲食用補填物」とは、任意の飲食物に添加され、この飲食物に好ましい特性を付与し得る任意の物質をいう。本発明の飲食用補填物は、安定化されたＳ－アデノシルメチオニンを含む任意の製品をいう。本発明の飲食用補填物における好ましい特性としては、例えば、肝硬変などの肝障害、鬱病、関節炎、骨関節症、軟骨保護、アルツハイマー病、ＨＩＶ感染による末梢神経障害または脊髄症等に対する効果が挙げられるが、これらに限定されない。
In the present specification, the “food supplement” refers to any substance that can be added to any food and drink and that can impart favorable characteristics to the food or drink. The food and drink supplement of the present invention refers to any product containing stabilized S-adenosylmethionine. Preferred properties of the food and drink supplement of the present invention include, for example, effects on liver disorders such as cirrhosis, depression, arthritis, osteoarthritis, cartilage protection, Alzheimer's disease, peripheral neuropathy caused by HIV infection, or myelopathy. However, it is not limited to these.
（好ましい実施形態の説明）
以下に好ましい実施形態の説明を記載するが、この実施形態は本発明の例示であり、本発明の範囲はそのような好ましい実施形態に限定されないことが理解されるべきである。当業者はまた、以下のような好ましい実施例を参考にして、本発明の範囲内にある改変、変更などを容易に行うことができることが理解されるべきである。 (Description of Preferred Embodiment)
The description of the preferred embodiment is described below, but it should be understood that this embodiment is an illustration of the present invention and that the scope of the present invention is not limited to such a preferred embodiment. It should be understood that those skilled in the art can easily make modifications, changes and the like within the scope of the present invention with reference to the following preferred embodiments.
以下に好ましい実施形態の説明を記載するが、この実施形態は本発明の例示であり、本発明の範囲はそのような好ましい実施形態に限定されないことが理解されるべきである。当業者はまた、以下のような好ましい実施例を参考にして、本発明の範囲内にある改変、変更などを容易に行うことができることが理解されるべきである。 (Description of Preferred Embodiment)
The description of the preferred embodiment is described below, but it should be understood that this embodiment is an illustration of the present invention and that the scope of the present invention is not limited to such a preferred embodiment. It should be understood that those skilled in the art can easily make modifications, changes and the like within the scope of the present invention with reference to the following preferred embodiments.
本発明の組成物は、従来のＳ－アデノシルメチオニンを含む組成物と比較して、長期間（例えば、１ヶ月間、２ヶ月間、３ヶ月間、４ヶ月間、５ヶ月間、６ヶ月間、１年間、またはそれ以上）経過した後に、調製直後のＳ－アデノシルメチオニンの約６０％以上、約６５％以上、約７０％以上、約７５％以上、約８０％以上、約８５％以上、約９０％以上、約９５％以上、または約１００％のＳ－アデノシルメチオニンを含む。好ましい実施形態において、本発明の組成物は、加速試験機内で約３０日後に調製直後のＳ－アデノシルメチオニンの約８０％以上のＳ－アデノシルメチオニンを含み、好ましくは加速試験機内で約４０日後に調製直後のＳ－アデノシルメチオニンの約８０％以上のＳ－アデノシルメチオニンを含み、より好ましくは加速試験機内で約６０日後に調製直後のＳ－アデノシルメチオニンの約８０％以上のＳ－アデノシルメチオニンを含む。
The composition of the present invention has a longer period of time (eg, 1 month, 2 months, 3 months, 4 months, 5 months, 6 months, compared to a composition comprising conventional S-adenosylmethionine. About 60% or more, about 65% or more, about 70% or more, about 75% or more, about 80% or more, about 85% of S-adenosylmethionine immediately after preparation. More than about 90%, about 95% or more, or about 100% of S-adenosylmethionine. In a preferred embodiment, the composition of the present invention comprises about 80% or more of S-adenosylmethionine as prepared immediately after about 30 days in an accelerated tester, preferably about 40% in an accelerated tester. About 80% or more of S-adenosylmethionine immediately after preparation, more preferably about 80% or more of S-adenosylmethionine immediately after preparation in about 60 days in an accelerated tester. -Contains adenosylmethionine.
本発明の組成物は、Ｓ－アデノシルメチオニンと酸性メタリン酸ナトリウムとを含む混合物を乾燥することによって得られる粉末であり得る。この乾燥は、例えば凍結乾燥または噴霧乾燥により行うことができる。例えば、本発明における乾燥は、約３日間またはそれ以上凍結乾燥を行うことにより達成され得る。本発明における乾燥はまた、入口温度１２０～２３０℃、出口温度１００℃～７０℃で所望の量の粉末化が達成されるまで噴霧乾燥を行うことによっても達成され得る。
The composition of the present invention may be a powder obtained by drying a mixture containing S-adenosylmethionine and sodium acid metaphosphate. This drying can be performed, for example, by freeze drying or spray drying. For example, drying in the present invention can be accomplished by lyophilization for about 3 days or longer. Drying in the present invention can also be accomplished by spray drying until the desired amount of pulverization is achieved at an inlet temperature of 120-230 ° C and an outlet temperature of 100 ° C-70 ° C.
本発明の飲食用組成物は、肝硬変などの肝障害、鬱病、関節炎、骨関節症、軟骨保護、アルツハイマー病、ＨＩＶ感染による末梢神経障害または脊髄症等に対して、有用な効果を有を有し得る。本発明の飲食用組成物は、飲食用補填物であり得る。
The composition for eating and drinking of the present invention has a useful effect on liver disorders such as cirrhosis, depression, arthritis, osteoarthritis, cartilage protection, Alzheimer's disease, peripheral neuropathy caused by HIV infection or myelopathy. Can do. The composition for eating and drinking of the present invention can be a food and drink supplement.
（本発明の飲食用組成物）
本発明の組成物は、飲食用組成物（栄養補助食品、健康食品を含む）であり得る。 (Eating and drinking composition of the present invention)
The composition of the present invention may be a composition for eating and drinking (including nutritional supplements and health foods).
本発明の組成物は、飲食用組成物（栄養補助食品、健康食品を含む）であり得る。 (Eating and drinking composition of the present invention)
The composition of the present invention may be a composition for eating and drinking (including nutritional supplements and health foods).
本発明の飲食用組成物は、健康食品（特定保健用食品、栄養機能食品）、栄養補助食品（サプリメント）、食品添加物または食品補填物などを包含する。代表的には、本発明の飲食用組成物は、Ｓ－アデノシルメチオニン、および酸性メタリン酸ナトリウムの混合物を乾燥させて粉末としたものである。本発明の飲食用組成物は、Ｓ－アデノシルメチオニンを産生する酵母を含み得る。粉末状の本発明の飲食用組成物は、食品添加物または食品補填物として他の食品に添加して摂取されてもよいし、粉末状の本発明の飲食用組成物自体が、健康食品または栄養補助食品（サプリメント）等として単独で摂取されてもよい。本発明の組成物は、必要に応じてデキストリン、乳糖、澱粉等の賦型剤や香料、色素等とともにペレット、錠剤、顆粒等に加工されたり、またゼラチン等で被覆してカプセルに成形加工されてもよい。本発明の組成物は、健康食品または栄養補助食品（サプリメント）として用いるのに特に適している。代表的には、本発明の飲食用組成物は、１００ｇ当たり約３ｇまたはそれ以上のＳ－アデノシルメチオニンを含む。
The food and drink composition of the present invention includes health foods (specific health foods, functional nutrition foods), nutritional supplements (supplements), food additives, food supplements, and the like. Typically, the food and beverage composition of the present invention is a powder obtained by drying a mixture of S-adenosylmethionine and acidic sodium metaphosphate. The edible composition of the present invention may contain a yeast that produces S-adenosylmethionine. The powdered food and beverage composition of the present invention may be ingested by being added to other foods as a food additive or food supplement, or the powdered food and beverage composition of the present invention itself is a health food or It may be taken alone as a dietary supplement (supplement) or the like. The composition of the present invention may be processed into pellets, tablets, granules, etc. together with excipients such as dextrin, lactose, starch and the like, fragrances, pigments, etc., as necessary, and coated with gelatin or the like to be processed into capsules. May be. The compositions of the present invention are particularly suitable for use as health foods or dietary supplements. Typically, the edible composition of the present invention comprises about 3 g or more S-adenosylmethionine per 100 g.
本発明の飲食用組成物におけるＳ－アデノシルメチオニンの配合量は、当該食品の種類や状態等により一律に規定しがたいが、Ｓ－アデノシルメチオニン含量で１０～５０００ｍｇ／１食、好ましくは１００～１０００ｍｇ／１食であり、サプリメントの場合には約１０～１００％（好ましくは、３０～１００％、より好ましくは５０～１００％、さらにより好ましくは８０～１００％）、飲料もしくは一般食品などの場合には約０．０１％以下であり得る。
The amount of S-adenosylmethionine in the composition for eating and drinking according to the present invention is difficult to define uniformly depending on the type and condition of the food, but the S-adenosylmethionine content is 10 to 5000 mg / meal, preferably 100 to 1000 mg / meal, about 10 to 100% (preferably 30 to 100%, more preferably 50 to 100%, even more preferably 80 to 100%) in the case of supplements, beverages or general foods Etc., it may be about 0.01% or less.
本発明の飲食用組成物は、食品に通常用いられる賦形剤または添加剤を配合して、錠剤、タブレット剤、丸剤、顆粒剤、散剤、粉剤、カプセル剤、水和剤、乳剤、液剤、エキス剤、またはエリキシル剤等の剤型に調製することもできる。食品に通常用いられる賦形剤としては、シロップ、アラビアゴム、ショ糖、乳糖、粉末還元麦芽糖、セルロース糖、マンニトール、マルチトール、デキストラン、デンプン類、ゼラチン、ソルビット、トラガント、ポリビニルピロリドンのような結合剤；ショ糖脂肪酸エステル、グリセリン脂肪酸エステル、ステアリン酸マグネシウム、ステアリン酸カルシウム、タルク、ポリエチレングリコールのような潤沢剤；ジャガイモ澱粉のような崩壊剤；ラウリル硫酸ナトリウムのような湿潤剤等が挙げられる。添加剤としては、香料、緩衝剤、増粘剤、着色剤、安定剤、乳化剤、分散剤、懸濁化剤、防腐剤などが挙げられる。
The composition for eating and drinking of the present invention is blended with excipients or additives usually used in foods, tablets, tablets, pills, granules, powders, powders, capsules, wettable powders, emulsions, liquids. , Extract, or elixir. Common excipients used in food include syrup, gum arabic, sucrose, lactose, powdered reduced maltose, cellulose sugar, mannitol, maltitol, dextran, starches, gelatin, sorbit, tragacanth, polyvinylpyrrolidone Agents; sucrose fatty acid esters, glycerin fatty acid esters, magnesium stearate, calcium stearate, talc, polyethylene glycol, etc .; disintegrants such as potato starch; wetting agents such as sodium lauryl sulfate. Examples of additives include fragrances, buffers, thickeners, colorants, stabilizers, emulsifiers, dispersants, suspending agents, preservatives, and the like.
（本発明の医薬組成物）
本発明の組成物は、医薬組成物（獣医学用薬剤を含む）であり得る。 (Pharmaceutical composition of the present invention)
The composition of the present invention may be a pharmaceutical composition (including veterinary drugs).
本発明の組成物は、医薬組成物（獣医学用薬剤を含む）であり得る。 (Pharmaceutical composition of the present invention)
The composition of the present invention may be a pharmaceutical composition (including veterinary drugs).
本発明の組成物を医薬品に製剤化したもの（以下、本発明の医薬組成物という）は、経口投与製剤であってもよいし、非経口投与製剤であってもよい。また、本発明の医薬組成物は、固形製剤であっても液体製剤であってもよい。
The pharmaceutical preparation of the composition of the present invention (hereinafter referred to as the pharmaceutical composition of the present invention) may be an oral administration preparation or a parenteral administration preparation. The pharmaceutical composition of the present invention may be a solid preparation or a liquid preparation.
固形製剤としては、例えば、散剤、顆粒剤、錠剤、タブレット剤、丸剤、カプセル剤、チュアブル剤などが挙げられ、液体製剤としては、乳剤、液剤、シロップ剤などが挙げられる。本発明の医薬組成物は、１００ｇ当たり約３ｇまたはそれ以上のＳ－アデノシルメチオニンを含む。
Examples of solid preparations include powders, granules, tablets, tablets, pills, capsules, chewables, and the like, and examples of liquid preparations include emulsions, liquids, and syrups. The pharmaceutical composition of the present invention comprises about 3 g or more of S-adenosylmethionine per 100 g.
固形製剤は、有効成分である本発明のＳ－アデノシルメチオニンおよび酸性メタリン酸ナトリウムに、薬学的に受容可能なキャリアまたは添加剤を配合することによって調製され得る。例えば、白糖、乳糖、ブドウ糖、でんぷん、マンニットのような賦形剤；アラビアゴム、ゼラチン、結晶セルロース、ヒドロキシプロピルセルロース、メチルセルロースのような結合剤；カルメロース、デンプンのような崩壊剤；無水クエン酸、ラウリン酸ナトリウム、グリセロールのような安定剤などが、本発明の医薬組成物の製剤化のために配合され得る。さらに、本発明の医薬組成物は、ゼラチン、白糖、アラビアゴム、カルナバロウなどでコーティングまたはカプセル化され得る。
A solid preparation can be prepared by blending a pharmaceutically acceptable carrier or additive with the active ingredient S-adenosylmethionine of the present invention and sodium acid metaphosphate. For example, excipients such as sucrose, lactose, glucose, starch, mannitol; binders such as gum arabic, gelatin, crystalline cellulose, hydroxypropylcellulose, methylcellulose; disintegrants such as carmellose, starch; anhydrous citric acid Stabilizers such as sodium laurate, glycerol, and the like can be formulated for the formulation of the pharmaceutical composition of the present invention. Furthermore, the pharmaceutical composition of the present invention may be coated or encapsulated with gelatin, sucrose, gum arabic, carnauba wax and the like.
液体製剤は、例えば、有効成分である本発明のＳ－アデノシルメチオニンおよび酸性メタリン酸ナトリウムを、水、エタノール、グリセリン、シロップ、またはこれらの混合液に溶解または分散させることにより、調製され得る。本発明の医薬組成物には、さらに、甘味料、防腐剤、粘滑剤、滑沢剤、希釈剤、緩衝剤、または着色剤のような添加剤が添加され得る。
The liquid preparation can be prepared by, for example, dissolving or dispersing the active ingredient S-adenosylmethionine of the present invention and acidic sodium metaphosphate in water, ethanol, glycerin, syrup, or a mixture thereof. The pharmaceutical composition of the present invention may further contain additives such as sweeteners, preservatives, demulcents, lubricants, diluents, buffers, or coloring agents.
非経口投与製剤は、当業者の公知の任意の非経口投与用の製剤であり得る。本発明の医薬組成物の非経口投与製剤としては、クリーム、スプレー、ゲル、軟膏、膏薬などが挙げられるが、これらに限定されない。本発明のＳ－アデノシルメチオニンおよび酸性メタリン酸ナトリウムを含む医薬組成物はまた、（例えば、浸漬されかつ乾燥された）包帯、ガーゼ、もしくはパッチへと直接注入され得、次いで、これらが局所に適用され得る。
The parenteral preparation can be any parenteral preparation known to those skilled in the art. Examples of parenteral preparations for the pharmaceutical composition of the present invention include, but are not limited to, creams, sprays, gels, ointments, salves and the like. Pharmaceutical compositions comprising S-adenosylmethionine of the present invention and acidic sodium metaphosphate can also be injected directly into bandages, gauze, or patches (eg, soaked and dried), which are then topically applied. Can be applied.
本発明の医薬組成物の製剤化および投与のための技術は、例えば、ＲＥＭＩＮＧＴＯＮ’Ｓ ＰＨＡＲＭＡＣＥＵＴＩＣＡＬ ＳＣＩＥＮＣＥＳ（Ｍａｃｋ Ｐｕｂｌｉｓｈｉｎｇ Ｃｏ．，Ｅａｓｔｏｎ，Ｐａ．）に見いだされ得る。
The technique for formulating and administering the pharmaceutical composition of the present invention can be found in, for example, REMINGTON'S PHARMACEUTICAL SCIENCES (Mack Publishing Co., Easton, Pa.).
本発明の医薬組成物の有効量および投与方法は、投与方法、処置されている状態および処置されている状態の重症度により変動し得る。通常の医師または獣医は、本発明の医薬組成物の有効量および投与方法を容易に決定することができる。
The effective amount and method of administration of the pharmaceutical composition of the present invention can vary depending on the method of administration, the condition being treated and the severity of the condition being treated. The ordinary physician or veterinarian can readily determine the effective amount and method of administration of the pharmaceutical composition of the present invention.
（酸性メタリン酸ナトリウム）
メタリン酸ナトリウムは、リン酸（例えば、Ｐ２Ｏ５）とアルカリ（例えば、苛性ソーダまたは炭酸ソーダ）との当モル反応生成物を高温で熔融し、脱水縮合させて得られる縮合リン酸塩の総称であり、分子構造的には、単一物でなく、環状体や長鎖の鎖状構造を含む中性の縮合リン酸塩の混合物である。 (Acid sodium metaphosphate)
Sodium metaphosphate is a general term for a condensed phosphate obtained by melting an equimolar reaction product of phosphoric acid (for example, P 2 O 5 ) and an alkali (for example, caustic soda or sodium carbonate) at a high temperature and subjecting it to dehydration condensation. In terms of molecular structure, it is not a single substance but a mixture of neutral condensed phosphates containing cyclic structures and long-chain structures.
メタリン酸ナトリウムは、リン酸（例えば、Ｐ２Ｏ５）とアルカリ（例えば、苛性ソーダまたは炭酸ソーダ）との当モル反応生成物を高温で熔融し、脱水縮合させて得られる縮合リン酸塩の総称であり、分子構造的には、単一物でなく、環状体や長鎖の鎖状構造を含む中性の縮合リン酸塩の混合物である。 (Acid sodium metaphosphate)
Sodium metaphosphate is a general term for a condensed phosphate obtained by melting an equimolar reaction product of phosphoric acid (for example, P 2 O 5 ) and an alkali (for example, caustic soda or sodium carbonate) at a high temperature and subjecting it to dehydration condensation. In terms of molecular structure, it is not a single substance but a mixture of neutral condensed phosphates containing cyclic structures and long-chain structures.
これに対して、酸性メタリン酸ナトリウムは、リン酸（例えば、Ｐ２Ｏ５）と当モル未満のアルカリ（例えば、苛性ソーダまたは炭酸ソーダ）との反応生成物を熔融し、脱水縮合して得られる高分子の酸性縮合リン酸塩混合物であり、原料のモル比、反応温度等の製造条件により、異なる組成のものが得られるが、分子構造的には、環状体、鎖状体の他、中性のメタリン酸塩にはみられない網状体を含む点に特徴がある。
In contrast, acidic sodium metaphosphate is obtained by melting a reaction product of phosphoric acid (for example, P 2 O 5 ) and less than an equivalent amount of alkali (for example, caustic soda or sodium carbonate) and dehydrating and condensing it. It is a mixture of acidic condensed phosphates of macromolecules, and different compositions can be obtained depending on the production conditions such as the molar ratio of raw materials and reaction temperature. It is characterized in that it contains a network that is not found in sex metaphosphate.
上記メタリン酸ナトリウムと酸性メタリン酸ナトリウムとは、リン酸（例えば、Ｐ２Ｏ５）とアルカリ（例えば、苛性ソーダまたは炭酸ソーダ）との仕込比率を変更することによって、いずれも製造することができ、そのような製造方法は当業者には周知である。
メタリン酸ナトリウムおよび酸性メタリン酸ナトリウムは、いずれも、保水剤または金属イオン封鎖剤として使用される食品添加物である。最終製品をより酸性にしたい場合に酸性メタリン酸ナトリウムが使用されることが多いが、他に用途および効果においてこれら２つの添加物における差異は知られていなかった。 Both the sodium metaphosphate and acidic sodium metaphosphate can be produced by changing the charging ratio of phosphoric acid (for example, P 2 O 5 ) and alkali (for example, caustic soda or sodium carbonate), Such manufacturing methods are well known to those skilled in the art.
Both sodium metaphosphate and acidic sodium metaphosphate are food additives used as water retention agents or sequestering agents. Acidic sodium metaphosphate is often used when it is desired to make the final product more acidic, but no other difference in use and effectiveness in these two additives has been known.
メタリン酸ナトリウムおよび酸性メタリン酸ナトリウムは、いずれも、保水剤または金属イオン封鎖剤として使用される食品添加物である。最終製品をより酸性にしたい場合に酸性メタリン酸ナトリウムが使用されることが多いが、他に用途および効果においてこれら２つの添加物における差異は知られていなかった。 Both the sodium metaphosphate and acidic sodium metaphosphate can be produced by changing the charging ratio of phosphoric acid (for example, P 2 O 5 ) and alkali (for example, caustic soda or sodium carbonate), Such manufacturing methods are well known to those skilled in the art.
Both sodium metaphosphate and acidic sodium metaphosphate are food additives used as water retention agents or sequestering agents. Acidic sodium metaphosphate is often used when it is desired to make the final product more acidic, but no other difference in use and effectiveness in these two additives has been known.
本明細書において、酸性メタリン酸ナトリウムは、式：｛ＮａｘＨｙ（ＰＯ３）ｘ＋ｙ｝ｎ（ｘは１以上の任意の数であり、ｙは１以上の任意の数であり、ｎは２以上の任意の数である）で表される化合物をいう。
In this specification, acidic sodium metaphosphate is represented by the formula: {Na x H y (PO 3 ) x + y } n (x is an arbitrary number of 1 or more, y is an arbitrary number of 1 or more, and n is It is an arbitrary number of 2 or more).
本発明のある実施形態において、本発明において用いられる酸性メタリン酸ナトリウムのｐＨは、２．２以下である。
In an embodiment of the present invention, the pH of the acidic sodium metaphosphate used in the present invention is 2.2 or less.
本発明のある実施形態において、本発明において用いられる酸性メタリン酸ナトリウムは、式：｛ＮａｘＨｙ（ＰＯ３）ｘ＋ｙ｝ｎで表され、ｘとｙはそれぞれ、酸性メタリン酸ナトリウムのｐＨが２．２以下であるような数である。
In an embodiment of the present invention, the acidic sodium metaphosphate used in the present invention is represented by the formula: {Na x H y (PO 3 ) x + y } n , where x and y are each a pH of acidic sodium metaphosphate. The number is 2.2 or less.
本発明のある実施形態において、本発明において用いられる酸性メタリン酸ナトリウムの数平均重合度は、２以上の任意の数であり、より好ましくは１０～３００、さらに好ましくは１０～２３、代表的には１４である。
In an embodiment of the present invention, the number average polymerization degree of acidic sodium metaphosphate used in the present invention is an arbitrary number of 2 or more, more preferably 10 to 300, still more preferably 10 to 23, typically Is 14.
酸性メタリン酸ナトリウムは多数の製造者によって製造および販売されている。市販されている酸性メタリン酸ナトリウムとしては、燐化学工業株式会社（日本、富山）製の酸性ヘキサメタリン酸ナトリウム、エフシー化学株式会社（日本、大阪）製のニューエフシリンサンＦ、オルガノフードテック株式会社（日本、埼玉）製のポリリンサン １－Ｇ、大洋化学工業株式会社（日本、東京）製のマスコリンＦ－２、太平化学産業株式会社（日本、大阪）製のウルトラポリン、上野製薬株式会社（日本、大阪）製のタリンサンＵ（登録商標）、株式会社ポリホス化学研究所（日本、大阪）製のウルトラポリホスなどが挙げられるが、これらに限定されない。
Acidic sodium metaphosphate is manufactured and sold by a number of manufacturers. Commercially available acidic sodium metaphosphates include sodium acidic hexametaphosphate manufactured by Phosphorus Chemical Co., Ltd. (Toyama, Japan), New Fcillin Sun F manufactured by FC Chemical Co., Ltd. (Osaka, Japan), Organo Food Tech Co., Ltd. Polylin Sun 1-G manufactured by (Saitama, Japan), Muscorin F-2 manufactured by Taiyo Chemical Co., Ltd. (Tokyo, Japan), Ultraporin manufactured by Taihei Chemical Industrial Co., Ltd. (Osaka, Japan), Ueno Pharmaceutical Co., Ltd. ( Examples include, but are not limited to, Tallinsan U (registered trademark) manufactured by Osaka, Japan and Ultrapolyphos manufactured by Polyphos Chemical Laboratory Co., Ltd. (Osaka, Japan).
（Ｓ－アデノシルメチオニンを含む医薬組成物）
Ｓ－アデノシルメチオニンは、種々の医薬用途を有することが周知である。例えば、Ｓ－アデノシルメチオニンは、肝臓障害を緩和する（例えば、肝硬変による死亡率を減少させる）こと（例えば、Ｌｉｅｂｅｒ ＣＳ． Ｒｏｌｅ ｏｆ Ｓ－ａｄｅｎｏｓｙｌ－Ｌ－ｍｅｔｈｉｏｎｉｎｅ ｉｎ ｔｈｅ ｔｒｅａｔｍｅｎｔ ｏｆ ｌｉｖｅｒ ｄｉｓｅａｓｅｓ． Ｊ Ｈｅｐａｔｏｌ １９９９；３０：１１５５-９；Ｗｉｌｌｉａｍｓ Ｒ， Ｌｉｅｂｅｒ ＣＳ． Ｔｈｅ ｒｏｌｅ ｏｆ ＳＡＭｅ ｉｎ ｔｈｅ ｔｒｅａｔｍｅｎｔ ｏｆ ｌｉｖｅｒ ｄｉｓｅａｓｅ． Ｄｒｕｇｓ １９９０；４０（ｓｕｐｐｌ）：１-２；Ｍａｔｏ ＪＭ， Ｃａｍａｒａ Ｊ， Ｆｅｒｎａｎｄｅｚ ｄｅ Ｐａｚ Ｊ， ｅｔ ａｌ． Ｓ－Ａｄｅｎｏｓｙｌｍｅｔｈｉｏｎｉｎｅ ｉｎ ａｌｃｏｈｏｌｉｃ ｌｉｖｅｒ ｃｉｒｒｈｏｓｉｓ： ａ ｒａｎｄｏｍｉｚｅｄ， ｐｌａｃｅｂｏ－ｃｏｎｔｒｏｌｌｅｄ， ｄｏｕｂｌｅ－ｂｌｉｎｄ， ｍｕｌｔｉｃｅｎｔｅｒ ｃｌｉｎｉｃａｌ ｔｒｉａｌ． Ｊ Ｈｅｐａｔｏｌ １９９９；３０：１０８１-９などを参照のこと）、鬱病に対して治療効果を有すること（例えば、Ｊａｎｉｃａｋ ＰＧ， Ｌｉｐｉｎｓｋｉ ＪＤ， Ｃｏｍａｔｙ ＪＥ， ｅｔ ａｌ． Ｓ－Ａｄｅｎｏｓｙｌｍｅｔｈｉｏｎｉｎｅ： ａ ｌｉｔｅｒａｔｕｒｅ ｒｅｖｉｅｗ ａｎｄ ｐｒｅｌｉｍｉｎａｒｙ ｒｅｐｏｒｔ． Ａｌａ Ｊ Ｍｅｄ Ｓｃｉ １９８８；２５：３０６-１３；Ｆｒｉｅｄｅｌ ＨＡ， Ｇｏａ ＫＬ， Ｂｅｎｆｉｅｌｄ Ｐ． Ｓ－Ａｄｅｎｏｓｙｌ－Ｌ－ｍｅｔｈｉｏｎｉｎｅ： ａ ｒｅｖｉｅｗ ｏｆ ｉｔｓ ｔｈｅｒａｐｅｕｔｉｃ ｐｏｔｅｎｔｉａｌ ｉｎ ｌｉｖｅｒ ｄｙｓｆｕｎｃｔｉｏｎ ａｎｄ ａｆｆｅｃｔｉｖｅ ｄｉｓｏｒｄｅｒｓ ｉｎ ｒｅｌａｔｉｏｎ ｔｏ ｉｔｓ ｐｈｙｓｉｏｌｏｇｉｃａｌ ｒｏｌｅ ｉｎ ｃｅｌｌ ｍｅｔａｂｏｌｉｓｍ． Ｄｒｕｇｓ １９８９；３８：３８９-４１６；Ｂｒｅｓｓａ ＧＭ． Ｓ－Ａｄｅｎｏｓｙｌ－Ｌ－ｍｅｔｈｉｏｎｉｎｅ （ＳＡＭｅ） ａｓ ａｎｔｉｄｅｐｒｅｓｓａｎｔ： ｍｅｔａ－ａｎａｌｙｓｉｓ ｏｆ ｃｌｉｎｉｃａｌ ｓｔｕｄｉｅｓ． Ａｃｔａ Ｎｅｕｒｏｌ Ｓｃａｎｄ １９９４；１５４：７-１４などを参照のこと）、関節炎の処置に有用であること（例えば、Ｂｒａｄｌｅｙ ＪＤ， Ｆｌｕｓｓｅｒ Ｄ， Ｋａｔｚ ＢＰ， ｅｔ ａｌ． Ａ ｒａｎｄｏｍｉｚｅｄ， ｄｏｕｂｌｅ ｂｌｉｎｄ， ｐｌａｃｅｂｏ ｃｏｎｔｒｏｌｌｅｄ ｔｒｉａｌ ｏｆ ｉｎｔｒａｖｅｎｏｕｓ ｌｏａｄｉｎｇ ｗｉｔｈ Ｓ－ａｄｅｎｏｓｙｌｍｅｔｈｉｏｎｉｎｅ （ＳＡＭ） ｆｏｌｌｏｗｅｄ ｂｙ ｏｒａｌ ＳＡＭ ｔｈｅｒａｐｙ ｉｎ ｐａｔｉｅｎｔｓ ｗｉｔｈ ｋｎｅｅ ｏｓｔｅｏａｒｔｈｒｉｔｉｓ． Ｊ Ｒｈｅｕｍａｔｏｌ １９９４；２１：９０５～１１；Ｐａｄｏｖａ Ｃ． Ｓ－Ａｄｅｎｏｓｙｌｍｅｔｈｉｏｎｉｎｅ ｉｎ ｔｈｅ ｔｒｅａｔｍｅｎｔ ｏｆ ｏｓｔｅｏａｒｔｈｒｉｔｉｓ： ｒｅｖｉｅｗ ｏｆ ｔｈｅ ｃｌｉｎｉｃａｌ ｓｔｕｄｉｅｓ． Ａｍ Ｊ Ｍｅｄ １９８７；８３：６０～５を参照のこと）、アルツハイマー病を改善し得ること（例えば、Ｍｏｒｉｓｏｎ， Ｌ． Ｄ．， Ｓｍｉｔｈ， Ｄ． Ｄ．， ａｎｄ Ｋｉｓｈ， Ｓ． Ｊ．， Ｂｒａｉｎ Ｓ－ａｄｅｎｏｓｙｌｍｅｔｈｉｏｎｉｎｅ ｌｅｖｅｌｓ ａｒｅ ｓｅｖｅｒｅｌｙ ｄｅｃｒｅａｓｅｄ ｉｎ Ａｌｚｈｅｉｍｅｒ’ｓ ｄｉｓｅａｓｅ． Ｊ． Ｎｅｕｒｏｃｈｅｍ．， ６７， １３２８-１３３１ （１９９６）を参照のこと）、ＨＩＶ感染による末梢神経障害または脊髄症を改善し得ること（例えば、Ｋｅａｔｉｎｇ ＪＮ， Ｔｒｉｍｂｌｅ ＫＣ， Ｍｕｌｃａｈｙ Ｆ， Ｓｃｏｔｔ ＪＭ， Ｗｅｉｒ ＤＧ， Ｅｖｉｄｅｎｃｅ ｏｆ ｂｒａｉｎ ｍｅｔｈｌｔｒａｎｓｆｅｒａｓｅ ｉｎｈｉｂｉｔｉｏｎ ａｎｄ ｅａｒｌｙ ｂｒａｉｎ ｉｎｖｏｌｖｅｍｅｎｔ ｉｎ ＨＩＶ－ｐｏｓｉｔｉｖｅ ｐａｔｉｅｎｔｓ． Ｌａｎｃｅｔ， ３３７， ９３５－９３９， （１９９１）；Ｓｕｒｅｔｅｅｓ Ｒ， Ｈｙｌａｎｄ Ｋ， Ｓｍｉｔｈ Ｉ．， Ｃｅｎｔｒａｌ ｎｅｒｖｏｕｓ ｓｙｓｔｅｍ ｍｅｔｈｙｌ－ｇｒｏｕｐ ｍｅｔａｂｏｌｉｓｍ ｉｎ ｃｈｉｌｄｒｅｎ ｗｉｔｈ ｎｅｕｒｏｌｏｇｉｃａｌ ｃｏｍｐｌｉｃａｔｉｏｎｓ ｏｆ ＨＩＶ ｉｎｆｅｃｔｉｏｎ． Ｌａｎｃｅｔ， ３３５， ６１９－６２１， （１９９０）；Ｃａｓｔａｇｎａ Ａ， Ｌｅ Ｇｒａｚｉｅ Ｃ， Ａｃｃｏｒｄｉｎｉ Ａ， Ｇｉｕｌｉｄｏｒｉ Ｐ， Ｃａｖａｌｌｉ Ｇ， Ｂｏｔｔｉｇｌｉｅｒｉ Ｔ， Ｌａｚｚａｒｉｎ Ａ．， Ｃｒｅｂｒｏｓｐｉｎａｌ ｆｌｕｉｄ Ｓ－ａｄｅｎｏｓｙｌ－ｍｅｔｈｉｏｎｉｎｅ （ＳＡＭｅ） ａｎｄ ｇｌｕｔａｔｈｉｏｎｅ ｃｏｎｃｅｎｔｒａｔｉｏｎｓ ｉｎ ＨＩＶ ｉｎｆｅｃｔｉｏｎ ： ｅｆｆｅｃｔ ｏｆ ｐａｒｅｎｔｅｒａｌ ｔｒｅａｔｍｅｎｔ ｗｉｔｈ ＳＡＭｅ．， Ｎｅｕｒｏｌｏｇｙ， ４５， １６７８－１６８３， （１９９５）などを参照のこと）などの医薬用途を有することが知られている。 (Pharmaceutical composition containing S-adenosylmethionine)
S-adenosylmethionine is well known to have a variety of pharmaceutical uses. For example, S-adenosylmethionine alleviates liver damage (eg, reduces mortality due to cirrhosis) (eg, Lieber CS. Role of S-adenosyl-L-methionine in the treatment of liver diseases. J Hepatol). 1999; 30: 1155-9; Williams R, Lieber CS. The role of SAMe in the treatment of liver disease. Drugs 1990; 40 (suppl): 1-2, Mato JM, eJaF. S-Adenylosyllineine in alcoholic liver cirrhosis: a random Ized, placebo-controlled, double-blind, multicenter clinical trial. See J Hepatol 1999; 30: 1081-9, etc.), have a therapeutic effect on depression (eg, Janicak PG, M , Et al.S-Adenosylmethionine: a literature review and premier report report.Ala J Med Sci 1988; 25: 306-13; in liv . Er dysfunction and affective disorders in relation to its physiological role in cell metabolism Drugs 1989; 38:.. 389-416; Bressa GM S-Adenosyl-L-methionine (SAMe) as antidepressant: meta-analysis of clinical studies Acta Neurol Scand 1994; 154: 7-14, etc.) and useful for the treatment of arthritis (see, for example, Bradley JD, Flosser D, Katz BP, et al. A randomized, double blind, placebo controlled trial of intravenous loading with S-adenosyltherthene te te te r a te s a te s a te s a s ed a s ti s s s ed ner ti s e n a te s a ti s e a ner ti s ed s a ner ti s e n a ti s e n a s s ed a s i n a s i n a ti s e n a i n a t e n a s ti s e n a s e n a i n a n i s s ti s e n a s i n a n s ti s e n a s s ed s a s o J Rheumatol 1994; 21: 905-11; Padova C.I. S-Adenylosyllineine in the treatment of osteoarthritis: review of the clinical studies. Am J Med 1987; 83: 60-5), and can improve Alzheimer's disease (eg, Morison, LD, Smith, DD, and Kish, SJ, Brain S). -Adenosylmethine levels are gradually developed in Alzheimer's disease. See J. Neurochem., 67, 1328-1331 (1996), may improve peripheral neuropathy or myelopathy due to HIV infection, eg N , Trimble KC, Mulcahy F, Scott JM, Weir DG, Evidence of brain methyltransferase inhibition and earl . Brain involvement in HIV-positive patients Lancet, 337, 935-939, (1991);. Suretees R, Hyland K, Smith I., Central nervous system methyl-group metabolism in children with neurological complications of HIV infection Lancet, 335, 619-621, (1990); Castagna A, Le Grazie C, Accordini A, Giulidri P, Cavalli G, Bottiglieri T, Lazzarin A., Crebrospinal fluid S-adden. Ethionine (SAMe) and glutation contentions in HIV effect: see the use of effect of parental treatment with SAMe., Neurology, 45, 1678-1683 (1995), etc.).
Ｓ－アデノシルメチオニンは、種々の医薬用途を有することが周知である。例えば、Ｓ－アデノシルメチオニンは、肝臓障害を緩和する（例えば、肝硬変による死亡率を減少させる）こと（例えば、Ｌｉｅｂｅｒ ＣＳ． Ｒｏｌｅ ｏｆ Ｓ－ａｄｅｎｏｓｙｌ－Ｌ－ｍｅｔｈｉｏｎｉｎｅ ｉｎ ｔｈｅ ｔｒｅａｔｍｅｎｔ ｏｆ ｌｉｖｅｒ ｄｉｓｅａｓｅｓ． Ｊ Ｈｅｐａｔｏｌ １９９９；３０：１１５５-９；Ｗｉｌｌｉａｍｓ Ｒ， Ｌｉｅｂｅｒ ＣＳ． Ｔｈｅ ｒｏｌｅ ｏｆ ＳＡＭｅ ｉｎ ｔｈｅ ｔｒｅａｔｍｅｎｔ ｏｆ ｌｉｖｅｒ ｄｉｓｅａｓｅ． Ｄｒｕｇｓ １９９０；４０（ｓｕｐｐｌ）：１-２；Ｍａｔｏ ＪＭ， Ｃａｍａｒａ Ｊ， Ｆｅｒｎａｎｄｅｚ ｄｅ Ｐａｚ Ｊ， ｅｔ ａｌ． Ｓ－Ａｄｅｎｏｓｙｌｍｅｔｈｉｏｎｉｎｅ ｉｎ ａｌｃｏｈｏｌｉｃ ｌｉｖｅｒ ｃｉｒｒｈｏｓｉｓ： ａ ｒａｎｄｏｍｉｚｅｄ， ｐｌａｃｅｂｏ－ｃｏｎｔｒｏｌｌｅｄ， ｄｏｕｂｌｅ－ｂｌｉｎｄ， ｍｕｌｔｉｃｅｎｔｅｒ ｃｌｉｎｉｃａｌ ｔｒｉａｌ． Ｊ Ｈｅｐａｔｏｌ １９９９；３０：１０８１-９などを参照のこと）、鬱病に対して治療効果を有すること（例えば、Ｊａｎｉｃａｋ ＰＧ， Ｌｉｐｉｎｓｋｉ ＪＤ， Ｃｏｍａｔｙ ＪＥ， ｅｔ ａｌ． Ｓ－Ａｄｅｎｏｓｙｌｍｅｔｈｉｏｎｉｎｅ： ａ ｌｉｔｅｒａｔｕｒｅ ｒｅｖｉｅｗ ａｎｄ ｐｒｅｌｉｍｉｎａｒｙ ｒｅｐｏｒｔ． Ａｌａ Ｊ Ｍｅｄ Ｓｃｉ １９８８；２５：３０６-１３；Ｆｒｉｅｄｅｌ ＨＡ， Ｇｏａ ＫＬ， Ｂｅｎｆｉｅｌｄ Ｐ． Ｓ－Ａｄｅｎｏｓｙｌ－Ｌ－ｍｅｔｈｉｏｎｉｎｅ： ａ ｒｅｖｉｅｗ ｏｆ ｉｔｓ ｔｈｅｒａｐｅｕｔｉｃ ｐｏｔｅｎｔｉａｌ ｉｎ ｌｉｖｅｒ ｄｙｓｆｕｎｃｔｉｏｎ ａｎｄ ａｆｆｅｃｔｉｖｅ ｄｉｓｏｒｄｅｒｓ ｉｎ ｒｅｌａｔｉｏｎ ｔｏ ｉｔｓ ｐｈｙｓｉｏｌｏｇｉｃａｌ ｒｏｌｅ ｉｎ ｃｅｌｌ ｍｅｔａｂｏｌｉｓｍ． Ｄｒｕｇｓ １９８９；３８：３８９-４１６；Ｂｒｅｓｓａ ＧＭ． Ｓ－Ａｄｅｎｏｓｙｌ－Ｌ－ｍｅｔｈｉｏｎｉｎｅ （ＳＡＭｅ） ａｓ ａｎｔｉｄｅｐｒｅｓｓａｎｔ： ｍｅｔａ－ａｎａｌｙｓｉｓ ｏｆ ｃｌｉｎｉｃａｌ ｓｔｕｄｉｅｓ． Ａｃｔａ Ｎｅｕｒｏｌ Ｓｃａｎｄ １９９４；１５４：７-１４などを参照のこと）、関節炎の処置に有用であること（例えば、Ｂｒａｄｌｅｙ ＪＤ， Ｆｌｕｓｓｅｒ Ｄ， Ｋａｔｚ ＢＰ， ｅｔ ａｌ． Ａ ｒａｎｄｏｍｉｚｅｄ， ｄｏｕｂｌｅ ｂｌｉｎｄ， ｐｌａｃｅｂｏ ｃｏｎｔｒｏｌｌｅｄ ｔｒｉａｌ ｏｆ ｉｎｔｒａｖｅｎｏｕｓ ｌｏａｄｉｎｇ ｗｉｔｈ Ｓ－ａｄｅｎｏｓｙｌｍｅｔｈｉｏｎｉｎｅ （ＳＡＭ） ｆｏｌｌｏｗｅｄ ｂｙ ｏｒａｌ ＳＡＭ ｔｈｅｒａｐｙ ｉｎ ｐａｔｉｅｎｔｓ ｗｉｔｈ ｋｎｅｅ ｏｓｔｅｏａｒｔｈｒｉｔｉｓ． Ｊ Ｒｈｅｕｍａｔｏｌ １９９４；２１：９０５～１１；Ｐａｄｏｖａ Ｃ． Ｓ－Ａｄｅｎｏｓｙｌｍｅｔｈｉｏｎｉｎｅ ｉｎ ｔｈｅ ｔｒｅａｔｍｅｎｔ ｏｆ ｏｓｔｅｏａｒｔｈｒｉｔｉｓ： ｒｅｖｉｅｗ ｏｆ ｔｈｅ ｃｌｉｎｉｃａｌ ｓｔｕｄｉｅｓ． Ａｍ Ｊ Ｍｅｄ １９８７；８３：６０～５を参照のこと）、アルツハイマー病を改善し得ること（例えば、Ｍｏｒｉｓｏｎ， Ｌ． Ｄ．， Ｓｍｉｔｈ， Ｄ． Ｄ．， ａｎｄ Ｋｉｓｈ， Ｓ． Ｊ．， Ｂｒａｉｎ Ｓ－ａｄｅｎｏｓｙｌｍｅｔｈｉｏｎｉｎｅ ｌｅｖｅｌｓ ａｒｅ ｓｅｖｅｒｅｌｙ ｄｅｃｒｅａｓｅｄ ｉｎ Ａｌｚｈｅｉｍｅｒ’ｓ ｄｉｓｅａｓｅ． Ｊ． Ｎｅｕｒｏｃｈｅｍ．， ６７， １３２８-１３３１ （１９９６）を参照のこと）、ＨＩＶ感染による末梢神経障害または脊髄症を改善し得ること（例えば、Ｋｅａｔｉｎｇ ＪＮ， Ｔｒｉｍｂｌｅ ＫＣ， Ｍｕｌｃａｈｙ Ｆ， Ｓｃｏｔｔ ＪＭ， Ｗｅｉｒ ＤＧ， Ｅｖｉｄｅｎｃｅ ｏｆ ｂｒａｉｎ ｍｅｔｈｌｔｒａｎｓｆｅｒａｓｅ ｉｎｈｉｂｉｔｉｏｎ ａｎｄ ｅａｒｌｙ ｂｒａｉｎ ｉｎｖｏｌｖｅｍｅｎｔ ｉｎ ＨＩＶ－ｐｏｓｉｔｉｖｅ ｐａｔｉｅｎｔｓ． Ｌａｎｃｅｔ， ３３７， ９３５－９３９， （１９９１）；Ｓｕｒｅｔｅｅｓ Ｒ， Ｈｙｌａｎｄ Ｋ， Ｓｍｉｔｈ Ｉ．， Ｃｅｎｔｒａｌ ｎｅｒｖｏｕｓ ｓｙｓｔｅｍ ｍｅｔｈｙｌ－ｇｒｏｕｐ ｍｅｔａｂｏｌｉｓｍ ｉｎ ｃｈｉｌｄｒｅｎ ｗｉｔｈ ｎｅｕｒｏｌｏｇｉｃａｌ ｃｏｍｐｌｉｃａｔｉｏｎｓ ｏｆ ＨＩＶ ｉｎｆｅｃｔｉｏｎ． Ｌａｎｃｅｔ， ３３５， ６１９－６２１， （１９９０）；Ｃａｓｔａｇｎａ Ａ， Ｌｅ Ｇｒａｚｉｅ Ｃ， Ａｃｃｏｒｄｉｎｉ Ａ， Ｇｉｕｌｉｄｏｒｉ Ｐ， Ｃａｖａｌｌｉ Ｇ， Ｂｏｔｔｉｇｌｉｅｒｉ Ｔ， Ｌａｚｚａｒｉｎ Ａ．， Ｃｒｅｂｒｏｓｐｉｎａｌ ｆｌｕｉｄ Ｓ－ａｄｅｎｏｓｙｌ－ｍｅｔｈｉｏｎｉｎｅ （ＳＡＭｅ） ａｎｄ ｇｌｕｔａｔｈｉｏｎｅ ｃｏｎｃｅｎｔｒａｔｉｏｎｓ ｉｎ ＨＩＶ ｉｎｆｅｃｔｉｏｎ ： ｅｆｆｅｃｔ ｏｆ ｐａｒｅｎｔｅｒａｌ ｔｒｅａｔｍｅｎｔ ｗｉｔｈ ＳＡＭｅ．， Ｎｅｕｒｏｌｏｇｙ， ４５， １６７８－１６８３， （１９９５）などを参照のこと）などの医薬用途を有することが知られている。 (Pharmaceutical composition containing S-adenosylmethionine)
S-adenosylmethionine is well known to have a variety of pharmaceutical uses. For example, S-adenosylmethionine alleviates liver damage (eg, reduces mortality due to cirrhosis) (eg, Lieber CS. Role of S-adenosyl-L-methionine in the treatment of liver diseases. J Hepatol). 1999; 30: 1155-9; Williams R, Lieber CS. The role of SAMe in the treatment of liver disease. Drugs 1990; 40 (suppl): 1-2, Mato JM, eJaF. S-Adenylosyllineine in alcoholic liver cirrhosis: a random Ized, placebo-controlled, double-blind, multicenter clinical trial. See J Hepatol 1999; 30: 1081-9, etc.), have a therapeutic effect on depression (eg, Janicak PG, M , Et al.S-Adenosylmethionine: a literature review and premier report report.Ala J Med Sci 1988; 25: 306-13; in liv . Er dysfunction and affective disorders in relation to its physiological role in cell metabolism Drugs 1989; 38:.. 389-416; Bressa GM S-Adenosyl-L-methionine (SAMe) as antidepressant: meta-analysis of clinical studies Acta Neurol Scand 1994; 154: 7-14, etc.) and useful for the treatment of arthritis (see, for example, Bradley JD, Flosser D, Katz BP, et al. A randomized, double blind, placebo controlled trial of intravenous loading with S-adenosyltherthene te te te r a te s a te s a te s a s ed a s ti s s s ed ner ti s e n a te s a ti s e a ner ti s ed s a ner ti s e n a ti s e n a s s ed a s i n a s i n a ti s e n a i n a t e n a s ti s e n a s e n a i n a n i s s ti s e n a s i n a n s ti s e n a s s ed s a s o J Rheumatol 1994; 21: 905-11; Padova C.I. S-Adenylosyllineine in the treatment of osteoarthritis: review of the clinical studies. Am J Med 1987; 83: 60-5), and can improve Alzheimer's disease (eg, Morison, LD, Smith, DD, and Kish, SJ, Brain S). -Adenosylmethine levels are gradually developed in Alzheimer's disease. See J. Neurochem., 67, 1328-1331 (1996), may improve peripheral neuropathy or myelopathy due to HIV infection, eg N , Trimble KC, Mulcahy F, Scott JM, Weir DG, Evidence of brain methyltransferase inhibition and earl . Brain involvement in HIV-positive patients Lancet, 337, 935-939, (1991);. Suretees R, Hyland K, Smith I., Central nervous system methyl-group metabolism in children with neurological complications of HIV infection Lancet, 335, 619-621, (1990); Castagna A, Le Grazie C, Accordini A, Giulidri P, Cavalli G, Bottiglieri T, Lazzarin A., Crebrospinal fluid S-adden. Ethionine (SAMe) and glutation contentions in HIV effect: see the use of effect of parental treatment with SAMe., Neurology, 45, 1678-1683 (1995), etc.).
本明細書中で、鬱病とは、代表的に精神病性の鬱病をいう。
In this specification, depression typically refers to psychotic depression.
（本発明の組成物の製造）
好ましい実施形態において、本発明の組成物は、Ｓ－アデノシルメチオニン産生能を有する酵母を培養し、Ｓ－アデノシルメチオニンを産生させ、この酵母培養培地に酸性メタリン酸ナトリウムを添加することによって製造される。この酵母は、好ましくは酵母Ｓａｃｃｈａｒｏｍｙｃｅｓ ｃｅｒｅｖｉｓｉａｅ Ｋ－７株（清酒酵母協会７号）である。酵母培養培地への酸性メタリン酸ナトリウムの添加は、酵母の培養中に行われてもよいし、培養後に行われてもよい。好ましくは、酵母を培養してＳ－アデノシルメチオニンを産生させた後に培養液を除き、酵母菌体の濃縮液を得て、その濃縮液に酸性メタリン酸ナトリウムを添加する。この酵母菌体の濃縮液は、培養液を遠心分離（例えば、８，０００ｒｐｍ）し、上清を除いて、菌体を回収し、その回収した菌体に除いた上清液を適量加え、菌体濃縮液とすることによって調製され得る。 (Production of the composition of the present invention)
In a preferred embodiment, the composition of the present invention is produced by culturing yeast having the ability to produce S-adenosylmethionine, producing S-adenosylmethionine, and adding acidic sodium metaphosphate to the yeast culture medium. Is done. This yeast is preferably the yeast Saccharomyces cerevisiae K-7 strain (Sake Yeast Association No. 7). The addition of acidic sodium metaphosphate to the yeast culture medium may be performed during the culture of the yeast or may be performed after the culture. Preferably, after the yeast is cultured to produce S-adenosylmethionine, the culture solution is removed to obtain a yeast cell concentrate, and sodium metaphosphate is added to the concentrate. This yeast cell concentrate is obtained by centrifuging the culture (for example, 8,000 rpm), removing the supernatant, collecting the cells, and adding an appropriate amount of the supernatant removed to the collected cells, It can be prepared by preparing a bacterial cell concentrate.
好ましい実施形態において、本発明の組成物は、Ｓ－アデノシルメチオニン産生能を有する酵母を培養し、Ｓ－アデノシルメチオニンを産生させ、この酵母培養培地に酸性メタリン酸ナトリウムを添加することによって製造される。この酵母は、好ましくは酵母Ｓａｃｃｈａｒｏｍｙｃｅｓ ｃｅｒｅｖｉｓｉａｅ Ｋ－７株（清酒酵母協会７号）である。酵母培養培地への酸性メタリン酸ナトリウムの添加は、酵母の培養中に行われてもよいし、培養後に行われてもよい。好ましくは、酵母を培養してＳ－アデノシルメチオニンを産生させた後に培養液を除き、酵母菌体の濃縮液を得て、その濃縮液に酸性メタリン酸ナトリウムを添加する。この酵母菌体の濃縮液は、培養液を遠心分離（例えば、８，０００ｒｐｍ）し、上清を除いて、菌体を回収し、その回収した菌体に除いた上清液を適量加え、菌体濃縮液とすることによって調製され得る。 (Production of the composition of the present invention)
In a preferred embodiment, the composition of the present invention is produced by culturing yeast having the ability to produce S-adenosylmethionine, producing S-adenosylmethionine, and adding acidic sodium metaphosphate to the yeast culture medium. Is done. This yeast is preferably the yeast Saccharomyces cerevisiae K-7 strain (Sake Yeast Association No. 7). The addition of acidic sodium metaphosphate to the yeast culture medium may be performed during the culture of the yeast or may be performed after the culture. Preferably, after the yeast is cultured to produce S-adenosylmethionine, the culture solution is removed to obtain a yeast cell concentrate, and sodium metaphosphate is added to the concentrate. This yeast cell concentrate is obtained by centrifuging the culture (for example, 8,000 rpm), removing the supernatant, collecting the cells, and adding an appropriate amount of the supernatant removed to the collected cells, It can be prepared by preparing a bacterial cell concentrate.
別の実施形態において、本発明の組成物は、上記のように酵母によって産生されたか、または酵母内に産生されたＳ-アデノシルメチオニンを精製し、その精製されたＳ-アデノシルメチオニンに対し、または化学的に合成されたＳ－アデノシルメチオニンに対し、酸性メタリン酸ナトリウムを添加することによっても製造され得る。Ｓ－アデノシルメチオニンの精製法は当該分野においては周知である。本発明におけるＳ－アデノシルメチオニンの精製は、Ｓ－アデノシルメチオニンの濃度を高める任意の方法によって達成され得る。１つの例として、本発明におけるＳ－アデノシルメチオニンの精製は、Ｓ－アデノシルメチオニンを産生した酵母菌体を凍結・融解することにより得られた抽出液を濃縮および晶析することにより達成され得る。Ｓ－アデノシルメチオニン抽出液の濃縮は、Ｓ－アデノシルメチオニンの濃縮を達成することができる当業者に周知の方法によって行うことができる。この濃縮法としては、例えば、合成樹脂または陽イオン交換樹脂による吸着と逆透析による濃縮との組み合わせが挙げられるが、これに限定されない。Ｓ－アデノシルメチオニンの濃縮のために使用され得る吸着剤としては、合成樹脂（例えば、合成樹脂セパビーズＳＰ－２００（三菱化学株式会社、日本、東京））が挙げられるが、これに限定されない。Ｓ－アデノシルメチオニンの濃縮のために使用され得るイオン交換樹脂としては、弱酸性陽イオン交換樹脂（例えば、アンバーライトＩＲＣ－５０（オルガノ株式会社、日本、東京））が挙げられるが、これに限定されない。Ｓ－アデノシルメチオニンの濃縮のための逆透析は、逆浸透膜（例えば、逆浸透Ｒｅｖｅｒｓｅ Ｏｓｍｏｓｉｓ（ＲＯ）：製品名ロメンブラ(東レ株式会社、日本、東京)）を用いた透析が挙げられるが、これに限定されない。Ｓ－アデノシルメチオニン濃縮液の晶析は、例えば、アセトン-メタノール系溶媒を用いることによって行うことができるが、これに限定されない。
In another embodiment, the composition of the present invention purifies S-adenosylmethionine produced by or produced in yeast as described above and against the purified S-adenosylmethionine. Alternatively, it can also be produced by adding acidic sodium metaphosphate to chemically synthesized S-adenosylmethionine. Methods for purifying S-adenosylmethionine are well known in the art. Purification of S-adenosylmethionine in the present invention can be accomplished by any method that increases the concentration of S-adenosylmethionine. As an example, the purification of S-adenosylmethionine in the present invention is achieved by concentrating and crystallizing an extract obtained by freezing and thawing yeast cells that produced S-adenosylmethionine. obtain. Concentration of the S-adenosylmethionine extract can be performed by methods well known to those skilled in the art that can achieve enrichment of S-adenosylmethionine. Examples of the concentration method include, but are not limited to, a combination of adsorption by a synthetic resin or cation exchange resin and concentration by reverse dialysis. Adsorbents that can be used for concentration of S-adenosylmethionine include, but are not limited to, synthetic resins (eg, synthetic resin Sepabeads SP-200 (Mitsubishi Chemical Corporation, Tokyo, Japan)). Examples of ion exchange resins that can be used for the concentration of S-adenosylmethionine include weakly acidic cation exchange resins (for example, Amberlite IRC-50 (Organo Corporation, Tokyo, Japan)). It is not limited. Reverse dialysis for concentration of S-adenosylmethionine includes dialysis using a reverse osmosis membrane (for example, reverse osmosis Reverse Osmosis (RO): product name Romenbra (Toray Industries, Inc., Tokyo, Japan)). It is not limited to this. Crystallization of the S-adenosylmethionine concentrate can be performed by using, for example, an acetone-methanol solvent, but is not limited thereto.
特定の実施形態において、Ｓ－アデノシルメチオニンを産生した酵母を含む濃縮液に酸性メタリン酸ナトリウムを添加した後、この混合物を乾燥し得る。乾燥方法としては、凍結乾燥、噴霧乾燥または減圧乾燥などが挙げられるが、これらに限定されない。本発明における乾燥方法としては凍結乾燥が好ましい。特定の実施形態において、上記混合物を、－８０℃で一晩凍結し、凍結乾燥を７２ｈ行うことによって乾燥させることができる。
In certain embodiments, after adding acidic sodium metaphosphate to a concentrate containing yeast that produced S-adenosylmethionine, the mixture may be dried. Examples of the drying method include, but are not limited to, freeze drying, spray drying, and reduced pressure drying. As the drying method in the present invention, freeze-drying is preferred. In certain embodiments, the mixture can be dried at −80 ° C. overnight and lyophilized for 72 h.
上記酵母を培養する際に使用する炭素源は、酵母が資化し得るものであれば特に制限はなく、例えば、グルコース、ショ糖、澱粉、廃糖蜜等の炭水化物、エタノール等のアルコール、または酢酸等の有機酸が挙げられる。窒素源は、使用する酵母が資化し得るものであれば特に制限はなく、例えば、アンモニア、硝酸、尿素等の無機体窒素化合物、または酵母エキス、麦芽エキス等の有機体窒素化合物を含むものが挙げられる。また、無機塩類としては、リン酸、カリウム、ナトリウム、マグネシウム、カルシウム、鉄、亜鉛、マンガン、コバルト、銅、モリブデン等の塩が用いられ得る。さらに、Ｓ－アデノシルメチオニンの骨格を構成するメチオニン、アデニン、アデノシルリボヌクレオシドを添加して培養することもできる。
The carbon source used when 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, etc. The organic acid is mentioned. The nitrogen source is not particularly limited as long as the yeast to be used can assimilate, and includes, for example, inorganic nitrogen compounds such as ammonia, nitric acid, urea, or organic nitrogen compounds such as yeast extract and malt extract. Can be mentioned. Moreover, as inorganic salts, salts of phosphoric acid, potassium, sodium, magnesium, calcium, iron, zinc, manganese, cobalt, copper, molybdenum and the like can be used. Further, methionine, adenine, and adenosylribonucleoside constituting the skeleton of S-adenosylmethionine can be added and cultured.
本発明におけるＳ－アデノシルメチオニン産生酵母の培養は、嫌気条件、好気条件のいずれでも実施可能であるが、酵母菌体を効率良く増殖させるために好気条件が好ましい。本発明におけるＳ－アデノシルメチオニン産生酵母の培養温度は、酵母が増殖できる範囲内の任意の温度であるが、１５～４０℃の範囲での培養が好ましく、２５～３５℃の範囲がさらに好ましい。本発明におけるＳ－アデノシルメチオニン産生酵母の培養時のｐＨは、酵母が増殖できる範囲内の任意のｐＨであるが、ｐＨ３．５～８．０の範囲での培養が好ましく、ｐＨ４．０～６．５の範囲がさらに好ましい。その他、本発明におけるＳ－アデノシルメチオニン産生酵母の培養方法および培養条件は、当業者は一般的な酵母の培養方法または培養条件に従って適切に決定することができる。特定の実施形態において、酵母は５Ｌ容ジャーファーメンター（仕込み培地量：３Ｌ）を用いて、培養温度２８℃、攪拌速度 ５００ｒｐｍ、培養時間３６－４８ｈ、通気量０．５ＶＶＭ、培地組成（ｗ／１００ｍＬ）：グルコース５％、酵母エキス０．７５％、ペプトン２．０％、メチオニン０．１５％の条件で培養される。
The cultivation of S-adenosylmethionine-producing yeast in the present invention can be carried out under either anaerobic conditions or aerobic conditions, but aerobic conditions are preferred in order to efficiently grow yeast cells. The culture temperature of the S-adenosylmethionine-producing yeast in the present invention is an arbitrary temperature within the range in which the yeast can grow, but is preferably cultured in the range of 15 to 40 ° C, more preferably in the range of 25 to 35 ° C. . The pH during the culture of the S-adenosylmethionine-producing yeast in the present invention is an arbitrary pH within the range in which the yeast can grow, but the culture in the range of pH 3.5 to 8.0 is preferable, and pH 4.0 to A range of 6.5 is more preferred. In addition, the culture method and culture conditions for S-adenosylmethionine-producing yeast in the present invention can be appropriately determined by those skilled in the art according to general yeast culture methods or culture conditions. In a specific embodiment, the yeast is a 5 L jar fermenter (feed medium amount: 3 L), the culture temperature is 28 ° C., the stirring speed is 500 rpm, the culture time is 36-48 h, the aeration rate is 0.5 VVM, the medium composition (w / 100 mL): cultured under conditions of 5% glucose, 0.75% yeast extract, 2.0% peptone, and 0.15% methionine.
本明細書において引用された、科学文献、特許、特許出願などの参考文献は、その全体が、各々具体的に記載されたのと同じ程度に本明細書において参考として援用される。
References such as scientific literature, patents, and patent applications cited in this specification are incorporated herein by reference in their entirety to the same extent as if they were specifically described.
以上、本発明を、理解の容易のために好ましい実施形態を示して説明してきた。以下に、実施例に基づいて本発明を説明するが、上述の説明および以下の実施例は、例示の目的のみに提供され、本発明を限定する目的で提供したのではない。従って、本発明の範囲は、本明細書に具体的に記載された実施形態にも実施例にも限定されず、請求の範囲によってのみ限定される。
As described above, the present invention has been described by showing preferred embodiments for easy understanding. In the following, the present invention will be described based on examples, but the above description and the following examples are provided only for the purpose of illustration, not for the purpose of limiting the present invention. Accordingly, the scope of the present invention is not limited to the embodiments or examples specifically described in this specification, but is limited only by the scope of the claims.
（実施例１．各種リン酸化合物の安定化効果および酸性処理の影響の検討）
本実施例では、従来からＳ－アデノシルメチオニンを安定化することが知られているリン酸化合物であるポリリン酸ナトリウムおよびメタリン酸ナトリウムについて、その安定化効果を確認した。 (Example 1. Examination of stabilization effect of various phosphate compounds and influence of acid treatment)
In this example, the stabilizing effect of sodium polyphosphate and sodium metaphosphate, which have been conventionally known to stabilize S-adenosylmethionine, was confirmed.
本実施例では、従来からＳ－アデノシルメチオニンを安定化することが知られているリン酸化合物であるポリリン酸ナトリウムおよびメタリン酸ナトリウムについて、その安定化効果を確認した。 (Example 1. Examination of stabilization effect of various phosphate compounds and influence of acid treatment)
In this example, the stabilizing effect of sodium polyphosphate and sodium metaphosphate, which have been conventionally known to stabilize S-adenosylmethionine, was confirmed.
酵母Ｓａｃｃｈａｒｏｍｙｃｅｓ ｃｅｒｅｖｉｓｉａｅ Ｋ－７株（清酒酵母協会７号）、５Ｌ容ジャーファーメンター（仕込み培地量：３Ｌ）を用いて、培養温度２８℃、攪拌速度 ５００ｒｐｍ、培養時間３６－４８ｈ、通気量０．５ＶＶＭ、培地組成（ｗ／１００ｍＬ）：グルコース５％、酵母エキス０．７５％、ペプトン２．０％、メチオニン０．１５％で培養した。この培養液を遠心分離（８，０００ｒｐｍ）し、上清を除いて、菌体を回収した。回収した菌体に除いた上清液を適量加え、菌体濃縮液を調製した。濃縮液中のＳ－アデノシルメチオニン濃度を測定し、ピロリン酸ナトリウム（Ｎａ４Ｐ２Ｏ７：太洋化学工業株式会社（日本、東京）製のピロリン酸四ナトリウム（結晶・無水））、ポリリン酸ナトリウム（Ｎａ５Ｐ３Ｏ１０：太洋化学工業株式会社（日本、東京）製のトリポリリン酸ナトリウム）、およびメタリン酸ナトリウム（（ＮａＰＯ３）ｎ：太洋化学工業株式会社（日本、東京）製のヘキサメタリン酸ナトリウム）を、それぞれＳ－アデノシルメチオニンの４倍量になるように菌体濃縮液に添加した。調製したサンプルを－８０℃で一晩凍結した。凍結乾燥を７２ｈ行い、酵母粉末を調製した。この酵母粉末をアルミパウチに梱包し、加速試験機（Ａｄｖａｎｔｅｃ，モデルＴＨＥ０５１ＦＡ）内（４０℃、湿度７５％）で保管した。この条件での加速試験機１日の保管は、常温保管の６日に相当する。定時的に酵母粉末のサンプリングを行い、過塩素酸を用いてＳ－アデノシルメチオニンの抽出を行った。具体的には、酵母粉末０．０２ｇに１０％過塩素酸１ｍＬを加え、１時間抽出を行い、遠心分離（１０，０００ｒｐｍ，１０分）により上清（抽出液）を回収した。Ｓ－アデノシルメチオニンの測定は、ＵＰＬＣ（Ｗａｔｅｒｓ，モデルＴＵＶ）を用い、抽出液を０．１％ギ酸＋５ｍＭノナンスルフォン酸ナトリウム混合液とアセトニトリルによるグラジェントで分析した。使用したカラムは、ＵＫ－Ｃ１８（インタクト株式会社（日本、東京）；４．６×２５０ｍｍ，３μｍ）であった。結果を以下の表１に示す。結果は、各サンプルの調製時の値を１００％として相対値で示されていることに注意されたい。
Using yeast Saccharomyces cerevisiae K-7 strain (Sake Yeast Association No. 7), 5 L jar fermenter (feeding medium amount: 3 L), culture temperature 28 ° C., stirring speed 500 rpm, culture time 36-48 h, aeration rate 0. 5 VVM, medium composition (w / 100 mL): cultured with glucose 5%, yeast extract 0.75%, peptone 2.0%, methionine 0.15%. The culture was centrifuged (8,000 rpm), the supernatant was removed, and the cells were collected. An appropriate amount of the supernatant liquid removed from the recovered cells was added to prepare a cell concentrate. The concentration of S-adenosylmethionine in the concentrate was measured and sodium pyrophosphate (Na 4 P 2 O 7 : tetrasodium pyrophosphate (crystal / anhydrous) manufactured by Taiyo Chemical Co., Ltd., Tokyo, Japan), polyphosphorus Sodium phosphate (Na 5 P 3 O 10 : sodium tripolyphosphate manufactured by Taiyo Chemical Co., Ltd., Tokyo, Japan) and sodium metaphosphate ((NaPO 3 ) n : Taiyo Chemical Co., Ltd. (Tokyo, Japan) Sodium hexametaphosphate) was added to the cell concentrate so as to be 4 times the amount of S-adenosylmethionine. The prepared sample was frozen at −80 ° C. overnight. Lyophilization was performed for 72 hours to prepare yeast powder. The yeast powder was packed in an aluminum pouch and stored in an acceleration tester (Advantec, model THE051FA) (40 ° C., humidity 75%). One day storage of the accelerated testing machine under these conditions corresponds to six days of room temperature storage. Yeast powder was sampled regularly and S-adenosylmethionine was extracted using perchloric acid. Specifically, 1 mL of 10% perchloric acid was added to 0.02 g of yeast powder, extraction was performed for 1 hour, and the supernatant (extract) was collected by centrifugation (10,000 rpm, 10 minutes). For the measurement of S-adenosylmethionine, UPLC (Waters, model TUV) was used, and the extract was analyzed by a gradient of 0.1% formic acid + 5 mM sodium nonanesulfonate and acetonitrile. The column used was UK-C18 (Intact Corporation (Tokyo, Japan); 4.6 × 250 mm, 3 μm). The results are shown in Table 1 below. Note that the results are shown as relative values, with the value at the time of preparation of each sample being 100%.
表１．各種リン酸化合物による安定化効果
Table 1. Stabilization effect by various phosphate compounds
表１に示されるように、安定化剤無添加のＳ－アデノシルメチオニンと比較して、安定化剤としてピロリン酸ナトリウム、ポリリン酸ナトリウムまたはメタリン酸ナトリウムを添加したＳ－アデノシルメチオニンにおいては、ある程度の安定性の向上が観察された。しかしながら、この安定性の向上では不十分であると考えられるため、さらなる効率的な安定化法を検討した。
As shown in Table 1, compared to S-adenosylmethionine without addition of a stabilizer, in S-adenosylmethionine to which sodium pyrophosphate, sodium polyphosphate or sodium metaphosphate was added as a stabilizer, Some improvement in stability was observed. However, since this improvement in stability is considered insufficient, a more efficient stabilization method was investigated.
上記のＳ－アデノシルメチオニンとピロリン酸ナトリウム、ポリリン酸ナトリウム、またはメタリン酸ナトリウムとを含む組成物はアルカリ性を呈する。Ｓ－アデノシルメチオニンの安定化に対するｐＨの影響を検討するために、ピロリン酸ナトリウム、ポリリン酸ナトリウム、またはメタリン酸ナトリウムによるＳ－アデノシルメチオニンの安定化を、酸性条件下で行い、その安定化の程度を検証した。酸性処理は、Ｓ－アデノシルメチオニンの４倍量で各種リン酸化合物を添加した後に、７８％硫酸でｐＨを１に調整することによって行った。
The composition containing the above S-adenosylmethionine and sodium pyrophosphate, sodium polyphosphate, or sodium metaphosphate exhibits alkalinity. In order to examine the effect of pH on the stabilization of S-adenosylmethionine, stabilization of S-adenosylmethionine with sodium pyrophosphate, sodium polyphosphate, or sodium metaphosphate was carried out under acidic conditions. We verified the degree of. The acid treatment was performed by adding various phosphoric acid compounds in 4 times the amount of S-adenosylmethionine and then adjusting the pH to 1 with 78% sulfuric acid.
具体的には、酵母Ｓａｃｃｈａｒｏｍｙｃｅｓ ｃｅｒｅｖｉｓｉａｅ Ｋ－７株（清酒酵母協会７号）、５Ｌ容ジャーファーメンター（仕込み培地量：３Ｌ）を用いて、培養温度２８℃、攪拌速度 ５００ｒｐｍ、培養時間３６－４８ｈ、通気量０．５ＶＶＭ、培地組成（ｗ／１００ｍＬ）：グルコース５％、酵母エキス０．７５％、ペプトン２．０％、メチオニン０．１５％で培養した。この培養液を遠心分離（８，０００ｒｐｍ）し、上清を除いて、菌体を回収した。回収した菌体に除いた上清液を適量加え、菌体濃縮液を調製した。濃縮液中のＳ－アデノシルメチオニン濃度を測定し、ピロリン酸ナトリウム（Ｎａ４Ｐ２Ｏ７：太洋化学工業株式会社（日本、東京）製のピロリン酸四ナトリウム（結晶・無水））、ポリリン酸ナトリウム（Ｎａ５Ｐ３Ｏ１０：太洋化学工業株式会社（日本、東京）製のトリポリリン酸ナトリウム）、およびメタリン酸ナトリウム（（ＮａＰＯ３）ｎ：太洋化学工業株式会社（日本、東京）製のヘキサメタリン酸ナトリウム）を、それぞれＳ－アデノシルメチオニンの４倍量になるように菌体濃縮液に添加した。各サンプルに７８％硫酸を添加し、ｐＨ１になるようにｐＨを調整した。調製したサンプルを－８０℃で一晩凍結した。凍結乾燥を７２ｈ行い、酵母粉末を調製した。この酵母粉末をアルミパウチに梱包し、加速試験機加速試験機（Ａｄｖａｎｔｅｃ，モデルＴＨＥ０５１ＦＡ）内（４０℃、湿度７５％）で保管した。この条件での加速試験機１日の保管は、常温保管の６日に相当する。定時的に酵母粉末のサンプリングを行い、過塩素酸を用いてＳ－アデノシルメチオニンの抽出を行った。具体的には、酵母粉末０．０２ｇに１０％過塩素酸１ｍＬを加え、１時間抽出を行い、遠心分離（１０，０００ｒｐｍ，１０分）により上清（抽出液）を回収した。Ｓ－アデノシルメチオニンの測定は、ＵＰＬＣ（Ｗａｔｅｒｓ，モデルＴＵＶ）を用い、抽出液を０．１％ギ酸＋５ｍＭノナンスルフォン酸ナトリウム混合液とアセトニトリルによるグラジェントで分析した。結果を以下の表２に示す。結果は、各サンプルの調製時の値を１００％として相対値で示されていることに注意されたい。
Specifically, using a yeast Saccharomyces cerevisiae K-7 strain (Sake Yeast Association No. 7), a 5 L jar fermenter (feeding medium amount: 3 L), a culture temperature of 28 ° C., a stirring speed of 500 rpm, and a culture time of 36 to 48 h. Aeration rate 0.5 VVM, medium composition (w / 100 mL): Glucose 5%, yeast extract 0.75%, peptone 2.0%, methionine 0.15%. The culture was centrifuged (8,000 rpm), the supernatant was removed, and the cells were collected. An appropriate amount of the supernatant liquid removed from the recovered cells was added to prepare a cell concentrate. The concentration of S-adenosylmethionine in the concentrate was measured and sodium pyrophosphate (Na 4 P 2 O 7 : tetrasodium pyrophosphate (crystal / anhydrous) manufactured by Taiyo Chemical Co., Ltd., Tokyo, Japan), polyphosphorus Sodium phosphate (Na 5 P 3 O 10 : sodium tripolyphosphate manufactured by Taiyo Chemical Co., Ltd., Tokyo, Japan) and sodium metaphosphate ((NaPO 3 ) n : Taiyo Chemical Industries, Ltd. (Tokyo, Japan) Sodium hexametaphosphate) was added to the cell concentrate so as to be 4 times the amount of S-adenosylmethionine. 78% sulfuric acid was added to each sample, and the pH was adjusted to pH 1. The prepared sample was frozen at −80 ° C. overnight. Lyophilization was performed for 72 hours to prepare yeast powder. This yeast powder was packed in an aluminum pouch and stored in an accelerated tester (Advantec, model THE051FA) (40 ° C., humidity 75%). One day storage of the accelerated testing machine under these conditions corresponds to six days of room temperature storage. Yeast powder was sampled regularly and S-adenosylmethionine was extracted using perchloric acid. Specifically, 1 mL of 10% perchloric acid was added to 0.02 g of yeast powder, extraction was performed for 1 hour, and the supernatant (extract) was collected by centrifugation (10,000 rpm, 10 minutes). For the measurement of S-adenosylmethionine, UPLC (Waters, model TUV) was used, and the extract was analyzed by a gradient of 0.1% formic acid + 5 mM sodium nonanesulfonate and acetonitrile. The results are shown in Table 2 below. Note that the results are shown as relative values, with the value at the time of preparation of each sample being 100%.
表２．酸性条件下での各種リン酸化合物による安定化効果
Table 2. Stabilization effect of various phosphate compounds under acidic conditions
表１および表２の結果を、図１にまとめる。
The results of Table 1 and Table 2 are summarized in FIG.
以上の結果より、ピロリン酸ナトリウム、ポリリン酸ナトリウムおよびメタリン酸ナトリウムによって、無添加と比較すると一定の安定化効果が得られるが、それらは不十分であること、および酸性条件下でこれらの物質による安定化を行っても有意な安定性向上は観察されないことが実証された。
From the above results, sodium pyrophosphate, sodium polyphosphate, and sodium metaphosphate provide a certain stabilizing effect compared to no addition, but they are insufficient and due to these substances under acidic conditions It was demonstrated that no significant improvement in stability was observed with stabilization.
（実施例２．酸性メタリン酸ナトリウムによるＳ－アデノシルメチオニンの安定化）
本実施例では、酸性メタリン酸ナトリウムによるＳ－アデノシルメチオニンの安定化効果を検討した。 (Example 2. Stabilization of S-adenosylmethionine with sodium acid metaphosphate)
In this example, the stabilization effect of S-adenosylmethionine by acidic sodium metaphosphate was examined.
本実施例では、酸性メタリン酸ナトリウムによるＳ－アデノシルメチオニンの安定化効果を検討した。 (Example 2. Stabilization of S-adenosylmethionine with sodium acid metaphosphate)
In this example, the stabilization effect of S-adenosylmethionine by acidic sodium metaphosphate was examined.
酵母Ｓａｃｃｈａｒｏｍｙｃｅｓ ｃｅｒｅｖｉｓｉａｅ Ｋ－７株（清酒酵母協会７号）、５Ｌ容ジャーファーメンター（仕込み培地量：３Ｌ）を用いて、培養温度２８℃、攪拌速度 ５００ｒｐｍ、培養時間３６－４８ｈ、通気量０．５ＶＶＭ、培地組成（ｗ／１００ｍＬ）：グルコース５％、酵母エキス０．７５％、ペプトン２．０％、メチオニン０．１５％で培養した。この培養液を遠心分離（８，０００ｒｐｍ）し、上清を除いて、菌体を回収した。回収した菌体に除いた上清液を適量加え、菌体濃縮液を調製した。濃縮液中のＳ－アデノシルメチオニン濃度を測定し、酸性メタリン酸ナトリウム（｛ＮａｘＨｙ（ＰＯ３）ｘ＋ｙ｝ｎ（燐化学工業株式会社（日本、富山）製の酸性ヘキサメタリン酸ナトリウム）を、Ｓ－アデノシルメチオニンの２．５倍量、５倍量、７．５倍量および１０倍量になるように菌体濃縮液に添加した。調製した４つのサンプルを－８０℃で一晩凍結した。凍結乾燥を７２ｈ行い、酵母粉末を調製した。この酵母粉末をアルミパウチに梱包し、加速試験機加速試験機（Ａｄｖａｎｔｅｃ，モデルＴＨＥ０５１ＦＡ）内（４０℃、湿度７５％）で保管した。この条件での加速試験機１日の保管は、常温保管の６日に相当する。定時的に酵母粉末のサンプリングを行い、過塩素酸を用いてＳ－アデノシルメチオニンの抽出を行った。具体的には、酵母粉末０．０２ｇに１０％過塩素酸１ｍＬを加え、１時間抽出を行い、遠心分離（１０，０００ｒｐｍ，１０分）により上清（抽出液）を回収した。Ｓ－アデノシルメチオニンの測定は、ＵＰＬＣ（Ｗａｔｅｒｓ，モデルＴＵＶ）を用い、抽出液を０．１％ギ酸＋５ｍＭノナンスルフォン酸ナトリウム混合液とアセトニトリルによるグラジェントで分析した。結果を以下の表３および図２に示す。結果は、各サンプルの調製時の値を１００％として相対値で示されていることに注意されたい。
Using yeast Saccharomyces cerevisiae K-7 strain (Sake Yeast Association No. 7), 5 L jar fermenter (feeding medium amount: 3 L), culture temperature 28 ° C., stirring speed 500 rpm, culture time 36-48 h, aeration rate 0. 5 VVM, medium composition (w / 100 mL): cultured with glucose 5%, yeast extract 0.75%, peptone 2.0%, methionine 0.15%. The culture was centrifuged (8,000 rpm), the supernatant was removed, and the cells were collected. An appropriate amount of the supernatant liquid removed from the recovered cells was added to prepare a cell concentrate. The concentration of S-adenosylmethionine in the concentrate was measured, and sodium acid metaphosphate ({Na x H y (PO 3 ) x + y } n (acid sodium hexametaphosphate manufactured by Rin Chemical Industry Co., Ltd., Toyama, Japan)) , S-adenosylmethionine 2.5 times, 5 times, 7.5 times, and 10 times the amount were added to the cell concentrate. The yeast powder was packed in an aluminum pouch and stored in an accelerated tester (Advantec, model THE051FA) (40 ° C., 75% humidity). One day storage of the accelerated test machine under these conditions corresponds to 6 days of storage at room temperature, sampling yeast powder on a regular basis, and extracting S-adenosylmethionine using perchloric acid. Specifically, 1 mL of 10% perchloric acid was added to 0.02 g of yeast powder, extraction was performed for 1 hour, and the supernatant (extract) was collected by centrifugation (10,000 rpm, 10 minutes). For the measurement of S-adenosylmethionine, UPLC (Waters, model TUV) was used, and the extract was analyzed by a gradient of 0.1% formic acid + 5 mM sodium nonanesulfonate and acetonitrile, and the results are shown in Table 3 below. The results are shown in Fig. 2. Note that the results are shown as relative values, with the value at the time of preparation of each sample being 100%.
表３．酸性メタリン酸ナトリウムによる安定化効果
Table 3. Stabilization effect by sodium acid metaphosphate
驚くべきことに、酸性メタリン酸ナトリウムによって、Ｓ－アデノシルメチオニンの予想外に顕著な安定化が達成された。この安定化効果は、試験した２．５倍量～１０倍量の全ての濃度において観察され、２．５倍量～７．５倍量の濃度においてより安定化が達成され、特に５倍量～７．５倍量の濃度において顕著な安定化が達成された。メタリン酸ナトリウムの添加、または酸性条件下でのメタリン酸ナトリウムの添加によっては顕著な安定化が達成されなかったことを示した実施例１の結果に鑑みると、表３において実証された酸性メタリン酸ナトリウムによるＳ－アデノシルメチオニンの顕著な安定化は全く予想外である。
Surprisingly, unexpectedly significant stabilization of S-adenosylmethionine was achieved with acidic sodium metaphosphate. This stabilizing effect is observed at all concentrations of 2.5 to 10 times tested, and more stabilization is achieved at concentrations of 2.5 to 7.5 times, especially 5 times. Significant stabilization was achieved at concentrations up to 7.5 times. In view of the results of Example 1 which showed that no significant stabilization was achieved by the addition of sodium metaphosphate or by addition of sodium metaphosphate under acidic conditions, the acidic metaphosphate demonstrated in Table 3 The remarkable stabilization of S-adenosylmethionine by sodium is totally unexpected.
また、上記条件での加速試験機１日の保管は、常温保管の６日に相当することから、表３の結果より、酸性メタリン酸ナトリウムを添加したＳ－アデノシルメチオニンを常温保管した場合、約１年経過後においても約７５～９０％程度が安定のまま残存することが分かる。これは、Ｓ－アデノシルメチオニンの飲食用、栄養補助用、医薬用、生薬用又は獣医学用への応用において有用である。
In addition, storage of the accelerated test machine for 1 day under the above conditions corresponds to 6 days of storage at room temperature. From the results in Table 3, when S-adenosylmethionine added with sodium acid metaphosphate was stored at room temperature, It can be seen that about 75 to 90% remains stable even after about one year. This is useful in the application of S-adenosylmethionine to food and drink, nutritional supplement, pharmaceutical, herbal medicine or veterinary medicine.
（実施例３．種々の酸性メタリン酸ナトリウム製品によるＳ－アデノシルメチオニン安定化効果）
本実施例では、製造元の異なる種々の酸性メタリン酸ナトリウム製品について、Ｓ－アデノシルメチオニン安定化効果の差異を検討した。 Example 3. S-adenosylmethionine stabilization effect by various acidic sodium metaphosphate products
In this example, the difference in S-adenosylmethionine stabilization effect was examined for various acidic sodium metaphosphate products from different manufacturers.
本実施例では、製造元の異なる種々の酸性メタリン酸ナトリウム製品について、Ｓ－アデノシルメチオニン安定化効果の差異を検討した。 Example 3. S-adenosylmethionine stabilization effect by various acidic sodium metaphosphate products
In this example, the difference in S-adenosylmethionine stabilization effect was examined for various acidic sodium metaphosphate products from different manufacturers.
酵母Ｓａｃｃｈａｒｏｍｙｃｅｓ ｃｅｒｅｖｉｓｉａｅ Ｋ－７株（清酒酵母協会７号）、５Ｌ容ジャーファーメンター（仕込み培地量：３Ｌ）を用いて、培養温度２８℃、攪拌速度 ５００ｒｐｍ、培養時間３６－４８ｈ、通気量０．５ＶＶＭ、培地組成（ｗ／１００ｍＬ）：グルコース５％、酵母エキス０．７５％、ペプトン２．０％、メチオニン０．１５％で培養した。この培養液を遠心分離（８，０００ｒｐｍ）し、上清を除いて、菌体を回収した。回収した菌体に除いた上清液を適量加え、菌体濃縮液を調製した。濃縮液中のＳ－アデノシルメチオニン濃度を測定し、燐化学工業株式会社（日本、富山）製の酸性ヘキサメタリン酸ナトリウム、エフシー化学株式会社（日本、大阪）製のニューエフシリンサンＦ、オルガノフードテック株式会社（日本、埼玉）製のポリリンサン １－Ｇ、大洋化学工業株式会社（日本、東京）製のマスコリンＦ－２、太平化学産業株式会社（日本、大阪）製のウルトラポリン、上野製薬株式会社（日本、大阪）製のタリンサンＵ（登録商標）、または、株式会社ポリホス化学研究所（日本、大阪）製のウルトラポリホスを、Ｓ－アデノシルメチオニンの４倍量になるように菌体濃縮液に添加した。また、比較例として、メタリン酸ナトリウム（オルガノフードテック株式会社（日本、埼玉）製のポリリンサン ５－Ｂおよび米山化学工業株式会社（日本、大阪）製のメタリン酸ナトリウム）をそれぞれ４倍量になるように菌体濃縮液に添加した。調製したサンプルを－８０℃で一晩凍結した。凍結乾燥を７２ｈ行い、酵母粉末を調製した。この酵母粉末をアルミパウチに梱包し、加速試験機加速試験機（Ａｄｖａｎｔｅｃ，モデルＴＨＥ０５１ＦＡ）内（４０℃、湿度７５％）で保管した。この条件での加速試験機１日の保管は、常温保管の６日に相当する。定時的に酵母粉末のサンプリングを行い、過塩素酸を用いてＳ－アデノシルメチオニンの抽出を行った。具体的には、酵母粉末０．０２ｇに１０％過塩素酸１ｍＬを加え、１時間抽出を行い、遠心分離（１０，０００ｒｐｍ，１０分）により上清（抽出液）を回収した。Ｓ－アデノシルメチオニンの測定は、ＵＰＬＣ（Ｗａｔｅｒｓ，モデルＴＵＶ）を用い、抽出液を０．１％ギ酸＋５ｍＭノナンスルフォン酸ナトリウム混合液とアセトニトリルによるグラジェントで分析した。各製品についての結果を以下の表４および図３に示す。以下の表における各項目と製品との対応は、以下の通りである。
Using yeast Saccharomyces cerevisiae K-7 strain (Sake Yeast Association No. 7), 5 L jar fermenter (feeding medium amount: 3 L), culture temperature 28 ° C., stirring speed 500 rpm, culture time 36-48 h, aeration rate 0. 5 VVM, medium composition (w / 100 mL): cultured with glucose 5%, yeast extract 0.75%, peptone 2.0%, methionine 0.15%. The culture was centrifuged (8,000 rpm), the supernatant was removed, and the cells were collected. An appropriate amount of the supernatant liquid removed from the recovered cells was added to prepare a cell concentrate. The concentration of S-adenosylmethionine in the concentrate was measured, and sodium acid hexametaphosphate manufactured by Phosphorus Chemical Industries, Ltd. (Toyama, Japan), New Fcillin Sun F, Organofood manufactured by FC Chemical Co., Ltd. (Osaka, Japan) Polyrinsan 1-G manufactured by Tech Co., Ltd. (Saitama, Japan), Muscorin F-2 manufactured by Taiyo Chemical Co., Ltd. (Tokyo, Japan), Ultraporin manufactured by Taihei Chemical Industrial Co., Ltd. (Osaka, Japan), Ueno Pharmaceutical Tallinsan U (registered trademark) manufactured by Osaka Co., Ltd. (Osaka, Japan) or Ultrapolyphos produced by Polyphos Chemical Laboratories (Osaka, Japan) is used in a quantity 4 times that of S-adenosylmethionine. Added to body concentrate. In addition, as a comparative example, sodium metaphosphate (polyphosphorusan 5-B manufactured by Organo Food Tech Co., Ltd. (Saitama, Japan) and sodium metaphosphate manufactured by Yoneyama Chemical Co., Ltd. (Osaka, Japan)) was each quadrupled It added to the microbial cell concentrate so that it might become. The prepared sample was frozen at −80 ° C. overnight. Lyophilization was performed for 72 hours to prepare yeast powder. This yeast powder was packed in an aluminum pouch and stored in an accelerated tester (Advantec, model THE051FA) (40 ° C., humidity 75%). One day storage of the accelerated testing machine under these conditions corresponds to six days of room temperature storage. Yeast powder was sampled regularly and S-adenosylmethionine was extracted using perchloric acid. Specifically, 1 mL of 10% perchloric acid was added to 0.02 g of yeast powder, extraction was performed for 1 hour, and the supernatant (extract) was collected by centrifugation (10,000 rpm, 10 minutes). For the measurement of S-adenosylmethionine, UPLC (Waters, model TUV) was used, and the extract was analyzed by a gradient of 0.1% formic acid + 5 mM sodium nonanesulfonate and acetonitrile. The results for each product are shown in Table 4 below and FIG. The correspondence between each item in the table below and the product is as follows.
Ａ．燐化学工業株式会社（日本、富山）製の酸性ヘキサメタリン酸ナトリウム
Ｂ．エフシー化学株式会社（日本、大阪）製のニューエフシリンサンＦ
Ｃ．オルガノフードテック株式会社（日本、埼玉）製のポリリンサン １－Ｇ
Ｄ．大洋化学工業株式会社（日本、東京）製のマスコリンＦ－２
Ｅ．太平化学産業株式会社（日本、大阪）製のウルトラポリン
Ｆ．上野製薬株式会社（日本、大阪）製のタリンサンＵ（登録商標）
Ｇ．株式会社ポリホス化学研究所（日本、大阪）製のウルトラポリホス
Ｈ．（比較例）オルガノフードテック株式会社（日本、埼玉）製のポリリンサン ５－Ｂ
Ｉ．（比較例）米山化学工業株式会社（日本、大阪）製のメタリン酸ナトリウム
なお、結果は、各サンプルの調製時の値を１００％として相対値で示されていることに注意されたい。 A. Acid sodium hexametaphosphate manufactured by Phosphorus Chemical Industries, Ltd. (Toyama, Japan) New Fsilin Sun F manufactured by FSC Ltd. (Osaka, Japan)
C. Polylinsan 1-G manufactured by Organo Food Tech Co., Ltd. (Saitama, Japan)
D. Muscorin F-2 manufactured by Taiyo Chemical Industries (Tokyo, Japan)
E. Ultraporin manufactured by Taihei Chemical Industry Co., Ltd. (Osaka, Japan) Talinsan U (registered trademark) manufactured by Ueno Pharmaceutical Co., Ltd. (Osaka, Japan)
G. Ultra Polyphos H.P. manufactured by Polyphos Chemical Laboratory Co., Ltd. (Osaka, Japan) (Comparative example) Polyphosphorus 5-B manufactured by Organo Foodtech Co., Ltd. (Saitama, Japan)
I. (Comparative example) Sodium metaphosphate manufactured by Yoneyama Chemical Co., Ltd. (Osaka, Japan) Note that the results are shown as relative values with the value at the time of preparation of each sample being 100%.
Ｂ．エフシー化学株式会社（日本、大阪）製のニューエフシリンサンＦ
Ｃ．オルガノフードテック株式会社（日本、埼玉）製のポリリンサン １－Ｇ
Ｄ．大洋化学工業株式会社（日本、東京）製のマスコリンＦ－２
Ｅ．太平化学産業株式会社（日本、大阪）製のウルトラポリン
Ｆ．上野製薬株式会社（日本、大阪）製のタリンサンＵ（登録商標）
Ｇ．株式会社ポリホス化学研究所（日本、大阪）製のウルトラポリホス
Ｈ．（比較例）オルガノフードテック株式会社（日本、埼玉）製のポリリンサン ５－Ｂ
Ｉ．（比較例）米山化学工業株式会社（日本、大阪）製のメタリン酸ナトリウム
なお、結果は、各サンプルの調製時の値を１００％として相対値で示されていることに注意されたい。 A. Acid sodium hexametaphosphate manufactured by Phosphorus Chemical Industries, Ltd. (Toyama, Japan) New Fsilin Sun F manufactured by FSC Ltd. (Osaka, Japan)
C. Polylinsan 1-G manufactured by Organo Food Tech Co., Ltd. (Saitama, Japan)
D. Muscorin F-2 manufactured by Taiyo Chemical Industries (Tokyo, Japan)
E. Ultraporin manufactured by Taihei Chemical Industry Co., Ltd. (Osaka, Japan) Talinsan U (registered trademark) manufactured by Ueno Pharmaceutical Co., Ltd. (Osaka, Japan)
G. Ultra Polyphos H.P. manufactured by Polyphos Chemical Laboratory Co., Ltd. (Osaka, Japan) (Comparative example) Polyphosphorus 5-B manufactured by Organo Foodtech Co., Ltd. (Saitama, Japan)
I. (Comparative example) Sodium metaphosphate manufactured by Yoneyama Chemical Co., Ltd. (Osaka, Japan) Note that the results are shown as relative values with the value at the time of preparation of each sample being 100%.
表４．種々の酸性メタリン酸ナトリウム製品によるＳ－アデノシルメチオニン安定化
Table 4. Stabilization of S-adenosylmethionine by various acidic sodium metaphosphate products
製品によって若干のばらつきはあるものの、種々の酸性メタリン酸ナトリウム製品によって、Ｓ－アデノシルメチオニンの優れた安定化が達成されることが明らかになった。
It was revealed that excellent stabilization of S-adenosylmethionine was achieved by various acidic sodium metaphosphate products, although there was some variation from product to product.
（実施例４．酸性メタリン酸ナトリウム製品のロット間でのＳ－アデノシルメチオニン安定化効果の差異）
本実施例では、酸性メタリン酸ナトリウム製品のロット間でのＳ－アデノシルメチオニン安定化効果の差異を検討した。 (Example 4. Difference in S-adenosylmethionine stabilizing effect between lots of acidic sodium metaphosphate product)
In this example, the difference in S-adenosylmethionine stabilizing effect between lots of acidic sodium metaphosphate products was examined.
本実施例では、酸性メタリン酸ナトリウム製品のロット間でのＳ－アデノシルメチオニン安定化効果の差異を検討した。 (Example 4. Difference in S-adenosylmethionine stabilizing effect between lots of acidic sodium metaphosphate product)
In this example, the difference in S-adenosylmethionine stabilizing effect between lots of acidic sodium metaphosphate products was examined.
酵母Ｓａｃｃｈａｒｏｍｙｃｅｓ ｃｅｒｅｖｉｓｉａｅ Ｋ－７株（清酒酵母協会７号）、５Ｌ容ジャーファーメンター（仕込み培地量：３Ｌ）を用いて、培養温度２８℃、攪拌速度 ５００ｒｐｍ、培養時間３６－４８ｈ、通気量０．５ＶＶＭ、培地組成（ｗ／１００ｍＬ）：グルコース５％、酵母エキス０．７５％、ペプトン２．０％、メチオニン０．１５％で培養した。この培養液を遠心分離（８，０００ｒｐｍ）し、上清を除いて、菌体を回収した。回収した菌体に除いた上清液を適量加え、菌体濃縮液を調製した。濃縮液中のＳ－アデノシルメチオニン濃度を測定し、燐化学工業株式会社（日本、富山）製の酸性ヘキサメタリン酸ナトリウム、ロット「１１．０５．２１」または「１１．０８．２１」と、大洋化学工業株式会社（日本、東京）製のマスコリンＦ－２のロット「１」または「２」とを、Ｓ－アデノシルメチオニンの４倍量になるように菌体濃縮液に添加した。調製した４つのサンプルを－８０℃で一晩凍結した。凍結乾燥を７２ｈ行い、酵母粉末を調製した。この酵母粉末をアルミパウチに梱包し、加速試験機加速試験機（Ａｄｖａｎｔｅｃ，モデルＴＨＥ０５１ＦＡ）内（４０℃、湿度７５％）で保管した。この条件での加速試験機１日の保管は、常温保管の６日に相当する。定時的に酵母粉末のサンプリングを行い、過塩素酸を用いてＳ－アデノシルメチオニンの抽出を行った。具体的には、酵母粉末０．０２ｇに１０％過塩素酸１ｍＬを加え、１時間抽出を行い、遠心分離（１０，０００ｒｐｍ，１０分）により上清（抽出液）を回収した。Ｓ－アデノシルメチオニンの測定は、ＵＰＬＣ（Ｗａｔｅｒｓ，モデルＴＵＶ）を用い、抽出液を０．１％ギ酸＋５ｍＭノナンスルフォン酸ナトリウム混合液とアセトニトリルによるグラジェントで分析した。結果を以下の表５および図４に示す。以下の表における各項目と製品との対応は、以下の通りである。
Using yeast Saccharomyces cerevisiae K-7 strain (Sake Yeast Association No. 7), 5 L jar fermenter (feeding medium amount: 3 L), culture temperature 28 ° C., stirring speed 500 rpm, culture time 36-48 h, aeration rate 0. 5 VVM, medium composition (w / 100 mL): cultured with glucose 5%, yeast extract 0.75%, peptone 2.0%, methionine 0.15%. The culture was centrifuged (8,000 rpm), the supernatant was removed, and the cells were collected. An appropriate amount of the supernatant liquid removed from the recovered cells was added to prepare a cell concentrate. The concentration of S-adenosylmethionine in the concentrate was measured, and the acid sodium sodium metametaphosphate, lot “11.05.21” or “11.08.21” manufactured by Rin Kagaku Kogyo Co., Ltd. (Toyama, Japan) The lotin “1” or “2” of Mascoline F-2 manufactured by Chemical Industry Co., Ltd. (Tokyo, Japan) was added to the cell concentrate so as to be 4 times the amount of S-adenosylmethionine. Four prepared samples were frozen overnight at -80 ° C. Lyophilization was performed for 72 hours to prepare yeast powder. This yeast powder was packed in an aluminum pouch and stored in an accelerated tester (Advantec, model THE051FA) (40 ° C., humidity 75%). One day storage of the accelerated testing machine under these conditions corresponds to six days of room temperature storage. Yeast powder was sampled regularly and S-adenosylmethionine was extracted using perchloric acid. Specifically, 1 mL of 10% perchloric acid was added to 0.02 g of yeast powder, extraction was performed for 1 hour, and the supernatant (extract) was collected by centrifugation (10,000 rpm, 10 minutes). For the measurement of S-adenosylmethionine, UPLC (Waters, model TUV) was used, and the extract was analyzed by a gradient of 0.1% formic acid + 5 mM sodium nonanesulfonate and acetonitrile. The results are shown in Table 5 below and FIG. The correspondence between each item in the table below and the product is as follows.
Ａ．燐化学工業株式会社（日本、富山）製の酸性ヘキサメタリン酸ナトリウム、ロット「１１．０５．２１」
Ｂ．燐化学工業株式会社（日本、富山）製の酸性ヘキサメタリン酸ナトリウム、ロット「１１．０８．２」
Ｃ．大洋化学工業株式会社（日本、東京）製のマスコリンＦ－２のロット「１」
Ｄ．大洋化学工業株式会社（日本、東京）製のマスコリンＦ－２のロット「２」
なお、結果は、各サンプルの調製時の値を１００％として相対値で示されていることに注意されたい。 A. Acidic sodium hexametaphosphate, lot “11.05.21” manufactured by Phosphorus Chemical Industries, Ltd. (Toyama, Japan)
B. Sodium acid hexametaphosphate, lot "11.08.2", manufactured by Phosphorus Chemical Industries, Ltd. (Toyama, Japan)
C. Lot “1” of Muscorin F-2 manufactured by Taiyo Chemical Co., Ltd. (Tokyo, Japan)
D. Lot “2” of Muscorin F-2 manufactured by Taiyo Chemical Co., Ltd. (Tokyo, Japan)
Note that the results are shown as relative values with the value at the time of preparation of each sample as 100%.
Ｂ．燐化学工業株式会社（日本、富山）製の酸性ヘキサメタリン酸ナトリウム、ロット「１１．０８．２」
Ｃ．大洋化学工業株式会社（日本、東京）製のマスコリンＦ－２のロット「１」
Ｄ．大洋化学工業株式会社（日本、東京）製のマスコリンＦ－２のロット「２」
なお、結果は、各サンプルの調製時の値を１００％として相対値で示されていることに注意されたい。 A. Acidic sodium hexametaphosphate, lot “11.05.21” manufactured by Phosphorus Chemical Industries, Ltd. (Toyama, Japan)
B. Sodium acid hexametaphosphate, lot "11.08.2", manufactured by Phosphorus Chemical Industries, Ltd. (Toyama, Japan)
C. Lot “1” of Muscorin F-2 manufactured by Taiyo Chemical Co., Ltd. (Tokyo, Japan)
D. Lot “2” of Muscorin F-2 manufactured by Taiyo Chemical Co., Ltd. (Tokyo, Japan)
Note that the results are shown as relative values with the value at the time of preparation of each sample as 100%.
表５．酸性メタリン酸ナトリウム製品のロット間でのＳ－アデノシルメチオニン安定化効果の差異
Table 5. Difference in S-adenosylmethionine stabilization effect between lots of acidic sodium metaphosphate products
結果から明らかなように、各製品のロット間でのＳ－アデノシルメチオニン安定化効果における有意な差異は見出されなかった。
As is clear from the results, no significant difference in the S-adenosylmethionine stabilizing effect was found between lots of each product.
以上のように、本発明の好ましい実施形態を用いて本発明を例示してきたが、本発明は、この実施形態に限定して解釈されるべきものではない。本発明は、特許請求の範囲によってのみその範囲が解釈されるべきであることが理解される。当業者は、本発明の具体的な好ましい実施形態の記載から、本発明の記載および技術常識に基づいて等価な範囲を実施することができることが理解される。
As described above, the present invention has been exemplified using the preferred embodiment of the present invention, but the present invention should not be construed as being limited to this embodiment. It is understood that the scope of the present invention should be construed only by the claims. It is understood that those skilled in the art can implement an equivalent range based on the description of the present invention and the common general technical knowledge from the description of specific preferred embodiments of the present invention.
Claims (22)
- Ｓ－アデノシルメチオニンと酸性メタリン酸ナトリウムとを含む、飲食用組成物。 A dietary composition comprising S-adenosylmethionine and acidic sodium metaphosphate.
- 前記酸性メタリン酸ナトリウムを、前記Ｓ－アデノシルメチオニンの２．５倍量以上の濃度で含む、請求項１に記載の組成物。 The composition according to claim 1, comprising the acidic sodium metaphosphate at a concentration of 2.5 times or more the S-adenosylmethionine.
- 前記酸性メタリン酸ナトリウムを、前記Ｓ－アデノシルメチオニンの２．５倍量～１０倍量の濃度で含む、請求項１に記載の組成物。 The composition according to claim 1, comprising the acidic sodium metaphosphate in a concentration of 2.5 to 10 times that of the S-adenosylmethionine.
- 前記酸性メタリン酸ナトリウムを、前記Ｓ－アデノシルメチオニンの２．５倍量～７．５倍量の濃度で含む、請求項１に記載の組成物。 The composition according to claim 1, comprising the acidic sodium metaphosphate at a concentration of 2.5 to 7.5 times that of the S-adenosylmethionine.
- 前記酸性メタリン酸ナトリウムを、前記Ｓ－アデノシルメチオニンの５～７．５倍量の濃度で含む、請求項１に記載の組成物。 The composition according to claim 1, comprising the acidic sodium metaphosphate at a concentration of 5 to 7.5 times the S-adenosylmethionine.
- Ｓ－アデノシルメチオニンと酸性メタリン酸ナトリウムとを含む、医薬組成物。 A pharmaceutical composition comprising S-adenosylmethionine and acidic sodium metaphosphate.
- 前記酸性メタリン酸ナトリウムを、前記Ｓ－アデノシルメチオニンの２．５倍量以上の濃度で含む、請求項６に記載の医薬組成物。 The pharmaceutical composition according to claim 6, comprising the acidic sodium metaphosphate at a concentration of 2.5 times or more the S-adenosylmethionine.
- 前記酸性メタリン酸ナトリウムを、前記Ｓ－アデノシルメチオニンの２．５倍量～１０倍量の濃度で含む、請求項６に記載の医薬組成物。 The pharmaceutical composition according to claim 6, comprising the acidic sodium metaphosphate in a concentration of 2.5 to 10 times that of the S-adenosylmethionine.
- 前記酸性メタリン酸ナトリウムを、前記Ｓ－アデノシルメチオニンの２．５倍量～７．５倍量の濃度で含む、請求項６に記載の医薬組成物。 The pharmaceutical composition according to claim 6, comprising the acidic sodium metaphosphate at a concentration of 2.5 to 7.5 times that of the S-adenosylmethionine.
- 前記酸性メタリン酸ナトリウムを、前記Ｓ－アデノシルメチオニンの５～７．５倍量の濃度で含む、請求項６に記載の医薬組成物。 The pharmaceutical composition according to claim 6, comprising the acidic sodium metaphosphate in a concentration of 5 to 7.5 times the S-adenosylmethionine.
- 鬱病または関節炎の治療のための、請求項６に記載の医薬組成物。 7. A pharmaceutical composition according to claim 6 for the treatment of depression or arthritis.
- 安定なＳ－アデノシルメチオニンの製造方法であって、該Ｓ－アデノシルメチオニンを含む組成物に、酸性メタリン酸ナトリウムを添加する工程を包含する、製造方法。 A method for producing a stable S-adenosylmethionine, comprising a step of adding acidic sodium metaphosphate to a composition containing the S-adenosylmethionine.
- 前記酸性メタリン酸ナトリウムを、前記Ｓ－アデノシルメチオニンの２．５倍量以上の濃度で添加する、請求項１２に記載の製造方法。 The production method according to claim 12, wherein the acidic sodium metaphosphate is added at a concentration of 2.5 times or more the S-adenosylmethionine.
- 前記酸性メタリン酸ナトリウムを、前記Ｓ－アデノシルメチオニンの２．５倍量～１０倍量の濃度で添加する、請求項１２に記載の製造方法。 The production method according to claim 12, wherein the acidic sodium metaphosphate is added at a concentration of 2.5 to 10 times that of the S-adenosylmethionine.
- 前記酸性メタリン酸ナトリウムを、前記Ｓ－アデノシルメチオニンの２．５倍量～７．５倍量の濃度で添加する、請求項１２に記載の製造方法。 The production method according to claim 12, wherein the acidic sodium metaphosphate is added at a concentration of 2.5 to 7.5 times that of the S-adenosylmethionine.
- 前記酸性メタリン酸ナトリウムを、前記Ｓ－アデノシルメチオニンの５～７．５倍量の濃度で添加する、請求項１２に記載の製造方法。 The production method according to claim 12, wherein the acidic sodium metaphosphate is added at a concentration of 5 to 7.5 times the S-adenosylmethionine.
- 前記Ｓ－アデノシルメチオニンと前記酸性メタリン酸ナトリウムとを含む混合物を乾燥する工程をさらに包含する、請求項１２に記載の製造方法。 The method according to claim 12, further comprising a step of drying the mixture containing the S-adenosylmethionine and the acidic sodium metaphosphate.
- Ｓ－アデノシルメチオニンの安定化法であって、該Ｓ－アデノシルメチオニンを含む組成物に、酸性メタリン酸ナトリウムを添加する工程を包含する、方法。 A method for stabilizing S-adenosylmethionine comprising the step of adding acidic sodium metaphosphate to a composition comprising said S-adenosylmethionine.
- 前記酸性メタリン酸ナトリウムを、前記Ｓ－アデノシルメチオニンの２．５倍量以上の濃度で添加する、請求項１８に記載の方法。 The method according to claim 18, wherein the acidic sodium metaphosphate is added at a concentration of 2.5 times or more the S-adenosylmethionine.
- 前記酸性メタリン酸ナトリウムを、前記Ｓ－アデノシルメチオニンの２．５倍量～１０倍量の濃度で添加する、請求項１８に記載の方法。 The method according to claim 18, wherein the acidic sodium metaphosphate is added at a concentration of 2.5 to 10 times that of the S-adenosylmethionine.
- 前記酸性メタリン酸ナトリウムを、前記Ｓ－アデノシルメチオニンの２．５倍量～７．５倍量の濃度で添加する、請求項１８に記載の方法。 The method according to claim 18, wherein the acidic sodium metaphosphate is added at a concentration of 2.5 to 7.5 times that of the S-adenosylmethionine.
- 前記酸性メタリン酸ナトリウムを、前記Ｓ－アデノシルメチオニンの５～７．５倍量の濃度で添加する、請求項１８に記載の方法。 The method according to claim 18, wherein the acidic sodium metaphosphate is added at a concentration of 5 to 7.5 times the S-adenosylmethionine.
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| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2018042841A1 (en) * | 2016-08-31 | 2018-03-08 | 株式会社ホルス | Method for producing same-containing material, and external agent, cosmetic and health food comprising same-containing liquid material |
| CN108883128A (en) * | 2016-02-12 | 2018-11-23 | 欧弗有限公司 | Intra-articular application polymetaphosphate is to treat crystallographic arthropathy |
| JPWO2020090774A1 (en) * | 2018-10-30 | 2021-02-15 | 国立大学法人九州大学 | Onset risk assessment device, onset risk assessment method, program and food for dementia prevention |
Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| JPS61189293A (en) * | 1985-02-14 | 1986-08-22 | ジビフアルマ・エツセ・ピ・ア | Stable salt of polyanion and sam, manufacture and medicinal composition |
| JP2007197346A (en) * | 2006-01-25 | 2007-08-09 | National Research Inst Of Brewing | Stabilization agent for s-adenosylmethionine and stabilization method for the same |
-
2011
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Patent Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| JPS61189293A (en) * | 1985-02-14 | 1986-08-22 | ジビフアルマ・エツセ・ピ・ア | Stable salt of polyanion and sam, manufacture and medicinal composition |
| JP2007197346A (en) * | 2006-01-25 | 2007-08-09 | National Research Inst Of Brewing | Stabilization agent for s-adenosylmethionine and stabilization method for the same |
Cited By (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN108883128A (en) * | 2016-02-12 | 2018-11-23 | 欧弗有限公司 | Intra-articular application polymetaphosphate is to treat crystallographic arthropathy |
| WO2018042841A1 (en) * | 2016-08-31 | 2018-03-08 | 株式会社ホルス | Method for producing same-containing material, and external agent, cosmetic and health food comprising same-containing liquid material |
| JPWO2020090774A1 (en) * | 2018-10-30 | 2021-02-15 | 国立大学法人九州大学 | Onset risk assessment device, onset risk assessment method, program and food for dementia prevention |
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| JPWO2013080265A1 (en) | 2015-04-27 |
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