WO2013080265A1 - Stabilisation de s-adénosylméthionine avec du métaphosphate de sodium acide - Google Patents

Stabilisation de s-adénosylméthionine avec du métaphosphate de sodium acide Download PDF

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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
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adenosylmethionine
sodium metaphosphate
present
acidic sodium
concentration
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PCT/JP2011/006780
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English (en)
Japanese (ja)
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喜則 関口
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磐田化学工業株式会社
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Priority to JP2013546846A priority Critical patent/JP5808429B2/ja
Priority to PCT/JP2011/006780 priority patent/WO2013080265A1/fr
Publication of WO2013080265A1 publication Critical patent/WO2013080265A1/fr

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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • 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
    • 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
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • 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
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • 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
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P19/00—Drugs for skeletal disorders
    • A61P19/02—Drugs for skeletal disorders for joint disorders, e.g. arthritis, arthrosis
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/02—Drugs for disorders of the nervous system for peripheral neuropathies
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/24—Antidepressants
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • 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
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
    • A61P31/12—Antivirals
    • A61P31/14—Antivirals for RNA viruses
    • A61P31/18—Antivirals for RNA viruses for HIV

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

L'invention porte sur un nouveau procédé pour la stabilisation de S-adénosylméthionine. La présente invention porte également sur une composition à manger ou à boire, ladite composition contenant à la fois de la S-adénosylméthionine et du métaphosphate de sodium acide. La présente invention porte également sur un procédé pour la préparation de S-adénosylméthionine stable, ledit procédé comprenant une étape d'ajout de métaphosphate de sodium acide à une composition qui contient de la S-adénosylméthionine. La présente invention porte en outre sur un procédé pour la stabilisation de S-adénosylméthionine, ledit procédé comprenant une étape d'ajout de métaphosphate de sodium acide à une composition qui contient de la S-adénosylméthionine.
PCT/JP2011/006780 2011-12-02 2011-12-02 Stabilisation de s-adénosylméthionine avec du métaphosphate de sodium acide WO2013080265A1 (fr)

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Cited By (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2018042841A1 (fr) * 2016-08-31 2018-03-08 株式会社ホルス Procédé de production d'un matériau contenant same, et agent externe, produit cosmétique et aliment santé contenant le matériau liquide comprenant same
CN108883128A (zh) * 2016-02-12 2018-11-23 欧弗有限公司 关节内施用聚偏磷酸盐以治疗晶体性关节病
JPWO2020090774A1 (ja) * 2018-10-30 2021-02-15 国立大学法人九州大学 発症リスク評価装置、発症リスク評価方法、プログラム及び認知症予防用食品

Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JPS61189293A (ja) * 1985-02-14 1986-08-22 ジビフアルマ・エツセ・ピ・ア ポリアニオンとのｓａｍの安定な塩、その製法および有効成分としてそれを含有する抗脂肝剤
JP2007197346A (ja) * 2006-01-25 2007-08-09 National Research Inst Of Brewing Ｓ−アデノシルメチオニンの安定剤及び安定化方法

Patent Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JPS61189293A (ja) * 1985-02-14 1986-08-22 ジビフアルマ・エツセ・ピ・ア ポリアニオンとのｓａｍの安定な塩、その製法および有効成分としてそれを含有する抗脂肝剤
JP2007197346A (ja) * 2006-01-25 2007-08-09 National Research Inst Of Brewing Ｓ−アデノシルメチオニンの安定剤及び安定化方法

Cited By (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN108883128A (zh) * 2016-02-12 2018-11-23 欧弗有限公司 关节内施用聚偏磷酸盐以治疗晶体性关节病
WO2018042841A1 (fr) * 2016-08-31 2018-03-08 株式会社ホルス Procédé de production d'un matériau contenant same, et agent externe, produit cosmétique et aliment santé contenant le matériau liquide comprenant same
JPWO2020090774A1 (ja) * 2018-10-30 2021-02-15 国立大学法人九州大学 発症リスク評価装置、発症リスク評価方法、プログラム及び認知症予防用食品

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