WO2012011174A1 - Lipid metabolism improving agent, agent for enhancing lipid metabolism improving action, anti-obesity agent, and agent for enhancing anti-obesity action - Google Patents

Lipid metabolism improving agent, agent for enhancing lipid metabolism improving action, anti-obesity agent, and agent for enhancing anti-obesity action Download PDF

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WO2012011174A1
WO2012011174A1 PCT/JP2010/062314 JP2010062314W WO2012011174A1 WO 2012011174 A1 WO2012011174 A1 WO 2012011174A1 JP 2010062314 W JP2010062314 W JP 2010062314W WO 2012011174 A1 WO2012011174 A1 WO 2012011174A1
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group
acid bacteria
bacteria
bacterium
glucosidase inhibitor
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PCT/JP2010/062314
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French (fr)
Japanese (ja)
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真木 嶋川
知浩 川原
康浩 伊佐
裕史 大野
秀樹 山村
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ビオフェルミン製薬株式会社
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Priority to PCT/JP2010/062314 priority Critical patent/WO2012011174A1/en
Priority to JP2012525273A priority patent/JP5769710B2/en
Publication of WO2012011174A1 publication Critical patent/WO2012011174A1/en

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    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61KPREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00Medicinal preparations containing organic active ingredients
    • A61K31/045Hydroxy compounds, e.g. alcohols; Salts thereof, e.g. alcoholates
    • A61K31/047Hydroxy compounds, e.g. alcohols; Salts thereof, e.g. alcoholates having two or more hydroxy groups, e.g. sorbitol
    • AHUMAN NECESSITIES
    • A23FOODS OR FOODSTUFFS; TREATMENT THEREOF, NOT COVERED BY OTHER CLASSES
    • A23LFOODS, 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
    • A23L33/00Modifying nutritive qualities of foods; Dietetic products; Preparation or treatment thereof
    • A23L33/10Modifying nutritive qualities of foods; Dietetic products; Preparation or treatment thereof using additives
    • AHUMAN NECESSITIES
    • A23FOODS OR FOODSTUFFS; TREATMENT THEREOF, NOT COVERED BY OTHER CLASSES
    • A23LFOODS, 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
    • A23L33/00Modifying nutritive qualities of foods; Dietetic products; Preparation or treatment thereof
    • A23L33/10Modifying nutritive qualities of foods; Dietetic products; Preparation or treatment thereof using additives
    • A23L33/135Bacteria or derivatives thereof, e.g. probiotics
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61KPREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00Medicinal preparations containing organic active ingredients
    • A61K31/33Heterocyclic compounds
    • A61K31/395Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/44Non condensed pyridines; Hydrogenated derivatives thereof
    • A61K31/445Non condensed piperidines, e.g. piperocaine
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61KPREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K35/00Medicinal preparations containing materials or reaction products thereof with undetermined constitution
    • A61K35/66Microorganisms or materials therefrom
    • A61K35/74Bacteria
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61KPREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K35/00Medicinal preparations containing materials or reaction products thereof with undetermined constitution
    • A61K35/66Microorganisms or materials therefrom
    • A61K35/74Bacteria
    • A61K35/741Probiotics
    • A61K35/744Lactic acid bacteria, e.g. enterococci, pediococci, lactococci, streptococci or leuconostocs
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61KPREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K35/00Medicinal preparations containing materials or reaction products thereof with undetermined constitution
    • A61K35/66Microorganisms or materials therefrom
    • A61K35/74Bacteria
    • A61K35/741Probiotics
    • A61K35/744Lactic acid bacteria, e.g. enterococci, pediococci, lactococci, streptococci or leuconostocs
    • A61K35/745Bifidobacteria
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61KPREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K45/00Medicinal preparations containing active ingredients not provided for in groups A61K31/00 - A61K41/00
    • A61K45/06Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61PSPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P3/00Drugs for disorders of the metabolism
    • A61P3/04Anorexiants; Antiobesity agents
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61PSPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P3/00Drugs for disorders of the metabolism
    • A61P3/06Antihyperlipidemics
    • CCHEMISTRY; METALLURGY
    • C12BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
    • C12NMICROORGANISMS OR ENZYMES; COMPOSITIONS THEREOF; PROPAGATING, PRESERVING, OR MAINTAINING MICROORGANISMS; MUTATION OR GENETIC ENGINEERING; CULTURE MEDIA
    • C12N1/00Microorganisms, e.g. protozoa; Compositions thereof; Processes of propagating, maintaining or preserving microorganisms or compositions thereof; Processes of preparing or isolating a composition containing a microorganism; Culture media therefor
    • C12N1/20Bacteria; Culture media therefor

Definitions

  • the present invention relates to a composition having an action of improving lipid metabolism, an action of enhancing an action of improving lipid metabolism by bacteria such as lactic acid bacteria, an anti-obesity action and an action of enhancing an anti-obesity action. More specifically, the present invention relates to a composition having an action of reducing blood lipid concentration. The present invention also relates to a composition having an action of promoting or improving metabolism of fat, particularly visceral fat, which is excessively consumed by diet and accumulated in a living body, and improves obesity.
  • Patent Document 1 discloses a dead cell of Lactobacillus fermentum strain SBT10534 (FERM P-21667) having an effect of improving lipid metabolism.
  • Non-Patent Documents 1 and 2 disclose blood lipid lowering action of lactic acid bacteria.
  • an ⁇ -glucosidase inhibitor voglibose
  • Non-patent Document 3 it is said that when 0.2 mg of Basin (registered trademark) is orally administered three times a day for 56 weeks or more, blood triglyceride is significantly decreased and HDL-cholesterol is increased.
  • Basin registered trademark
  • the present invention is a lipid metabolism improving agent that can reduce blood lipids such as cholesterol and neutral fat, and can effectively prevent, improve or treat fat accumulation such as visceral fat, obesity and the like.
  • An object of the present invention is to provide an agent for improving lipid metabolism, an anti-obesity agent, an anti-obesity agent, and an agent for promoting the expression of lipid metabolism.
  • the present inventors have conducted extensive studies in view of the above problems, and as a result of examining lipid metabolism improving action and anti-obesity action for various substances, as a result, ⁇ -glucosidase (disaccharide-degrading enzyme) inhibitors and bacteria such as lactic acid bacteria have been used as animals. It was found that the blood lipid concentration can be significantly reduced by the specific synergistic effect of the combination of an ⁇ -glucosidase inhibitor and a bacterium such as lactic acid bacteria. It was also found that when an ⁇ -glucosidase inhibitor and a bacterium such as a lactic acid bacterium are administered in combination, weight gain can be suppressed and fat in the body (particularly visceral fat) can be reduced.
  • ⁇ -glucosidase disaccharide-degrading enzyme
  • ⁇ -Glucosidase inhibitor is an oral hypoglycemic agent widely used for the treatment of diabetes, and it has been reported in human clinical trials that ⁇ -glucosidase inhibitor (Voglibose) lowers blood lipids (Mimura) Kazuo, et al., Clinical and research, 1992, 69: 919).
  • This document reports that blood triglyceride is significantly decreased and HDL-cholesterol is increased, but the effect of basin (registered trademark) 0.2 mg at a time three times a day for 56 weeks or more. This is the effect obtained when administered.
  • the present inventors have observed that blood lipid reduction is observed in mice within 4 weeks of administration by administering an ⁇ -glucosidase inhibitor in combination with bacteria such as lactic acid bacteria. -It has been found that the combined use of glucosidase inhibitors and bacteria such as lactic acid bacteria produces a blood lipid lowering effect earlier than when only an ⁇ -glucosidase inhibitor is administered.
  • the present invention relates to the following (1) to (24).
  • An agent for improving lipid metabolism comprising an ⁇ -glucosidase inhibitor and administered in combination with at least one bacterium selected from the group consisting of bifidobacteria, lactic acid bacteria, saccharifying bacteria, and butyric acid bacteria.
  • the lipid metabolism improving agent according to the above (1) further comprising at least one bacterium selected from the group consisting of bifidobacteria, lactic acid bacteria, saccharifying bacteria, and butyric acid bacteria.
  • the ⁇ -glucosidase inhibitor has the general formula (I)
  • A is a hydroxyl group, phenoxy, thienyl, furyl, pyridyl, cyclohexyl, a chain hydrocarbon group having 1 to 10 carbon atoms which may have an optionally substituted phenyl group, a hydroxyl group, a hydroxymethyl group, methyl ,
  • R 1 and R 3 are the same or different and each represents a hydrogen atom, an optionally substituted linear, branched or cyclic saturated or unsaturated aliphatic hydrocarbon group, substituted Which may be a hydrocarbon ring, an aromatic ring or a heterocyclic ring, and R 2 is —H, —OH, —OR ′, —SH, —SR ′, —NH 2 , —NHR ′, —N (R ′) (R ′′), NH 2 CH 2 —, NHR′—CH 2 —, NR′R ′′ —CH 2 —, —COOH, —COOR ′, HO—CH 2 —, R′CO—NHCH 2 —, R′CO—NR ′′ CH 2 —, R′SO 2 NHCH 2 —, R′SO 2 —NR ′′ CH 2 —, R′—NH—CO—NH—CH 2 —, R′—NH—CS —NH—CH 2 —R′—SH
  • R 3 is —CH 2 OH and R 2 is a hydrogen atom or When —OH; R 3 is a hydrogen atom and R 2 is a hydrogen atom, —OH, —SO 3 H, —CN or —CH 2 —NH 2 ; or R 3 is —CH 2 —. When NH 2 and R 2 is —OH, R 1 is not a hydrogen atom.) Described in (1) or (2) above, which is 3,4,5-trihydroxypiperidine Lipid metabolism improving agent.
  • An action of improving lipid metabolism by the bacterium comprising an ⁇ -glucosidase inhibitor and being administered in combination with at least one bacterium selected from the group consisting of bifidobacteria, lactic acid bacterium, saccharifying bacterium and butyric acid bacterium Enhancer.
  • An anti-obesity agent comprising an ⁇ -glucosidase inhibitor and administered in combination with at least one bacterium selected from the group consisting of bifidobacteria, lactic acid bacterium, saccharifying bacterium, and butyric acid bacterium.
  • An anti-obesity effect enhancement by said bacterium characterized by comprising an ⁇ -glucosidase inhibitor and being administered in combination with at least one bacterium selected from the group consisting of bifidobacteria, lactic acid bacterium, saccharifying bacterium and butyric acid bacterium Agent.
  • a lipid produced by an ⁇ -glucosidase inhibitor comprising at least one bacterium selected from the group consisting of bifidobacteria, lactic acid bacteria, saccharifying bacteria, and butyric acid bacteria, and administered in combination with an ⁇ -glucosidase inhibitor Metabolism improving agent.
  • an anti- ⁇ -glucosidase inhibitor comprising at least one bacterium selected from the group consisting of bifidobacteria, lactic acid bacteria, saccharifying bacteria, and butyric acid bacteria, and administered in combination with an ⁇ -glucosidase inhibitor Obesity enhancing agent.
  • a lipid derived from an ⁇ -glucosidase inhibitor comprising at least one bacterium selected from the group consisting of bifidobacteria, lactic acid bacteria, saccharifying bacteria, and butyric acid bacteria, and administered in combination with an ⁇ -glucosidase inhibitor Metabolism improving action or anti-obesity action promoting agent.
  • a pharmaceutical comprising the agent according to any one of (1) to (10).
  • a food and drink composition for improving lipid metabolism comprising the lipid metabolism improving agent according to any one of (1) to (3).
  • a food and beverage composition for improving obesity comprising the anti-obesity agent according to (5).
  • a food and drink composition for enhancing lipid metabolism improving action by an ⁇ -glucosidase inhibitor comprising the lipid metabolism improving action enhancing agent according to (8).
  • a method for improving lipid metabolism comprising administering an ⁇ -glucosidase inhibitor to an animal in combination with at least one bacterium selected from the group consisting of bifidobacteria, lactic acid bacteria, saccharifying bacteria, and butyric acid bacteria.
  • An action for improving lipid metabolism by the bacterium characterized in that an ⁇ -glucosidase inhibitor is administered to an animal in combination with at least one bacterium selected from the group consisting of bifidobacteria, lactic acid bacterium, saccharifying bacterium and butyric acid bacterium. How to strengthen.
  • a method for improving or treating obesity comprising administering an ⁇ -glucosidase inhibitor to an animal in combination with at least one bacterium selected from the group consisting of bifidobacteria, lactic acid bacteria, saccharifying bacteria, and butyric acid bacteria.
  • An obesity-improving action by the bacterium characterized by administering an ⁇ -glucosidase inhibitor to an animal in combination with at least one bacterium selected from the group consisting of bifidobacteria, lactic acid bacteria, saccharifying bacteria, and butyric acid bacteria How to strengthen.
  • a lipid by an ⁇ -glucosidase inhibitor characterized in that at least one bacterium selected from the group consisting of bifidobacteria, lactic acid bacteria, saccharifying bacteria and butyric acid bacteria is administered to an animal in combination with an ⁇ -glucosidase inhibitor A method for enhancing the effect of improving metabolism.
  • Obesity by an ⁇ -glucosidase inhibitor characterized in that at least one bacterium selected from the group consisting of bifidobacteria, lactic acid bacteria, saccharifying bacteria and butyric acid bacteria is administered to an animal in combination with an ⁇ -glucosidase inhibitor
  • a lipid by an ⁇ -glucosidase inhibitor wherein the ⁇ -glucosidase inhibitor is administered to an animal in combination with at least one bacterium selected from the group consisting of bifidobacteria, lactic acid bacteria, saccharifying bacteria, and butyric acid bacteria
  • blood lipid can be effectively reduced, weight gain can be suppressed, and accumulation of fat such as visceral fat can be reduced, resulting in dyslipidemia (hyperlipidemia).
  • abnormalities of lipid metabolism such as obesity and visceral fat accumulation can be effectively prevented, improved or treated.
  • lifestyle-related diseases resulting from dyslipidemia, obesity and the like, metabolic syndrome and the like can be effectively prevented, ameliorated or treated.
  • the lipid metabolism improving agent, lipid metabolism improving action enhancer, anti-obesity agent, anti-obesity action enhancer, lipid metabolism improving action expression promoter and anti-obesity action expression promoter of the present invention are taken for a long time. However, there are few side effects and high safety.
  • FIG. 1 is a graph showing the change in body weight when mice in groups A to D were fed a test diet for 7 weeks.
  • FIG. 2 is a graph showing plasma triglyceride levels of mice in groups A to D.
  • FIG. 3 is a graph showing changes in body weight when mice of each of E to H groups were fed each test diet for 7 weeks.
  • FIG. 4 is a graph showing plasma total cholesterol levels in mice of each of E to H groups.
  • FIG. 5 is a diagram showing plasma triglyceride levels in mice of each of E to H groups.
  • FIG. 6 is a graph showing the relative weight of periuterine fat with respect to the body weight of the mice in each of E to H groups.
  • FIG. 7 is a graph showing changes in body weight when mice in groups I to L were fed a test diet for 7 weeks.
  • FIG. 8 is a graph showing plasma triglyceride levels in mice of each of the groups IL.
  • FIG. 9 is a graph showing the relative weight of periuterine fat with respect to the body weight of mice in each of the groups IL.
  • FIG. 10 is a diagram illustrating an internal structure of a nozzle edge portion in a spray drying apparatus having four flow path nozzles.
  • the lipid metabolism improving agent of the present invention contains an ⁇ -glucosidase inhibitor and is administered in combination with at least one bacterium selected from the group consisting of bifidobacteria, lactic acid bacteria, saccharifying bacteria, and butyric acid bacteria.
  • a combination of the bacterium and an ⁇ -glucosidase inhibitor it is possible to exert lipid metabolism improving effects such as excellent blood lipid lowering action, visceral fat reducing action, visceral fat accumulation reducing action and the like. Therefore, abnormal lipid metabolism can be effectively prevented, improved or treated.
  • prevention includes suppressing or delaying the onset.
  • Implication includes alleviation of symptoms as well as complete cure of symptoms or diseases.
  • An abnormality in lipid metabolism refers to a condition in which an abnormality is found in the balance of lipid components in a living body, and examples thereof include dyslipidemia (hyperlipidemia), obesity, and visceral fat accumulation.
  • the dyslipidemia includes, for example, a state in which blood lipid has a high value, a state in which blood HDL (high density lipoprotein) cholesterol has a low value, and the like.
  • the blood lipid is usually cholesterol, LDL cholesterol, neutral fat (triglyceride), phospholipid, free fatty acid and the like.
  • the lipid metabolism improving agent of the present invention exhibits an excellent effect in reducing blood lipids such as cholesterol, LDL cholesterol, and neutral fat (triglyceride). For this reason, the lipid metabolism improving agent of the present invention can effectively prevent, ameliorate, or treat hypercholesterolemia, hyper-LDL cholesterolemia, and hypertriglyceridemia that are dyslipidemia.
  • the cause of lipid metabolism abnormalities is not limited, and includes, for example, cases caused by a high fat diet or cases caused by age, lack of exercise, etc. in a normal diet.
  • Said dyslipidemia can have a significant impact on the progression of arteriosclerosis.
  • Arteriosclerosis causes narrowing or occlusion in the lumen of the arterial wall, and with a decrease in blood flow, various pathological conditions including, for example, transient ischemic attack, cerebral infarction, myocardial infarction, angina pectoris, etc. It can be a cause.
  • abnormal lipid metabolism is associated with obesity.
  • Obesity is a condition in which fat accumulates excessively in the body.
  • Obesity includes visceral fat accumulation type obesity.
  • the lipid metabolism-improving agent of the present invention has an action of suppressing weight gain, and further has an action of reducing visceral fat, an action of reducing the accumulation of visceral fat, and the like. Therefore, the lipid metabolism improving agent of the present invention can be suitably used as a medicament for preventing, improving or treating obesity.
  • An anti-obesity agent that contains an ⁇ -glucosidase inhibitor and is administered in combination with at least one bacterium selected from the group consisting of bifidobacteria, lactic acid bacteria, saccharifying bacteria, and butyric acid bacteria is also one aspect of the present invention.
  • Dyslipidemia and obesity can each cause various pathological conditions, but in conditions where these diseases overlap, such as metabolic syndrome, they promote arteriosclerosis and are fatal. It is easy to cause myocardial infarction, cerebral infarction, etc. Since the agent of the present invention can prevent, suppress, ameliorate or treat any of the above dyslipidemia and obesity diseases, lifestyle-related diseases, metabolic syndrome, etc. can also be prevented, suppressed, ameliorated or treated.
  • the lipid metabolism improving agent of the present invention is capable of enhancing the lipid metabolism improving action and anti-obesity action possessed by bacteria such as bifidobacteria, lactic acid bacteria, saccharifying bacteria, and butyric acid bacteria.
  • bacteria such as bifidobacteria, lactic acid bacteria, saccharifying bacteria, and butyric acid bacteria.
  • the ⁇ -glucosidase inhibitor is administered in combination with at least one bacterium selected from the group consisting of bifidobacteria, lactic acid bacterium, saccharifying bacterium and butyric acid bacterium, the bacterium has a blood lipid lowering action and a visceral fat reducing action.
  • the lipid metabolism improving action such as the above can be specifically and synergistically enhanced, whereby an excellent lipid metabolism improving effect and anti-obesity effect can be obtained.
  • the present invention also includes an agent for improving lipid metabolism by the bacterium, which comprises an ⁇ -glucosidase inhibitor and is administered in combination with at least one bacterium selected from the group consisting of bifidobacteria, lactic acid bacterium, saccharifying bacterium and butyric acid bacterium. To do.
  • the present invention also includes an anti-obesity action enhancer by the aforementioned bacterium, which comprises an ⁇ -glucosidase inhibitor and is administered in combination with at least one bacterium selected from the group consisting of bifidobacteria, lactic acid bacterium, saccharifying bacterium and butyric acid bacterium. To do.
  • Example 2 which will be described later, when GG-Ay mice showing obesity are fed with boglibose (0.0003%: 0.6 mg / kg / day) and reared for 7 weeks, suppression of weight gain and reduction of triglycerides are observed.
  • the present invention by using a combination of an ⁇ -glucosidase inhibitor and the above-mentioned bacterium, even if the dose of the ⁇ -glucosidase inhibitor is smaller than the usual amount, an excellent lipid metabolism improving action and anti-obesity action Is obtained. Therefore, the lipid metabolism improving action and the anti-obesity action can be effectively enhanced while reducing the side effects by reducing the dose of the ⁇ -glucosidase inhibitor.
  • the ⁇ -glucosidase inhibitor is at least selected from the group consisting of bifidobacteria, lactic acid bacteria, saccharifying bacteria and butyric acid bacteria. Since it is administered in combination with one kind of bacteria, the agent preferably further contains at least one kind of bacteria selected from the group consisting of bifidobacteria, lactic acid bacteria, saccharifying bacteria, and butyric acid bacteria.
  • At least one bacterium selected from the group consisting of bifidobacteria, lactic acid bacteria, saccharifying bacteria, and butyric acid bacteria has an action that promotes expression of lipid metabolism and anti-obesity action by an ⁇ -glucosidase inhibitor, an ⁇ -glucosidase inhibitor It has an action of effectively enhancing the lipid metabolism improving action and anti-obesity action.
  • the present invention includes at least one bacterium selected from the group consisting of bifidobacteria, lactic acid bacterium, saccharifying bacterium, and butyric acid bacterium, and enhances lipid metabolism improving action by an ⁇ -glucosidase inhibitor administered in combination with an ⁇ -glucosidase inhibitor
  • An agent and an anti-obesity action enhancer are also included. Such an agent also exhibits an excellent lipid metabolism improving action and anti-obesity action.
  • These agents preferably further contain an ⁇ -glucosidase inhibitor.
  • Examples of the ⁇ -glucosidase inhibitor used in the present invention include, for example, Japanese Patent Application Laid-Open Nos. 57-200335, 58-59946, 58-162597, and 58-216145.
  • A is a hydroxyl group, phenoxy, thienyl, furyl, pyridyl, cyclohexyl, a chain hydrocarbon group having 1 to 10 carbon atoms which may have an optionally substituted phenyl group, a hydroxyl group, a hydroxymethyl group, methyl Group, a cyclic hydrocarbon group having 5 or 6 carbon atoms which can have an amino group or a sugar residue) is preferable.
  • a in the general formula (I) includes, for example, a linear or branched saturated or unsaturated aliphatic hydrocarbon group having 1 to 10 carbon atoms.
  • a phenyl group which may be substituted with lower alkyl, lower alkoxy, halogen, phenyl or the like is included.
  • Sugar residue means a remaining group obtained by removing one hydrogen atom from a saccharide molecule, and examples thereof include sugar residues derived from monosaccharides and oligosaccharides.
  • N-substituted variolamine derivative represented by the above general formula (I) include (1) N-phenethylvariolamine, (2) N- (3-phenylallyl) biolamine, (3) N -Furfuryl violamine, (4) N-thienyl valol amine, (5) N- (3-pyridylmethyl) valol amine, (6) N- (4-bromobenzyl) viol amine, (7) N-[(R) - ⁇ -hydroxyphenethyl] variolamine, (8) N-[(S) - ⁇ -hydroxyphenethyl] variolamine, (9) N- ( ⁇ -hydroxy-2-methoxyphenethyl) Biolamine, (10) N- (3,5-di-tert-butyl-4-hydroxybenzyl) biolamine, (11) N- (cyclohexylmethyl) variol (13) N- (1,3-dihydroxy-2-propyl) variolamine, (14) N-
  • N- (1,3-dihydroxy-2-propyl) variolamine ie [2-hydroxy-1- (hydroxymethyl) ethyl] variolamine or 1L (1S)-(1 (OH), 2, 4,5 / 1,3) -5-[[2-hydroxy-1- (hydroxymethyl) ethyl] amino] -1-C- (hydroxymethyl) -1,2,3,4-cyclohexanetetrol (general Name: Voglibose) is particularly preferred.
  • N-substituted derivative of validadamine represented by the formula (wherein A is as defined above) is also preferably used.
  • valienamine N-substituted derivative represented by the above general formula (II) acarbose (generic name) [BAYg5421, Naturwissenschaften, Vol. 64, pp.
  • R 1 and R 3 are the same or different and each represents a hydrogen atom, an optionally substituted linear, branched or cyclic saturated or unsaturated aliphatic hydrocarbon group, substituted Which may be a hydrocarbon ring, an aromatic ring or a heterocyclic ring, and R 2 is —H, —OH, —OR ′, —SH, —SR ′, —NH 2 , —NHR ′, —N (R ′) (R ′′), NH 2 CH 2 —, NHR′—CH 2 —, NR′R ′′ —CH 2 —, —COOH, —COOR ′, HO—CH 2 —, R′CO—NHCH 2 —, R′CO—NR ′′ CH 2 —, R′SO 2 NHCH 2 —, R′SO 2 —NR ′′ CH 2 —, R′—NH—CO—NH—CH 2 —, R′—NH—CS —NH—CH 2 —R′—SH
  • R 3 is —CH 2 OH and R 2 is a hydrogen atom or When —OH; R 3 is a hydrogen atom and R 2 is a hydrogen atom, —OH, —SO 3 H, —CN or —CH 2 —NH 2 ; or R 3 is —CH 2 —. In the case of NH 2 and R 2 is —OH, R 1 is not a hydrogen atom (—H).) 3,4,5-trihydroxypiperidine is also suitable.
  • the linear, branched or cyclic saturated or unsaturated aliphatic hydrocarbon group which may be substituted includes, for example, an alkyl group, an alkenyl group, and an alkynyl group.
  • Etc. R 1 , R ′ and R ′′ may be the same or different, and may be substituted, preferably having 1 to 30 carbon atoms (more preferably 1 to 18 carbon atoms, more preferably 1 to 10 carbon atoms).
  • An alkyl group an optionally substituted alkenyl group having 2 to 18 carbon atoms, a carbon atom, an optionally substituted monocyclic, bicyclic or tricyclic aliphatic hydrocarbon having 3 to 10 carbon atoms, An aromatic ring, a heterocyclic ring, and the like.
  • an alkyl group having 1 to 10 carbon atoms which may have a substituent is preferable.
  • a hydroxyl group and the like are preferable.
  • R 3 is preferably a hydrogen atom, -CH 3, -CH 2 OH, -CH 2 -NH 2, NHR'-CH 2 -, NR'R''CH 2 -, R'CONH-CH 2 -, R′CO—NR ′′ CH 2 —, X—CH 2 — (X represents a halogen atom), R′O—CH 2 —, R′COOCH 2 —, R′SO 2 O—CH 2 —, R'SO 2 NHCH 2 -, R'SO 2 -NR''CH 2 -, R'NH-CO-NHCH 2 -, R'NHCS-NHCH 2 -, R'O-CO-NH- CH 2 —, —CN, —COOH, —COOR ′, —CONH 2 , —CONHR ′ or —CONR′R ′′ (R ′ and R ′′ are the same or different, and R 1 and R Is synonymous with.
  • R 1 is —CH 2 —CH 2 —OH
  • R 2 is a hydrogen atom
  • R 3 is —CH 2 —OH.
  • the compound (generic name: miglitol, chemical name: (-)-(2R, 3R, 4R, 5S) -1- (2-hydroxymethyl) piperidine-3,4,5-triol) is particularly preferred.
  • trestatin (trestatin), The Journal of Antibiotics, Volume 36, pages 1157 to 1175 (1983) and volume 37, pages 182 to 186 (1984), JP No. 54-163511
  • Adeposins [(adiposins), The Journal of Antibiotics, Vol. 35, pp. 1234-1236 (1982); Starch Chemistry (J. Jap, Soc. Starch Sci.) 26, 134-144 (1979), 27, 107-113 (1980); JP 54-106402; JP 54-106403; JP-A-55-64509; JP-A-56-123986; JP-A-56-125398], amylostatins ((amylostatins), agricultural and biological chemistry (Agric.
  • voglibose (generic name), acarbose (generic name) or miglitol (generic name) is more preferable, and voglibose or acarbose is particularly preferable.
  • ⁇ -glucosidase inhibitor in the present invention in addition to the compounds described above, substances having an ⁇ -glucosidase inhibitory action usually used in foods and drinks are also suitable.
  • a substance for example, at least one selected from Mars extract, Salacia, mulberry leaf extract and tea seed extract can be suitably used.
  • Malus extract is a plant extract component that inhibits ⁇ -glucosidase activity and promotes the in vitro elimination of carbohydrates.
  • Salacia is a vine-like plant that grows naturally in Sri Lanka, and the ingredient Sarasinol is said to have been used for dieting in India by drinking roots as tea for about 5,000 years ago, which is useful for diabetes. It is supposed to be.
  • Tea seed (TS) extract is one of the components of tea and strongly inhibits the absorption of sugar (glucose) by inhibiting the glycosidase activity necessary to absorb sugar in the digestive tract. This action reduces the intake energy from the carbohydrates and balances the intake calorie and the calorie consumption.
  • tea seed (TS) extract (trade name, manufactured by Tanglewood) and the like are preferable.
  • the bacterium used in the present invention is at least one bacterium selected from the group consisting of bifidobacteria, lactic acid bacterium, saccharifying bacterium, and butyric acid bacterium.
  • Bifidobacterium bifidum, B. longum, B. breve B. adolescentis, B. infantis, B. pseudolongum, B. thermophilum, etc . for example, Lactobacillus acidophilus, L. casei, L. gasseri, L. plantarum, L. delbrueckii subsp bulgaricus, L. delbrueckii subsp lactis, L. fermentum, L.
  • pentosaceus, Oenococcus oeni, etc. saccharifying bacteria such as acillus mesentericus and Bacillus polyformenticus; for example, sporic lactic acid bacteria such as Bacillus coagulans; Bacillus toyoi, B. et al. Examples include butyric acid bacteria such as licheniformis and Clostridium butyricum; and other useful bacteria. These cells can be easily obtained from, for example, an organization such as ATCC or IFO or the Japan Bifidobacteria Center. Moreover, what is marketed can also be used suitably.
  • the bacterium used in the present invention is at least one bacterium selected from the group consisting of bifidobacteria, lactic acid bacterium, saccharifying bacterium and butyric acid bacterium, but at least one selected from the group consisting of bifidobacteria, lactic acid bacterium and saccharifying bacterium.
  • bifidobacteria lactic acid bacterium, saccharifying bacterium and butyric acid bacterium
  • lactic acid bacteria and / or bifidobacteria are more preferred.
  • Bifidobacteria are more preferable, Bifidobacterium bifidum, Bifidobacterium umlongum, Bifidobacterium infantis, and Bifidobacterium breve are more preferable, and Bifidobacterium bifidum and Bifidobacterium longum are particularly preferable.
  • Bifidobacteria and lactic acid bacteria and saccharifying bacteria bifidobacteria and lactic acid bacteria and saccharifying bacteria
  • bifidobacteria and lactic acid bacteria bifidobacteria and saccharifying bacteria
  • a combination of lactic acid bacteria and saccharifying bacteria are preferred, (i) Bifidobacterium bifidum, (ii) (Iii) Lactobacillus Enter acidophilus, (iii) Lactobacillus Strgasseri, (iv) Streptococcus (Enterococcus) faecalis, (v) Streptococcus (Enterococcus) faecium, (vi) Bacillus subtilis, (vi) Bacillus mesentericus (i) to (i) to (i) Combinations of more than one species are preferred, among which (i) Bifidobacterium bifidum G9-1, (ii) Lactobac
  • the bacterium in the present invention one or more selected from the group consisting of Bifidobacterium bifidum G9-1, Lactobacillus acidophilus KS-13, Streptococcus (Enterococcus) faecalis 129 BIO 3B, and Bacillus subtilis 129 BIO H ( ⁇ ) is more preferable. Particularly preferred is one or more selected from the group consisting of Bifidobacterium id bifidum G9-1, Streptococcus (Enterococcus) faecalis 129 BIO 3B, and Bacillus subtilis 129 BIO H ( ⁇ ).
  • the blending ratio in the case of using two or more of Bifidobacteria, lactic acid bacteria, saccharifying bacteria, and butyric acid bacteria in combination is not particularly limited.
  • the above-mentioned cells can be obtained by culturing under known conditions or similar conditions.
  • a liquid medium containing glucose, yeast extract, peptone, etc. is usually used, and one or more of the bifidobacteria and lactic acid bacteria are usually about 4 at about 25 to 45 ° C.
  • Cultivate aerobically or anaerobically for about 72 hours collect bacterial cells from the culture, and wash to obtain wet bacterial cells.
  • aerobic culture is usually performed at about 25 to 45 ° C. for about 4 to 72 hours in one or two or more agar media containing meat extract, casein peptone, sodium chloride and the like. Then, the cells are collected from the medium and washed to obtain wet cells.
  • the at least one bacterium selected from the group consisting of bifidobacteria, lactic acid bacterium, saccharifying bacterium, and butyric acid bacterium used in the present invention a viable bacterium is preferable, but a processed product of the bacterium may be used.
  • the treated product of the bacterium refers to a product obtained by adding some treatment to at least one bacterium selected from the group consisting of bifidobacteria, lactic acid bacterium, saccharifying bacterium, and butyric acid bacterium, and the treatment is not particularly limited.
  • the treated product include a disruption solution of the microbial cells by ultrasonic waves, a culture solution or a culture supernatant of the microbial cells, and a solid residue obtained by separating them by solid-liquid separation means such as filtration or centrifugation. It is done.
  • a treatment solution obtained by removing a cell wall by an enzyme or mechanical means, a protein complex (protein, lipoprotein, glycoprotein, etc.) or a peptide complex (peptide, glycopeptide, etc.) obtained by trichloroacetic acid treatment or salting-out treatment, etc. ) Etc. are also mentioned as the treated product.
  • these concentrates, these dilutions, or these dried products are also included in the treated product.
  • the treated product in the present invention includes those obtained by further adding, for example, various chromatographic separations to the disrupted solution of the bacterial cells by ultrasonic waves, the cell culture solution or the culture supernatant.
  • a dead cell of at least one bacterium selected from the group consisting of bifidobacteria, lactic acid bacteria, saccharifying bacteria, and butyric acid bacteria is also included in the treated product in the present invention.
  • the dead cells can be obtained by, for example, enzyme treatment, heat treatment at about 100 ° C., treatment with drugs such as antibiotics, treatment with chemicals such as formalin, treatment with radiation such as ⁇ rays. it can.
  • the fungus used in the present invention may be a dried product (bacterial cell dried product), and the dried cell product is preferably a single micron dried cell product.
  • the dried microbial cell usually refers to a dried individual microbial cell or a collection of dried microbial cells.
  • Single micron means 1 to 10 ⁇ m by rounding off the first decimal place.
  • the viable cell rate in the preparation increases.
  • the effect of preventing and improving lifestyle diseases such as dyslipidemia and obesity is enhanced.
  • the said microbial cell is disperse
  • a solvent a known solvent used in the art may be used, but water is preferable.
  • ethanol may be added. By adding ethanol, ethanol is vaporized first, and then water is vaporized, so that stepwise drying is possible.
  • the bacterial cell liquid may be a suspension.
  • the solvent may be the same as shown above.
  • a suspending agent such as sodium alginate may be used.
  • the bacterial cell liquid is subjected to a drying operation by a spray dryer in order to produce a dried bacterial cell product.
  • the spray drying apparatus is preferably a spray drying apparatus equipped with a atomizing apparatus capable of forming single micron spray droplets.
  • the single-micron droplet means a spray droplet having a particle size of 1 to 10 ⁇ m rounded to the first decimal place.
  • the spray drying device examples include a spray drying device in which the atomization device is, for example, a rotary atomizer (rotary disk), a pressurized nozzle, or a two-fluid nozzle or a four-fluid nozzle using the force of compressed gas.
  • the spray drying apparatus may be any spray drying apparatus of the above type as long as it can form single micron spray droplets, but it is preferable to use a spray drying apparatus having a four-fluid nozzle.
  • the four-fluid nozzle has a gas flow channel and a liquid flow channel as one system, which are provided symmetrically at the two-system nozzle edge. It constitutes the slope that becomes the surface. Also, an external mixing type apparatus that gathers compressed gas and liquid from one side toward the collision focus at the tip of the nozzle edge is preferable. With this method, it is possible to spray for a long time without nozzle clogging.
  • the spray drying apparatus having a four-channel nozzle will be described in more detail with reference to FIG.
  • the bacterial cell liquid that springed out from the liquid channel 3 or 4 was thinly stretched and stretched on the fluid flow surface 5 by the high-speed gas flow exiting from the gas channel 1 or 2.
  • the liquid is atomized by a shock wave generated at the collision focal point 6 at the tip of the nozzle edge to form a single micron spray droplet 7.
  • an inert gas such as air, carbon dioxide, nitrogen gas, or argon gas
  • an inert gas such as carbon dioxide, nitrogen gas, or argon gas
  • the pressure of the compressed gas is usually about 1 to 15 kgf / cm 2 , preferably about 3 to 8 kgf / cm 2 .
  • the amount of gas in the nozzle is usually about 1 to 100 L / min, preferably about 10 to 20 L / min per 1 mm of the nozzle edge.
  • the inlet temperature of the drying chamber is usually about 2 to 400 ° C., preferably about 5 to 250 ° C., more preferably about 5 to 150 ° C. Even when the inlet temperature is about 200 to 400 ° C., the temperature in the drying chamber is not so high due to the heat of vaporization due to the evaporation of moisture, and by reducing the residence time in the drying chamber, Damage can be suppressed to some extent.
  • the outlet temperature is usually about 0 to 120 ° C., preferably about 5 to 90 ° C., more preferably about 5 to 70 ° C.
  • a dried microbial cell product in which these are mixed can be produced.
  • a dried bacterial cell product containing the two types of bacterial cells can be obtained.
  • the viable cell rate is increased and a preparation having a high viable cell rate can be provided. That is, it is preferable to spray single micron spray droplets in order to obtain a single micron dried cell.
  • the particle size of the spray droplets is reduced, the surface area per unit mass of the spray droplets increases, so that contact with the dry hot air is performed efficiently, and killing or damaging the cells due to the heat of the dry hot air as much as possible. Can be suppressed.
  • the viable cell rate is increased and a dried cell body having a large number of viable cells is obtained.
  • the combination of at least one bacterium selected from the group consisting of bifidobacteria, lactic acid bacterium, saccharifying bacterium and butyric acid bacterium and an ⁇ -glucosidase inhibitor in the present invention is not particularly limited.
  • the compound represented by the formula (I) preferably voglibose (generic name)
  • the ⁇ -glucosidase inhibitor is a compound represented by the above general formula (II) (preferably acarbose (generic name)
  • at least one selected from the group consisting of lactic acid bacteria, saccharifying bacteria and bifidobacteria should be used.
  • bifidobacteria and / or lactic acid bacteria are more preferable, and bifidobacteria are particularly preferable.
  • lactic acid bacteria and saccharified bacteria may be used.
  • the ⁇ -glucosidase inhibitor and a bacterium are used in such a combination, the ⁇ -glucosidase inhibitor and / or the lipid metabolism improving action and the anti-obesity action of the bacterium can be remarkably enhanced, and thus excellent lipid metabolism improvement. Action and anti-obesity effect are obtained.
  • an agent for improving lipid metabolism by bifidobacteria containing voglibose an agent for improving lipid metabolism by bifidobacteria containing acarbose or lactic acid bacteria, an agent for improving lipid metabolism by voglibose containing bifidobacteria or acarbose, an acarbose containing lactic acid bacteria
  • a lipid metabolism improving agent or the like is one of the preferred embodiments of the present invention.
  • Lipid metabolism improving agents, anti-obesity agents, and anti-obesity action enhancing agents that contain voglibose or acarbose and are administered in combination with bifidobacteria are also preferred embodiments of the present invention.
  • a lipid metabolism improving agent, an anti-obesity agent and an anti-obesity effect-enhancing agent which contain acarbose and are administered in combination with lactic acid bacteria are also one preferred embodiment of the present invention.
  • a lipid metabolism improving agent, an anti-obesity agent and an anti-obesity effect-enhancing agent containing bifidobacteria and administered in combination with voglibose or acarbose are also one preferred embodiment of the present invention.
  • a lipid metabolism improving agent, an anti-obesity agent and an anti-obesity effect-enhancing agent which contain lactic acid bacteria and are administered in combination with acarbose are also one preferred embodiment of the present invention.
  • the lipid metabolism improving agent comprising the ⁇ -glucosidase inhibitor of the present invention, the lipid metabolism improving effect enhancer by the fungus, the anti-obesity agent and the anti-obesity effect enhancer are a mixture of the ⁇ -glucosidase inhibitor and other components. Is easily manufactured. Lipid metabolism improving action enhancer and anti-obesity action enhancer by ⁇ -glucosidase inhibitor containing at least one bacterium selected from the group consisting of bifidobacteria, lactic acid bacterium, saccharifying bacterium and butyric acid bacterium, the bacterium and other components It is easily manufactured by mixing. Other components are not particularly limited as long as the effects of the present invention are exhibited.
  • the lipid metabolism improving agent, lipid metabolism improving action enhancer, anti-obesity agent and anti-obesity action enhancer of the present invention can be used in the form of pharmaceuticals, quasi drugs, food and drink, feeds and the like.
  • Such a pharmaceutical comprising the lipid metabolism improving agent, lipid metabolism improving action enhancer, anti-obesity agent or anti-obesity action enhancer of the present invention is also one aspect of the present invention.
  • the method of administering a combination of an ⁇ -glucosidase inhibitor and at least one bacterium selected from the group consisting of bifidobacteria, lactic acid bacteria, saccharifying bacteria and butyric acid bacteria is not particularly limited as long as the effects of the present invention are exhibited.
  • a preparation (composition) containing an ⁇ -glucosidase inhibitor and a preparation (composition) containing at least one bacterium selected from the group consisting of bifidobacteria, lactic acid bacteria, saccharifying bacteria, and butyric acid bacteria A method in which both preparations are administered separately or at the same time, both ⁇ -glucosidase inhibitors and at least one bacterium selected from the group consisting of bifidobacteria, lactic acid bacteria, saccharifying bacteria, and butyric acid bacteria Can be mentioned, but it is preferable to prepare and administer a preparation containing both components.
  • the dosage form may be a dosage form suitable for administration in consideration of the physicochemical properties and biological properties of each component.
  • a pharmaceutical it is suitable for oral administration and is preferably an internal preparation.
  • the internal dosage form include tablets, pellets, fine granules, powders, granules, pills, chewables, troches, liquids, suspensions and the like. Among these, tablets or powders are preferable.
  • each preparation is prepared by adding an excipient (for example, lactose, starch, etc.) in addition to an ⁇ -glucosidase inhibitor and / or at least one bacterium selected from the group consisting of bifidobacteria, lactic acid bacteria, saccharifying bacteria, and butyric acid bacteria.
  • an excipient for example, lactose, starch, etc.
  • bacterium selected from the group consisting of bifidobacteria, lactic acid bacteria, saccharifying bacteria, and butyric acid bacteria.
  • Crystalline cellulose or sodium phosphate Crystalline cellulose or sodium phosphate
  • binders eg starch, gelatin, carmellose sodium, methylcellulose, hydroxypropylmethylcellulose, hydroxypropylcellulose, polyvinylpyrrolidone, etc.
  • disintegrants eg starch, carmellose sodium, etc.
  • Reagents eg talc, magnesium stearate, calcium stearate, macrogol, sucrose fatty acid ester, etc.
  • stabilizers sodium bisulfite, sodium thiosulfate, sodium edetate, sodium citrate, ascorbic acid, dibutyl Mud carboxymethyl toluene
  • colorants Fukozai, brighteners, etc.
  • known additives such as a may contain appropriately used in the art.
  • the amount of the ⁇ -glucosidase inhibitor contained in the preparation can be usually determined by appropriately selecting from the range of about 0.0001 to 99% by mass in the final preparation.
  • the amount of at least one bacterium selected from the group consisting of bifidobacteria, lactic acid bacteria, saccharifying bacteria, and butyric acid bacteria contained in the preparation is usually appropriately selected from the range of about 0.000001 to 99% by mass in the final preparation. Can be determined.
  • Preparation of a composition containing an ⁇ -glucosidase inhibitor and at least one bacterium selected from the group consisting of bifidobacteria, lactic acid bacteria, saccharifying bacteria, and butyric acid bacteria is performed by mixing both components according to a conventional method of preparation.
  • the combination ratio of the ⁇ -glucosidase inhibitor in the composition and at least one bacterium selected from the group consisting of bifidobacteria, lactic acid bacterium, saccharifying bacterium, and butyric acid bacterium is an ⁇ -glucosidase inhibitor.
  • About 10 3 to 10 12 bacteria are preferable for about 0.05 to 500 mg, and about 10 5 to 10 11 bacteria for about 0.01 to 300 mg of the ⁇ -glucosidase inhibitor. It is particularly preferable to do this.
  • At least one bacterium selected from the group consisting of bifidobacteria, lactic acid bacterium, saccharifying bacterium, and butyric acid bacterium is generally anaerobic and weak against air or oxygen in a dry state, and is also resistant to high temperature and humidity.
  • compositions containing an ⁇ -glucosidase inhibitor and at least one bacterium selected from the group consisting of bifidobacteria, lactic acid bacteria, saccharifying bacteria, and butyric acid bacteria are made into a solid preparation
  • powders are simply mixed by a drying method.
  • the powder may be compressed into granules or tablets.
  • granules and tablets are produced by a wet method, they can be kneaded and dried using an aqueous solution of a binder to obtain a desired solid agent.
  • the powder or granule obtained in this way can be filled into a capsule to form a capsule.
  • a known tableting machine when manufacturing tablets, a known tableting machine may be used.
  • the tableting machine include a single-shot tableting machine and a rotary tableting machine.
  • the manufacturing method of a pill, a chewable agent, or a troche agent may be performed in accordance with a well-known method, for example, can be made with the same means as manufacturing a tablet.
  • an active ingredient ⁇ -glucosidase inhibitor and / or at least one bacterium selected from the group consisting of bifidobacteria, lactic acid bacteria, saccharifying bacteria, and butyric acid bacteria
  • a so-called stepwise mixing method is preferably employed.
  • the active ingredient can be mixed with 100 to 200 times its volume of powder to obtain a uniform powder, and this can be mixed with the remaining powder to obtain a uniform powder.
  • means such as L-drying, freeze-drying and spray-drying can be employed.
  • a dry cell of at least one bacterium selected from the group consisting of bifidobacteria, lactic acid bacterium, saccharification bacterium and butyric acid bacterium, an appropriate stabilizer such as monosodium glutamate, adonitol, etc.
  • Bacteria can be suspended in the added neutral buffer and dried by a method known per se.
  • the dose of the ⁇ -glucosidase inhibitor is usually about 0.001 to 500 mg / adult / dose, preferably about 0.001 to 100 mg / adult / dose, more preferably about 0.002 to 100 mg / adult. It is preferably administered orally between 2 to 4 times a day, usually 1 hour before meal to 2 hours after meal.
  • the ⁇ -glucosidase inhibitor is a violamine derivative represented by the above general formula (I)
  • the compound is usually about 0.001 to 20 mg / adult / dose (more preferably about 0.002 to 20 mg / day).
  • Adults / dose) 2-4 times a day, and it is effective to orally administer this at an appropriate time between 1 hour before meal and 2 hours after meal.
  • the dose of at least one bacterium selected from the group consisting of bifidobacteria, lactic acid bacterium, saccharifying bacterium, and butyric acid bacterium is usually about 10 3 to 10 in terms of the number of viable bacteria.
  • the measurement of the number of viable bacteria in the preparation varies depending on the bacterial cells, but can be easily measured by, for example, each bacterial cell quantification method described in the Japanese Pharmacopoeia Pharmaceutical Standards.
  • the lipid metabolism-improving agent, lipid metabolism-improving action enhancer, anti-obesity agent and anti-obesity action enhancer of the present invention are, for example, lifestyle-related diseases such as dyslipidemia, cardiovascular disease, heart disease and the like ( Animal). Individuals in need of obesity or obesity reserve weight loss are also suitable subjects. Furthermore, an individual who has dyslipidemia or the like (metabolic syndrome) mainly in obesity or an individual who is likely to do so is more preferable. Among them, an individual who develops obesity and / or dyslipidemia or an individual at risk thereof is more preferable, an individual who develops obesity and / or dyslipidemia is more preferable, and develops obesity and hyperlipidemia. Individuals are particularly preferred. As the individual, mammals such as humans, mice, rats, rabbits, dogs, cats, cows, horses, pigs and monkeys are preferable, and humans are particularly preferable.
  • the lipid metabolism-improving agent, lipid metabolism-improving action enhancer, anti-obesity agent and anti-obesity action enhancer of the present invention are a group consisting of an ⁇ -glucosidase inhibitor and bifidobacteria, lactic acid bacteria, saccharifying bacteria, and butyric acid bacteria, even in small amounts.
  • the lipid metabolism-improving agent, lipid metabolism-improving action enhancer, anti-obesity agent and anti-obesity action enhancer of the present invention can be used as the above-mentioned pharmaceuticals, as well as food and drink such as functional foods, foods for specified health use or drinks. It can be used as a product.
  • the food / beverage composition for lipid metabolism improvement containing the lipid metabolism improving agent of this invention is also one of this invention.
  • a food / beverage food composition for enhancing lipid metabolism improving action by an ⁇ -glucosidase inhibitor which includes the lipid metabolism improving action enhancing agent containing the bacterium, is also one aspect of the present invention.
  • the food / beverage composition for obesity improvement containing the anti-obesity agent of this invention is also one of this invention.
  • a food / beverage composition for enhancing obesity-improving action by at least one bacterium selected from the group consisting of bifidobacteria, lactic acid bacteria, saccharifying bacteria and butyric acid bacteria, comprising the anti-obesity action enhancing agent containing the ⁇ -glucosidase inhibitor is also provided. It is one of the inventions.
  • a food / beverage composition for enhancing obesity-improving action by an ⁇ -glucosidase inhibitor comprising the anti-obesity action-enhancing agent containing the above-mentioned bacteria, is also one aspect of the present invention.
  • the amount of the ⁇ -glucosidase inhibitor contained in the food / beverage product composition can usually be determined by appropriately selecting from the range of about 0.0001 to 99% by mass in the final composition.
  • the amount of at least one bacterium selected from the group consisting of bifidobacteria, lactic acid bacteria, saccharifying bacteria, and butyric acid bacteria contained in the food and drink composition is usually in the range of about 0.000001 to 99% by mass in the final composition. It can be selected and determined as appropriate.
  • the method for ingesting an ⁇ -glucosidase inhibitor and at least one bacterium selected from the group consisting of bifidobacteria, lactic acid bacteria, saccharifying bacteria, and butyric acid bacteria is not particularly limited as long as the effects of the present invention are exhibited.
  • a composition containing an ⁇ -glucosidase inhibitor and a composition containing at least one bacterium selected from the group consisting of bifidobacteria, lactic acid bacteria, saccharifying bacteria, and butyric acid bacteria are prepared separately.
  • a composition containing both components it is preferable to prepare and ingest a composition containing both components.
  • the form is not particularly limited.
  • food-drinks compositions can also be made into processing forms, such as a natural liquid food, a semi-digested nutrient food, a component nutrient food, or a drink agent.
  • the food-drinks composition concerning this invention is good also as an easily soluble formulation added to an alcoholic beverage or mineral water at the time of use.
  • the food / beverage composition according to the present invention includes, for example, confectionery such as biscuits, cookies, cakes, candy, chocolate, chewing gum, Japanese confectionery; bread, noodles, cooked rice or processed products thereof; sake, medicinal liquor, etc. Fermented foods; livestock farming foods such as yogurt, ham, bacon, sausage, mayonnaise; beverages such as fruit juice drinks, soft drinks, sports drinks, alcoholic drinks, and tea.
  • the food / beverage composition according to the present invention for example, under the control of a dietitian based on a doctor's meal, adds the food / beverage composition of the present invention to any food at the time of cooking in a hospital meal, It can also be given to patients in the form of food prepared in
  • the food / beverage composition of the present invention may be liquid or solid such as powder or granule.
  • the food / beverage composition according to the present invention may contain auxiliary components commonly used in the food field.
  • auxiliary component include lactose, sucrose, liquid sugar, honey, magnesium stearate, oxypropylcellulose, various vitamins, trace elements, citric acid, malic acid, fragrance, and inorganic salt.
  • the amount of intake of the food and beverage composition according to the present invention varies depending on the lifestyle-related disease state, age, sex, etc. of the mammal to be ingested, and cannot be generally stated, but it is not possible to say generally, ⁇ -glucosidase inhibitors and bifidobacteria, lactic acid bacteria, It is preferable to ingest at least one type of bacteria selected from the group consisting of saccharifying bacteria and butyric acid bacteria in the same amount as in the case of the above-described pharmaceuticals.
  • the present invention includes at least one bacterium selected from the group consisting of bifidobacteria, lactic acid bacterium, saccharifying bacterium, and butyric acid bacterium, and an action of improving lipid metabolism by an ⁇ -glucosidase inhibitor administered in combination with an ⁇ -glucosidase inhibitor or An agent for promoting the expression of anti-obesity action is also included.
  • an ⁇ -glucosidase inhibitor in combination with the above-mentioned bacteria, the dose of the ⁇ -glucosidase inhibitor can be adjusted so that the inhibitor exerts its lipid metabolism improving action such as blood lipid lowering action and anti-obesity action.
  • the dose of the ⁇ -glucosidase inhibitor is about 0.02 at a time.
  • this amount is orally administered 2 to 4 times a day before meals, an effective lipid metabolism improving effect is obtained about 4 to 8 weeks after the start of administration. For this reason, blood lipid and visceral fat can be reduced and weight gain can be suppressed.
  • the preferred amount of use of at least one bacterium selected from the group consisting of bifidobacteria, lactic acid bacteria, saccharifying bacteria and butyric acid bacteria is the same as the amount used in the lipid metabolism improving agent described above.
  • the expression promoter of lipid metabolism improving action or anti-obesity action by the ⁇ -glucosidase inhibitor of the present invention and preferred embodiments thereof are the same as the lipid metabolism improving enhancer by the ⁇ -glucosidase inhibitor described above.
  • the expression promoter for lipid metabolism improving action or anti-obesity action of the present invention can be used as a drug as well as the above-described lipid metabolism improving enhancer, and can also be used as food and drink.
  • the preferred combination of the ⁇ -glucosidase inhibitor and the bacterium in the expression promoting agent for improving lipid metabolism or anti-obesity is the same as that for the lipid metabolism improving agent described above.
  • lipid metabolism improving action or anti-obesity action promoting agent by voglibose or acarbose containing bifidobacteria and a lipid metabolism improving action or anti-obesity action promoting agent by acarbose containing lactic acid bacteria are preferred embodiments of the present invention.
  • a lipid metabolism improving action or anti-obesity action promoting agent by voglibose or acarbose containing bifidobacteria are preferred embodiments of the present invention.
  • a lipid metabolism improving action or anti-obesity action promoting agent by voglibose or acarbose containing bifidobacteria are preferred embodiments of the present invention.
  • a lipid metabolism improving action or anti-obesity action promoting agent by voglibose or acarbose containing bifidobacteria are preferred embodiments of the present invention.
  • the present invention also includes a method for improving lipid metabolism, wherein an ⁇ -glucosidase inhibitor is administered to an animal in combination with at least one bacterium selected from the group consisting of bifidobacteria, lactic acid bacteria, saccharifying bacteria, and butyric acid bacteria.
  • the present invention also enhances the lipid metabolism-improving action of the above-mentioned bacteria administered to animals by combining an ⁇ -glucosidase inhibitor with at least one bacterium selected from the group consisting of bifidobacteria, lactic acid bacteria, saccharifying bacteria, and butyric acid bacteria. Methods are also encompassed.
  • the present invention further includes a method for improving or treating obesity, wherein an ⁇ -glucosidase inhibitor is administered to an animal in combination with at least one bacterium selected from the group consisting of bifidobacteria, lactic acid bacteria, saccharifying bacteria, and butyric acid bacteria.
  • the present invention further enhances the obesity-improving action of the above-mentioned bacteria administered to animals by combining an ⁇ -glucosidase inhibitor with at least one bacteria selected from the group consisting of bifidobacteria, lactic acid bacteria, saccharifying bacteria and butyric acid bacteria. Methods are also encompassed.
  • the present invention provides an effect of improving lipid metabolism by an ⁇ -glucosidase inhibitor administered to an animal in combination with an ⁇ -glucosidase inhibitor at least one bacterium selected from the group consisting of bifidobacteria, lactic acid bacteria, saccharifying bacteria and butyric acid bacteria.
  • a method of enhancing is also included.
  • the present invention provides an obesity-improving action by an ⁇ -glucosidase inhibitor that is administered to an animal in combination with an ⁇ -glucosidase inhibitor at least one bacterium selected from the group consisting of bifidobacteria, lactic acid bacteria, saccharifying bacteria, and butyric acid bacteria.
  • a method of enhancing is also included.
  • the present invention relates to an action of improving lipid metabolism by an ⁇ -glucosidase inhibitor administered to an animal in combination with an ⁇ -glucosidase inhibitor at least one bacterium selected from the group consisting of bifidobacteria, lactic acid bacteria, saccharifying bacteria and butyric acid bacteria Also included are methods of promoting expression or anti-obesity effects.
  • Examples of the animal in the method of the present invention include the above-mentioned lifestyle-related diseases such as dyslipidemia or individuals (animals) that may be there; obesity or individuals who need to reduce weight of the obesity reserve army; hyperlipidemia mainly in obesity It is preferable to use an individual having metabolic syndrome (metabolic syndrome) or an individual having such a possibility.
  • the administration method, dosage, etc. of at least one bacterium selected from the group consisting of bifidobacteria, lactic acid bacteria, saccharification bacteria, and butyric acid bacteria, and the ⁇ -glucosidase inhibitor are the same as those in the lipid metabolism improving agent described above. is there.
  • % means “% by mass” unless otherwise specified.
  • BBG9-1 Bifidobacterium bifidum G9-1
  • BBG9-1 Bifidobacterium bifidum G9-1
  • BBG9-1 was prepared as follows. That is, after the BBG9-1 cryopreserved strain (Biofermin Pharmaceutical Co., Ltd.) was allowed to stand at 37 ° C.
  • the Bifidobacterium test liquid medium (1) in Japanese Pharmacopoeia Pharmaceutical Standards “Bifidobacterium” This culture was inoculated at a ratio (volume ratio) of 1 with respect to the liquid medium for bifidobacterial test (1) 100, followed by stationary culture at 37 ° C. for 18 hours. The obtained culture solution is centrifuged, washed three times with water, an appropriate amount of water is added, and 0.1 kg of glutamate and 0.5 kg of dextrin are added to 1 kg of wet cells, and the mixture is added to the spray drying apparatus. The cells were dried.
  • the Bifidobacterium BBG9-1 strain is contained as a component of a biopharmaceutical drug Biofermin tablet (trade name, manufactured by Biofermin Pharmaceutical Co., Ltd.), and can be obtained by purification from the tablet or the like by a usual method. is there.
  • the liquid medium (1) for testing the Bifidobacterium is mixed with the following components according to the method described in the Japanese Pharmacopoeia Pharmaceutical Standards “Bifidobacterium”, and heated at 121 ° C. for 10 minutes using a high-pressure steam sterilizer. And prepared by sterilization. 1000mL of beef / liver exudate Casein peptone 10g Glucose 10g Polysorbate 80 1g L-cystine 0.5g (Previously dissolved in 2 mL of dilute hydrochloric acid and added.) pH 7.0-7.2
  • the preparation method of the diluent (2) used in the examples is shown below.
  • Preparation of Diluent (2) According to the method described in the Japanese Pharmacopoeia Pharmaceutical Standards “Bifidobacteria”, the following components are mixed and sterilized by heating at 121 ° C. for 15 minutes using a high-pressure steam sterilizer Prepared.
  • Anhydrous sodium monohydrogen phosphate 6.0 g 4.5g potassium dihydrogen phosphate Polysorbate 80 0.5g L-cysteine hydrochloride 0.5g Kang 1.0g Purified water 1000mL pH 6.8-7.0
  • a method for preparing the agar medium for testing the Bifidobacterium is shown below.
  • the following components were mixed according to the method described in the Japanese Pharmacopoeia drug standard “Bifidobacteria”, sterilized by heating at 121 ° C. for 15 minutes using a high-pressure steam sterilizer, and then used.
  • Pig liver leachate 1000mL Casein peptone 20g Lactose 20g Glucose 10g Sodium chloride 5g 4g potassium dihydrogen phosphate Sodium L-glutamate 2g 2 g of L-cystine (preliminarily dissolved in 10% sodium hydroxide solution) Kanten 15g pH 6.7 to 6.9
  • Example 2 Lipid lowering and anti-obesity enhancing action by combined use of bifidobacteria and ⁇ -glucosidase inhibitor
  • BBG9-1 dried cells obtained by the method of Example 1 were used as lactic acid bacteria, and voglibose was used as an ⁇ -glucosidase inhibitor.
  • voglibose pulverized Basin (registered trademark) 0.2 (manufactured by Takeda Pharmaceutical Company Limited) was used.
  • KK-A y mice Female KK-A y mice (strain name KK-A y / TaJcl) were purchased at 8 weeks of age (purchased from Clea Japan) and then preliminarily reared for 2 weeks in individual cages.
  • the KK-A y mouse is a model mouse for diabetes.
  • commercially available powdered feed CE-2: manufactured by CLEA Japan, Inc.
  • tap water were freely ingested.
  • An oral glucose tolerance test (OGTT) was performed on the day of the experiment. That is, fasting was performed from the day before OGTT was performed, and a glucose solution (2 g / 5 mL / kg) was orally administered on the day of implementation.
  • OGTT oral glucose tolerance test
  • Group A a group to which CE-2 mixed with 10% dextrin is administered as a diet.
  • Group B a group to which CE-2 mixed with 10% of dry BBG9-1 cells (3.4 ⁇ 10 11 / g) obtained by the method of Example 1 was fed.
  • Group C a group to which CE-2 mixed with 0.0003% voglibose and 10% dextrin is administered as a diet.
  • Group D CE-2 mixed with 10% dry BBG9-1 cells obtained by the method of Example 1 (3.4 ⁇ 10 11 / g) and voglibose at a ratio of 0.0003% is fed as a diet. group.
  • the body weight change was measured when the feed was ingested for 7 weeks. Furthermore, whole blood was collected at the end of the test, and the neutral plasma level of the obtained plasma was measured. The significant difference between each group relative to the A group was evaluated using Dunnett test, and the significant difference between the two groups was evaluated using t test.
  • FIG. 1 shows the change in body weight when mice in groups A to D were fed each test diet for 7 weeks.
  • FIG. 2 shows the plasma triglyceride value (mg / dL) measured at the end of the test.
  • FIG. 1 represents the mean ⁇ standard error (SE) of 8 individuals.
  • SE standard error
  • open circles are mice administered with a diet containing CE-2 mixed with 10% dextrin (Group A).
  • Open squares are mice fed with CE-2 mixed with 10% of dry BBG9-1 cells (3.4 ⁇ 10 11 / g) obtained by the method of Example 1 (Group B).
  • White triangles represent mice fed with CE-2 mixed with 0.003% voglibose and 10% dextrin (Group C).
  • the black square is fed with 10% dry BBG9-1 cells (3.4 ⁇ 10 11 / g) obtained by the method of Example 1 and CE-2 mixed with voglibose at a rate of 0.0003%.
  • Mice Group D).
  • the values in the bar graph in FIG. 2 represent the mean ⁇ standard error (SE) of 8 individuals.
  • white is a mouse fed with CE-2 mixed with dextrin at a ratio of 10% (Group A).
  • Gray is a mouse fed with CE-2 mixed with 10% of dry BBG9-1 cells (3.4 ⁇ 10 11 / g) obtained by the method of Example 1 (Group B).
  • the slanted lines are mice fed with CE-2 mixed with voglibose 0.0003% and dextrin 10% (group C).
  • Black was fed with CE-2 mixed with 10% dry BBG9-1 cells obtained by the method of Example 1 (3.4 ⁇ 10 11 / g) and voglibose at a ratio of 0.0003%.
  • Mice (Group D).
  • Example 3> Lipid lowering and anti-obesity enhancing action by combined use of bifidobacteria and ⁇ -glucosidase inhibitor
  • BBG9-1 dry cells obtained by the method of Example 1 were used as lactic acid bacteria, and acarbose was used as an ⁇ -glucosidase inhibitor.
  • acarbose pulverized glucobay (registered trademark) 100 mg (manufactured by Bayer Yakuhin) was used.
  • KK-A y mice Female KK-A y mice (strain name KK-A y / TaJcl) were purchased at 8 weeks of age (purchased from Clea Japan) and then preliminarily reared for 2 weeks in individual cages.
  • the KK-A y mouse is a model mouse for diabetes.
  • commercially available powdered feed CE-2: manufactured by CLEA Japan, Inc.
  • tap water were freely ingested.
  • An oral glucose tolerance test (OGTT) was performed on the day of the experiment. That is, fasting was performed from the day before OGTT was performed, and a glucose solution (2 g / 5 mL / kg) was orally administered on the day of implementation.
  • OGTT oral glucose tolerance test
  • Group E a group to which CE-2 mixed with 10% dextrin is administered as a diet.
  • Group F A group to which CE-2 mixed with 10% of dry BBG9-1 cells (3.4 ⁇ 10 11 / g) obtained by the method of Example 1 was fed.
  • Group G Group administered with CE-2 mixed with 0.1% acarbose and 10% dextrin.
  • Group H Feeding CE-2 mixed with 10% dry BBG9-1 cells (3.4 ⁇ 10 11 / g) obtained by the method of Example 1 and 0.1% acarbose group.
  • the body weight change was measured when the feed was ingested for 7 weeks. Furthermore, whole blood was collected at the end of the test, and the total cholesterol level and neutral fat level in the obtained plasma were measured. Periuterine fat was removed and the relative weight per body weight was compared. The significant difference between each group with respect to the E group was evaluated using Dunnett test, and the significant difference between the two groups was evaluated using t test.
  • FIG. 3 shows the changes in body weight when the mice in groups E to H were fed each test diet for 7 weeks.
  • 4 and 5 show the total cholesterol level (mg / dL) in plasma and the neutral fat level (mg / dL) in plasma measured at the end of the test, respectively.
  • FIG. 6 shows the relative weight of periuterine fat (body fat percentage (%)) relative to the body weight at the end of the test.
  • BBG9-1 alone (Group F) and acarbose alone (Group G) did not suppress body weight gain, but the combination of BBG9-1 and acarbose increased body weight.
  • FIG. 3 shows the changes in body weight when the mice in groups E to H were fed each test diet for 7 weeks.
  • 4 and 5 show the total cholesterol level (mg / dL) in plasma and the neutral fat level (mg / dL) in plasma measured at the end of the test, respectively.
  • FIG. 6 shows the relative weight of
  • BBG9-1 alone did not suppress the increase in total cholesterol level (Group F), but acarbose alone significantly suppressed (Group G), but the combined use of BBG9-1 and voglibose was not effective in total cholesterol.
  • the increase in value was synergistically significantly suppressed (Group H).
  • BBG9-1 alone nor acarbose alone (G group) suppressed the increase in triglyceride, but the combined use of BBG9-1 and acarbose was neutral.
  • H group The tendency which suppressed the raise of a fat value was shown (H group).
  • Each point in FIG. 3 represents the mean ⁇ standard error (SE) of 9 individuals.
  • SE standard error
  • open circles are mice administered with CE-2 mixed with 10% dextrin (Group E).
  • Open squares are mice fed with CE-2 mixed with 10% of dry BBG9-1 cells (3.4 ⁇ 10 11 / g) obtained by the method of Example 1 (Group F).
  • White triangles represent mice administered with dietary CE-2 mixed with 0.1% acarbose and 10% dextrin (group G).
  • the black square is fed with CE-2 mixed with 10% dry BBG9-1 cells (3.4 ⁇ 10 11 / g) obtained by the method of Example 1 and 0.1% acarbose.
  • Mice Group H).
  • the values in the bar graph in FIG. 4 represent the mean ⁇ standard error (SE) of 9 individuals.
  • white is a mouse fed with CE-2 mixed with dextrin at a ratio of 10% (Group E).
  • Gray is a mouse fed with CE-2 mixed with 10% of dry BBG9-1 cells (3.4 ⁇ 10 11 / g) obtained by the method of Example 1 (Group F).
  • the hatched lines are mice administered with CE-2 mixed with 0.1% acarbose and 10% dextrin (Group G).
  • Black is fed with CE-2 mixed with 10% dry BBG9-1 cells (3.4 ⁇ 10 11 / g) obtained by the method of Example 1 and 0.1% acarbose.
  • Mice (Group H).
  • mice (group E) fed with CE-2 mixed with 10% dextrin were fed with mice (group E) fed with CE-2 mixed with 10% dextrin, respectively, the method of Example 1 Significant difference (###: p) from mice (group F) fed with CE-2 mixed with 10% of dry BBG9-1 cells (3.4 ⁇ 10 11 / g) obtained by ⁇ 0.001) and a significant difference ($: p ⁇ 0.05) from mice (Group G) fed with CE-2 mixed with 0.1% acarbose and 10% dextrin.
  • the values in the bar graph in FIG. 5 represent the mean ⁇ standard error (SE) of 9 individuals.
  • white is a mouse fed with CE-2 mixed with dextrin at a ratio of 10% (Group E).
  • Gray is a mouse fed with CE-2 mixed with 10% of dry BBG9-1 cells (3.4 ⁇ 10 11 / g) obtained by the method of Example 1 (Group F).
  • the hatched lines are mice administered with CE-2 mixed with 0.1% acarbose and 10% dextrin (Group G).
  • Black is fed with CE-2 mixed with 10% dry BBG9-1 cells (3.4 ⁇ 10 11 / g) obtained by the method of Example 1 and 0.1% acarbose.
  • Mice (Group H).
  • the values in the bar graph in FIG. 6 represent the mean ⁇ standard error (SE) of 9 individuals.
  • white is a mouse fed with CE-2 mixed with dextrin at a ratio of 10% (Group E).
  • Gray is a mouse fed with CE-2 mixed with 10% of dry BBG9-1 cells (3.4 ⁇ 10 11 / g) obtained by the method of Example 1 (Group F).
  • the hatched lines are mice administered with CE-2 mixed with 0.1% acarbose and 10% dextrin (Group G).
  • Black is fed with CE-2 mixed with 10% dry BBG9-1 cells (3.4 ⁇ 10 11 / g) obtained by the method of Example 1 and 0.1% acarbose.
  • Mice (Group H).
  • mice (group E) fed with CE-2 mixed with 10% dextrin were fed with mice (group E) fed with CE-2 mixed with 10% dextrin, respectively, the method of Example 1 Significant difference (###: p) from mice (group F) fed with CE-2 mixed with 10% of dry BBG9-1 cells (3.4 ⁇ 10 11 / g) obtained by ⁇ 0.001) and a significant difference ($: p ⁇ 0.05) from mice (Group G) fed with CE-2 mixed with 0.1% acarbose and 10% dextrin.
  • the same results as above can be obtained by using bifidobacteria, lactic acid bacteria, saccharifying bacteria or butyric acid bacteria other than BBG9-1.
  • the same results as above can be obtained by using an ⁇ -glucosidase inhibitor other than voglibose and acarbose.
  • Example 4> (Preparation of dried lactic acid bacteria and measurement of the number of viable bacteria in the dried bacteria) 1.
  • Preparation Method of Bacteria (3B: Streptococcus faecalis 129 BIO 3B)
  • the dry cell product of 3B was prepared as follows. That is, after the 3B cryopreserved strain (Biofermin Pharmaceutical Co., Ltd.) was allowed to stand at 37 ° C. for 24 hours, this was added to the liquid medium for lactamine test (2) (described in the Japanese Pharmacopoeia Pharmaceutical Standards “Lactamine” section).
  • the cultured bacterial solution was inoculated at a ratio (volume ratio) of 1 with respect to the liquid medium for lactamine test (2) 100, followed by stationary culture at 37 ° C.
  • strain is contained as components, such as biopharmaceuticals of biopharmaceuticals (brand name, Biofermin Pharmaceutical Co., Ltd.), and can be obtained by refine
  • the above-mentioned liquid medium for lactamine test (2) is mixed with the following components according to the method described in the section of the Japanese Pharmacopoeia Standard “Lactamine”, and heated at 121 ° C. for 15 minutes using a high-pressure steam sterilizer. And prepared by sterilization.
  • Polysorbate 80 3g L-cysteine hydrochloride 1g 800 mL of purified water pH 6.8 ⁇ 0.1 Tomato juice * was prepared by adding an equal amount of purified water to tomato juice, boiled with occasional stirring, adjusted to pH 6.8, and filtered.
  • the agar medium for lactamine test (2) was prepared by adding 20 g of agar to the liquid medium for lactamine test (2) and sterilizing by heating at 121 ° C. for 15 minutes using a high-pressure steam sterilizer.
  • Example 5 Lipid lowering and anti-obesity enhancing action by combined use of lactic acid bacteria and ⁇ -glucosidase inhibitor
  • 3B dried cells obtained by the method of Example 4 were used as lactic acid bacteria, and acarbose was used as an ⁇ -glucosidase inhibitor.
  • acarbose pulverized glucobay (registered trademark) 100 mg (manufactured by Bayer Yakuhin) was used.
  • KK-A y mice Female KK-A y mice (strain name KK-A y / TaJcl) were purchased at 8 weeks of age (purchased from Clea Japan) and then preliminarily reared for 2 weeks in individual cages.
  • the KK-A y mouse is a model mouse for diabetes.
  • commercially available powdered feed CE-2: manufactured by CLEA Japan, Inc.
  • tap water were freely ingested.
  • An oral glucose tolerance test (OGTT) was performed on the day of the experiment. That is, fasting was performed from the day before OGTT was performed, and a glucose solution (2 g / 5 mL / kg) was orally administered on the day of implementation.
  • OGTT oral glucose tolerance test
  • Group I a group to which CE-2 mixed with 10% dextrin is administered as a diet.
  • Group J A group to which CE-2 mixed with 10% of 3B dry cells (7.0 ⁇ 10 11 / g) obtained by the method of Example 4 was fed.
  • Group K Group administered with CE-2 mixed with 0.1% acarbose and 10% dextrin.
  • Group L A group to which CE-2 mixed with 10% of dry 3B cells (7.0 ⁇ 10 11 / g) obtained by the method of Example 4 and acarbose at a ratio of 0.1% was administered as a diet.
  • the body weight change was measured when the feed was ingested for 7 weeks. Furthermore, whole blood was collected at the end of the test, and the neutral plasma level of the obtained plasma was measured. Periuterine fat was removed and the relative weight per body weight was compared. The significant difference between each group relative to the group I was evaluated using Dunnett test, and the significant difference between the two groups was evaluated using t test.
  • FIG. 7 shows changes in body weight when mice in groups I to L were fed each test diet for 7 weeks.
  • FIG. 8 shows the neutral fat level (mg / dL) in plasma measured at the end of the test.
  • FIG. 9 shows the relative weight of periuterine fat (body fat percentage (%)) relative to the body weight at the end of the test.
  • 3B alone (group J) and acarbose alone (group K) did not suppress the increase in body weight, but the combined use of 3B and acarbose significantly suppressed the increase in body weight. (L group).
  • FIG. 7 shows changes in body weight when mice in groups I to L were fed each test diet for 7 weeks.
  • FIG. 8 shows the neutral fat level (mg / dL) in plasma measured at the end of the test.
  • FIG. 9 shows the relative weight of periuterine fat (body fat percentage (%)) relative to the body weight at the end of the test.
  • Each point in FIG. 7 represents the mean ⁇ standard error (SE) of 9 individuals.
  • SE standard error
  • open circles are mice administered with a diet containing CE-2 mixed with 10% dextrin (group I).
  • White squares are mice fed with CE-2 mixed with 10% of 3B dry cells (7.0 ⁇ 10 11 / g) obtained by the method of Example 4 (Group J).
  • White triangles represent mice administered with dietary CE-2 mixed with 0.1% acarbose and 10% dextrin (group K).
  • Black squares represent mice fed with CE-2 mixed with 10% of 3B dry cells (7.0 ⁇ 10 11 / g) obtained by the method of Example 4 and 0.1% of acarbose. (Group L).
  • the values in the bar graph in FIG. 8 represent the mean ⁇ standard error (SE) of 9 individuals.
  • white is a mouse fed with CE-2 mixed with dextrin at a ratio of 10% (group I).
  • the gray color represents mice fed with CE-2 mixed with 10% of 3B dry cells (7.0 ⁇ 10 11 / g) obtained by the method of Example 4 (Group J).
  • the hatched lines are mice administered with CE-2 mixed with 0.1% acarbose and 10% dextrin (group K).
  • Black is a mouse fed with CE-2 mixed with 10% of 3B dry cells (7.0 ⁇ 10 11 / g) obtained by the method of Example 4 and 0.1% of acarbose. Yes (group L).
  • the values in the bar graph in FIG. 9 represent the mean ⁇ standard error (SE) of 9 individuals.
  • white is a mouse fed with CE-2 mixed with dextrin at a ratio of 10% (group I).
  • the gray color represents mice fed with CE-2 mixed with 10% of 3B dry cells (7.0 ⁇ 10 11 / g) obtained by the method of Example 4 (Group J).
  • the hatched lines are mice administered with CE-2 mixed with 0.1% acarbose and 10% dextrin (group K).
  • Black is a mouse fed with CE-2 mixed with 10% of 3B dry cells (7.0 ⁇ 10 11 / g) obtained by the method of Example 4 and 0.1% of acarbose. Yes (group L).
  • # Significant difference from mice (group J) fed with CE-2 mixed with 10% of 3B dry cells (7.0 ⁇ 10 11 / g) obtained by the method of Example 4 (#: P ⁇ 0.05).
  • Example 5 the same results as above can be obtained even if bifidobacteria, lactic acid bacteria, saccharifying bacteria or butyric acid bacteria other than 3B are used. In addition, the same result as above can be obtained by using an ⁇ -glucosidase inhibitor other than acarbose.
  • the present invention can prevent, improve or treat obesity, dyslipidemia, etc., it is useful for the prevention, improvement or treatment of lifestyle-related diseases, metabolic syndrome and the like.

Abstract

Disclosed is a lipid metabolism improving agent which is characterized by containing an α-glucosidase inhibitor and being administered in combination with at least one kind of bacterium that is selected from the group consisting of a bifidus bacterium, a lactic acid bacterium, a saccharification bacterium and a butyric acid bacterium.

Description

脂質代謝改善剤、脂質代謝改善作用増強剤、抗肥満剤及び抗肥満作用増強剤Lipid metabolism improving agent, lipid metabolism improving agent, anti-obesity agent and anti-obesity agent
 本発明は、脂質代謝の改善作用、乳酸菌等の菌による脂質代謝改善作用を増強する作用、抗肥満作用及び抗肥満作用を増強する作用を有する組成物に関する。さらに詳細には、本発明は、血中脂質濃度を低下させる作用を有する組成物に関する。本発明はまた、食餌により過多に摂取され、生体に蓄積される脂肪、特に、内臓脂肪等の代謝を促進又は改善し、肥満を改善する作用を有する組成物に関する。 The present invention relates to a composition having an action of improving lipid metabolism, an action of enhancing an action of improving lipid metabolism by bacteria such as lactic acid bacteria, an anti-obesity action and an action of enhancing an anti-obesity action. More specifically, the present invention relates to a composition having an action of reducing blood lipid concentration. The present invention also relates to a composition having an action of promoting or improving metabolism of fat, particularly visceral fat, which is excessively consumed by diet and accumulated in a living body, and improves obesity.
 近年、生活環境の変化により高脂肪食品を摂取する機会が増え、血中等のコレステロール、中性脂肪等の脂質濃度が高くなる傾向が強く、血中等の脂質濃度の上昇は、動脈硬化、肥満(肥満症)、脂肪肝等を始めとする様々な疾病の原因とされている。 In recent years, the chances of ingesting high-fat foods have increased due to changes in the living environment, and there is a strong tendency for lipids such as cholesterol and neutral fat in the blood to increase. Obesity), fatty liver, and other diseases.
 生体において、食餌として摂取された油脂は一旦分解され、小腸から吸収された後、再び中性脂肪(トリグリセリド)として再合成され血液中に出て行く。中性脂肪は筋肉などでエネルギーとして使われる重要な栄養素であるが、使用されなかった中性脂肪は、脂肪細胞に蓄積される。このため、血中脂質濃度が高いと、脂肪細胞に蓄積される中性脂肪が増加して肥満になりやすくなる。肥満は、癌、脳血管疾患、心臓病との関わりも強く、肥満がこれらの疾患になるリスクを上げることが報告されている。 In the living body, fats and oils ingested as a diet are once decomposed and absorbed from the small intestine, and then re-synthesized as neutral fat (triglyceride) and go out into the blood. Neutral fat is an important nutrient that is used as energy in muscles, etc., but neutral fat that is not used is accumulated in fat cells. For this reason, when the blood lipid concentration is high, the triglyceride accumulated in the fat cells increases and becomes obese. Obesity is strongly associated with cancer, cerebrovascular disease, and heart disease, and it has been reported that obesity increases the risk of these diseases.
 血中の脂質濃度の上昇を防ぐためには、摂取エネルギーの制限、運動等が効果的であるが、長年の生活習慣を変えることが必要であり、容易でない場合も多い。このため、脂質代謝改善作用を有する医薬又は食品について研究が行われている。 In order to prevent an increase in blood lipid concentration, it is effective to limit intake energy, exercise, etc., but it is necessary to change the lifestyle of many years and is often not easy. For this reason, research has been conducted on pharmaceuticals or foods having an action of improving lipid metabolism.
 特許文献1には、脂質代謝改善効果を有するラクトバチルス・ファーメンタム(Lactobacillus fermentum)SBT10534株(FERM P-21667)死菌体が開示されている。非特許文献1及び2には、乳酸菌の血中脂質低下作用が開示されている。ヒト臨床試験において、α-グルコシダーゼ阻害剤(ボグリボース)が血中脂質を下げることが報告されている(非特許文献3)。非特許文献3では、ベイスン(登録商標)1回0.2mgを1日3回56週間以上経口投与した場合に、血中トリグリセライドが有意に低下し、HDL-コレステロールが上昇するとされている。
 しかしながら、より優れた脂質代謝改善効果を有し、血中脂質の上昇、肥満、及びこれらに起因する生活習慣病等を効果的に予防及び改善することができる飲食品、医薬品等の開発が望まれていた。
Patent Document 1 discloses a dead cell of Lactobacillus fermentum strain SBT10534 (FERM P-21667) having an effect of improving lipid metabolism. Non-Patent Documents 1 and 2 disclose blood lipid lowering action of lactic acid bacteria. In human clinical trials, it has been reported that an α-glucosidase inhibitor (voglibose) lowers blood lipids (Non-patent Document 3). In Non-patent Document 3, it is said that when 0.2 mg of Basin (registered trademark) is orally administered three times a day for 56 weeks or more, blood triglyceride is significantly decreased and HDL-cholesterol is increased.
However, it is hoped to develop foods and drinks, pharmaceuticals, etc. that have a better lipid metabolism improving effect and can effectively prevent and ameliorate the rise in blood lipids, obesity, and lifestyle-related diseases resulting therefrom. It was rare.
特開2010-132580号公報JP 2010-132580 A
 本発明は、上記現状に鑑み、コレステロール、中性脂肪等の血中脂質を低下させることができ、内臓脂肪等の脂肪の蓄積、肥満等を効果的に予防、改善又は治療できる脂質代謝改善剤、脂質代謝改善作用増強剤、抗肥満剤、抗肥満作用増強剤、及び脂質代謝改善作用の発現促進剤を提供することを目的とする。 In view of the above-described situation, the present invention is a lipid metabolism improving agent that can reduce blood lipids such as cholesterol and neutral fat, and can effectively prevent, improve or treat fat accumulation such as visceral fat, obesity and the like. An object of the present invention is to provide an agent for improving lipid metabolism, an anti-obesity agent, an anti-obesity agent, and an agent for promoting the expression of lipid metabolism.
 本発明者らは、上記課題に鑑み鋭意研究を重ね、種々の物質について脂質代謝改善作用及び抗肥満作用を検討した結果、α-グルコシダーゼ(二糖類分解酵素)阻害剤及び乳酸菌等の菌を動物に投与すると、α-グルコシダーゼ阻害剤及び乳酸菌等の菌の組み合わせによる特異的な相乗効果によって、血中脂質濃度を有意に低下させることができることを見出した。また、α-グルコシダーゼ阻害剤及び乳酸菌等の菌を組み合わせて投与すると、体重増加を抑制でき、しかも体内の脂肪(特に内臓脂肪)を減少させることができることも見出した。α-グルコシダーゼ阻害剤は、糖尿病の治療に広く使用されている経口血糖降下剤であり、ヒト臨床試験において、α-グルコシダーゼ阻害剤(ボグリボース)が血中脂質を下げることが報告されている(三村和郎 他,臨床と研究,1992, 69 : 919)。この文献では、血中トリグリセライドが有意に低下し、HDL-コレステロールが上昇することが報告されているが、その効果は、ベイスン(登録商標)1回0.2mgを1日3回56週間以上経口投与した場合に得られる効果である。本発明者らは、実施例に示されるように、α-グルコシダーゼ阻害剤と乳酸菌等の菌とを組み合わせて投与することにより、投与4週間でマウスにおいて血中脂質低下が認められることから、α-グルコシダーゼ阻害剤と乳酸菌等の菌を併用することによって、α-グルコシダーゼ阻害剤のみを投与した場合と比較してより早く血中脂質低下効果が発現することを見出した。 The present inventors have conducted extensive studies in view of the above problems, and as a result of examining lipid metabolism improving action and anti-obesity action for various substances, as a result, α-glucosidase (disaccharide-degrading enzyme) inhibitors and bacteria such as lactic acid bacteria have been used as animals. It was found that the blood lipid concentration can be significantly reduced by the specific synergistic effect of the combination of an α-glucosidase inhibitor and a bacterium such as lactic acid bacteria. It was also found that when an α-glucosidase inhibitor and a bacterium such as a lactic acid bacterium are administered in combination, weight gain can be suppressed and fat in the body (particularly visceral fat) can be reduced. α-Glucosidase inhibitor is an oral hypoglycemic agent widely used for the treatment of diabetes, and it has been reported in human clinical trials that α-glucosidase inhibitor (Voglibose) lowers blood lipids (Mimura) Kazuo, et al., Clinical and research, 1992, 69: 919). This document reports that blood triglyceride is significantly decreased and HDL-cholesterol is increased, but the effect of basin (registered trademark) 0.2 mg at a time three times a day for 56 weeks or more. This is the effect obtained when administered. As shown in the Examples, the present inventors have observed that blood lipid reduction is observed in mice within 4 weeks of administration by administering an α-glucosidase inhibitor in combination with bacteria such as lactic acid bacteria. -It has been found that the combined use of glucosidase inhibitors and bacteria such as lactic acid bacteria produces a blood lipid lowering effect earlier than when only an α-glucosidase inhibitor is administered.
 また、乳酸菌により血中脂質濃度が低下することは知られているが、乳酸菌等の菌を単独で投与した場合と比較して、α-グルコシダーゼ阻害剤と乳酸菌等の菌とを併用した場合に、乳酸菌等の菌による血中脂質低下作用、体重増加抑制作用、内臓脂肪等の脂肪を減少させる作用等の脂質代謝改善作用及び抗肥満作用が相乗的に増強されることは、全く新しい知見であった。
 本発明者らは、上記知見に基づきさらに研究を重ね、本発明を完成するに至った。
In addition, it is known that blood lipid concentration is decreased by lactic acid bacteria, but when α-glucosidase inhibitor and lactic acid bacteria are used in combination, compared to the case where lactic acid bacteria are administered alone. It is a completely new finding that lipid metabolism improving action and anti-obesity action such as blood lipid lowering action, weight gain inhibiting action, visceral fat reducing action by lactic acid bacteria etc. are synergistically enhanced. there were.
The present inventors have further studied based on the above findings and have completed the present invention.
 すなわち、本発明は、以下の(1)~(24)に関する。
(1)α-グルコシダーゼ阻害剤を含み、ビフィズス菌、乳酸菌、糖化菌及び酪酸菌からなる群より選ばれる少なくとも1種の菌と組み合わせて投与されることを特徴とする脂質代謝改善剤。
(2)さらに、ビフィズス菌、乳酸菌、糖化菌及び酪酸菌からなる群より選ばれる少なくとも1種の菌を含む前記(1)に記載の脂質代謝改善剤。
(3)α-グルコシダーゼ阻害剤が、一般式(I)
That is, the present invention relates to the following (1) to (24).
(1) An agent for improving lipid metabolism, comprising an α-glucosidase inhibitor and administered in combination with at least one bacterium selected from the group consisting of bifidobacteria, lactic acid bacteria, saccharifying bacteria, and butyric acid bacteria.
(2) The lipid metabolism improving agent according to the above (1), further comprising at least one bacterium selected from the group consisting of bifidobacteria, lactic acid bacteria, saccharifying bacteria, and butyric acid bacteria.
(3) The α-glucosidase inhibitor has the general formula (I)
Figure JPOXMLDOC01-appb-C000005
Figure JPOXMLDOC01-appb-C000005
(式中、Aは、水酸基、フェノキシ、チエニル、フリル、ピリジル、シクロヘキシル、置換されていてもよいフェニル基を有しうる炭素数1~10の鎖状炭化水素基、水酸基、ヒドロキシメチル基、メチル基、アミノ基を有しうる炭素数5又は6員の環状炭化水素基又は糖残基を示す)で表わされるバリオールアミン誘導体、一般式(II) (In the formula, A is a hydroxyl group, phenoxy, thienyl, furyl, pyridyl, cyclohexyl, a chain hydrocarbon group having 1 to 10 carbon atoms which may have an optionally substituted phenyl group, a hydroxyl group, a hydroxymethyl group, methyl , A variolamine derivative represented by the general formula (II): a cyclic hydrocarbon group having 5 or 6 carbon atoms or a sugar residue which may have an amino group)
Figure JPOXMLDOC01-appb-C000006
Figure JPOXMLDOC01-appb-C000006
(式中、Aは、前記と同義である)で表わされるバリエナミンN-置換誘導体、一般式(III) (Wherein A is as defined above), a valienamine N-substituted derivative represented by the general formula (III)
Figure JPOXMLDOC01-appb-C000007
Figure JPOXMLDOC01-appb-C000007
(式中、Aは、前記と同義である)で表わされるバリダミンのN-置換誘導体、又は一般式(IV) (Wherein A is as defined above) or an N-substituted derivative of validamine, represented by the general formula (IV)
Figure JPOXMLDOC01-appb-C000008
Figure JPOXMLDOC01-appb-C000008
(式中、R及びRは、同一又は異なって、それぞれ水素原子、置換されていてもよい直鎖状、分枝状若しくは環式の飽和又は不飽和脂肪族炭化水素基、置換されていてもよい炭化水素環、芳香環又はヘテロ環であり、Rは、-H、-OH、-OR′、-SH、-SR′、-NH、-NHR′、-N(R′)(R′′)、NHCH-、NHR′-CH-、NR′R′′-CH-、-COOH、-COOR′、HO-CH-、R′CO-NHCH-、R′CO-NR′′CH-、R′SONHCH-、R′SO-NR′′CH-、R′-NH-CO-NH-CH-、R′-NH-CS-NH-CH-R′-O-CO-NH-CH-、-SOH、-CN、-CONH、-CONHR′又は-CONR′R′′であり、R′及びR′′は、同一又は異なって、それぞれRと同義である。Rが-CHOHであり、かつRが水素原子又は-OHである場合;Rが水素原子であり、かつRが水素原子、-OH、-SOH、-CN又は-CH-NHである場合;又はRが-CH-NHであり、かつRが-OHである場合には、Rは、水素原子でない。)で表わされる3,4,5-トリヒドロキシピペリジンである前記(1)又は(2)に記載の脂質代謝改善剤。
(4)α-グルコシダーゼ阻害剤を含み、ビフィズス菌、乳酸菌、糖化菌及び酪酸菌からなる群より選ばれる少なくとも1種の菌と組み合わせて投与されることを特徴とする前記菌による脂質代謝改善作用増強剤。
(5)α-グルコシダーゼ阻害剤を含み、ビフィズス菌、乳酸菌、糖化菌及び酪酸菌からなる群より選ばれる少なくとも1種の菌と組み合わせて投与されることを特徴とする抗肥満剤。
(6)α-グルコシダーゼ阻害剤を含み、ビフィズス菌、乳酸菌、糖化菌及び酪酸菌からなる群より選ばれる少なくとも1種の菌と組み合わせて投与されることを特徴とする前記菌による抗肥満作用増強剤。
(7)さらに、ビフィズス菌、乳酸菌、糖化菌及び酪酸菌からなる群より選ばれる少なくとも1種の菌を含む前記(4)~(6)のいずれか一項に記載の剤。
(8)ビフィズス菌、乳酸菌、糖化菌及び酪酸菌からなる群より選ばれる少なくとも1種の菌を含み、α-グルコシダーゼ阻害剤と組み合わせて投与されることを特徴とするα-グルコシダーゼ阻害剤による脂質代謝改善作用増強剤。
(9)ビフィズス菌、乳酸菌、糖化菌及び酪酸菌からなる群より選ばれる少なくとも1種の菌を含み、α-グルコシダーゼ阻害剤と組み合わせて投与されることを特徴とするα-グルコシダーゼ阻害剤による抗肥満作用増強剤。
(10)ビフィズス菌、乳酸菌、糖化菌及び酪酸菌からなる群より選ばれる少なくとも1種の菌を含み、α-グルコシダーゼ阻害剤と組み合わせて投与されることを特徴とするα-グルコシダーゼ阻害剤による脂質代謝改善作用又は抗肥満作用の発現促進剤。
(11)前記(1)~(10)のいずれか一項に記載の剤を含むことを特徴とする医薬品。
(12)前記(1)~(3)のいずれか一項に記載の脂質代謝改善剤を含むことを特徴とする脂質代謝改善用飲食品組成物。
(13)前記(4)に記載の脂質代謝改善作用増強剤を含むことを特徴とするビフィズス菌、乳酸菌、糖化菌及び酪酸菌からなる群より選ばれる少なくとも1種の菌による脂質代謝改善作用増強用飲食品組成物。
(14)前記(5)に記載の抗肥満剤を含むことを特徴とする肥満改善用飲食品組成物。
(15)前記(6)に記載の抗肥満作用増強剤を含むことを特徴とするビフィズス菌、乳酸菌、糖化菌及び酪酸菌からなる群より選ばれる少なくとも1種の菌による肥満改善作用増強用飲食品組成物。
(16)前記(8)に記載の脂質代謝改善作用増強剤を含むことを特徴とするα-グルコシダーゼ阻害剤による脂質代謝改善作用増強用飲食品組成物。
(17)前記(9)に記載の抗肥満作用増強剤を含むことを特徴とするα-グルコシダーゼ阻害剤による肥満改善作用増強用飲食品組成物。
(18)α-グルコシダーゼ阻害剤を、ビフィズス菌、乳酸菌、糖化菌及び酪酸菌からなる群より選ばれる少なくとも1種の菌と組み合わせて動物に投与することを特徴とする脂質代謝改善方法。
(19)α-グルコシダーゼ阻害剤を、ビフィズス菌、乳酸菌、糖化菌及び酪酸菌からなる群より選ばれる少なくとも1種の菌と組み合わせて動物に投与することを特徴とする前記菌による脂質代謝改善作用を増強する方法。
(20)α-グルコシダーゼ阻害剤を、ビフィズス菌、乳酸菌、糖化菌及び酪酸菌からなる群より選ばれる少なくとも1種の菌と組み合わせて動物に投与することを特徴とする肥満の改善又は治療方法。
(21)α-グルコシダーゼ阻害剤を、ビフィズス菌、乳酸菌、糖化菌及び酪酸菌からなる群より選ばれる少なくとも1種の菌と組み合わせて動物に投与することを特徴とする前記菌による肥満の改善作用を増強する方法。
(22)ビフィズス菌、乳酸菌、糖化菌及び酪酸菌からなる群より選ばれる少なくとも1種の菌を、α-グルコシダーゼ阻害剤と組み合わせて動物に投与することを特徴とするα-グルコシダーゼ阻害剤による脂質代謝改善作用を増強させる方法。
(23)ビフィズス菌、乳酸菌、糖化菌及び酪酸菌からなる群より選ばれる少なくとも1種の菌を、α-グルコシダーゼ阻害剤と組み合わせて動物に投与することを特徴とするα-グルコシダーゼ阻害剤による肥満の改善作用を増強する方法。
(24)α-グルコシダーゼ阻害剤を、ビフィズス菌、乳酸菌、糖化菌及び酪酸菌からなる群より選ばれる少なくとも1種の菌と組み合わせて動物に投与することを特徴とするα-グルコシダーゼ阻害剤による脂質代謝改善作用又は抗肥満作用の発現を促進する方法。
(Wherein R 1 and R 3 are the same or different and each represents a hydrogen atom, an optionally substituted linear, branched or cyclic saturated or unsaturated aliphatic hydrocarbon group, substituted Which may be a hydrocarbon ring, an aromatic ring or a heterocyclic ring, and R 2 is —H, —OH, —OR ′, —SH, —SR ′, —NH 2 , —NHR ′, —N (R ′) (R ″), NH 2 CH 2 —, NHR′—CH 2 —, NR′R ″ —CH 2 —, —COOH, —COOR ′, HO—CH 2 —, R′CO—NHCH 2 —, R′CO—NR ″ CH 2 —, R′SO 2 NHCH 2 —, R′SO 2 —NR ″ CH 2 —, R′—NH—CO—NH—CH 2 —, R′—NH—CS —NH—CH 2 —R′—O—CO—NH—CH 2 —, —SO 3 H, —CN, —CONH 2 , —CON HR ′ or —CONR′R ″, R ′ and R ″ are the same or different and have the same meaning as R 1. R 3 is —CH 2 OH and R 2 is a hydrogen atom or When —OH; R 3 is a hydrogen atom and R 2 is a hydrogen atom, —OH, —SO 3 H, —CN or —CH 2 —NH 2 ; or R 3 is —CH 2 —. When NH 2 and R 2 is —OH, R 1 is not a hydrogen atom.) Described in (1) or (2) above, which is 3,4,5-trihydroxypiperidine Lipid metabolism improving agent.
(4) An action of improving lipid metabolism by the bacterium comprising an α-glucosidase inhibitor and being administered in combination with at least one bacterium selected from the group consisting of bifidobacteria, lactic acid bacterium, saccharifying bacterium and butyric acid bacterium Enhancer.
(5) An anti-obesity agent comprising an α-glucosidase inhibitor and administered in combination with at least one bacterium selected from the group consisting of bifidobacteria, lactic acid bacterium, saccharifying bacterium, and butyric acid bacterium.
(6) An anti-obesity effect enhancement by said bacterium characterized by comprising an α-glucosidase inhibitor and being administered in combination with at least one bacterium selected from the group consisting of bifidobacteria, lactic acid bacterium, saccharifying bacterium and butyric acid bacterium Agent.
(7) The agent according to any one of (4) to (6), further comprising at least one bacterium selected from the group consisting of bifidobacteria, lactic acid bacteria, saccharifying bacteria, and butyric acid bacteria.
(8) A lipid produced by an α-glucosidase inhibitor, comprising at least one bacterium selected from the group consisting of bifidobacteria, lactic acid bacteria, saccharifying bacteria, and butyric acid bacteria, and administered in combination with an α-glucosidase inhibitor Metabolism improving agent.
(9) an anti-α-glucosidase inhibitor comprising at least one bacterium selected from the group consisting of bifidobacteria, lactic acid bacteria, saccharifying bacteria, and butyric acid bacteria, and administered in combination with an α-glucosidase inhibitor Obesity enhancing agent.
(10) A lipid derived from an α-glucosidase inhibitor, comprising at least one bacterium selected from the group consisting of bifidobacteria, lactic acid bacteria, saccharifying bacteria, and butyric acid bacteria, and administered in combination with an α-glucosidase inhibitor Metabolism improving action or anti-obesity action promoting agent.
(11) A pharmaceutical comprising the agent according to any one of (1) to (10).
(12) A food and drink composition for improving lipid metabolism, comprising the lipid metabolism improving agent according to any one of (1) to (3).
(13) Enhancement of lipid metabolism improving action by at least one bacterium selected from the group consisting of bifidobacteria, lactic acid bacteria, saccharifying bacteria, and butyric acid bacteria, comprising the lipid metabolism improving action enhancer according to (4) above Food and beverage composition.
(14) A food and beverage composition for improving obesity comprising the anti-obesity agent according to (5).
(15) Food and beverage for enhancing obesity-improving action by at least one bacterium selected from the group consisting of bifidobacteria, lactic acid bacteria, saccharifying bacteria and butyric acid bacteria, comprising the anti-obesity action enhancing agent according to (6) Product composition.
(16) A food and drink composition for enhancing lipid metabolism improving action by an α-glucosidase inhibitor, comprising the lipid metabolism improving action enhancing agent according to (8).
(17) A food / beverage composition for enhancing obesity-improving action by an α-glucosidase inhibitor, comprising the anti-obesity action enhancer according to (9).
(18) A method for improving lipid metabolism, comprising administering an α-glucosidase inhibitor to an animal in combination with at least one bacterium selected from the group consisting of bifidobacteria, lactic acid bacteria, saccharifying bacteria, and butyric acid bacteria.
(19) An action for improving lipid metabolism by the bacterium characterized in that an α-glucosidase inhibitor is administered to an animal in combination with at least one bacterium selected from the group consisting of bifidobacteria, lactic acid bacterium, saccharifying bacterium and butyric acid bacterium. How to strengthen.
(20) A method for improving or treating obesity comprising administering an α-glucosidase inhibitor to an animal in combination with at least one bacterium selected from the group consisting of bifidobacteria, lactic acid bacteria, saccharifying bacteria, and butyric acid bacteria.
(21) An obesity-improving action by the bacterium characterized by administering an α-glucosidase inhibitor to an animal in combination with at least one bacterium selected from the group consisting of bifidobacteria, lactic acid bacteria, saccharifying bacteria, and butyric acid bacteria How to strengthen.
(22) A lipid by an α-glucosidase inhibitor, characterized in that at least one bacterium selected from the group consisting of bifidobacteria, lactic acid bacteria, saccharifying bacteria and butyric acid bacteria is administered to an animal in combination with an α-glucosidase inhibitor A method for enhancing the effect of improving metabolism.
(23) Obesity by an α-glucosidase inhibitor, characterized in that at least one bacterium selected from the group consisting of bifidobacteria, lactic acid bacteria, saccharifying bacteria and butyric acid bacteria is administered to an animal in combination with an α-glucosidase inhibitor To enhance the improving action of
(24) A lipid by an α-glucosidase inhibitor, wherein the α-glucosidase inhibitor is administered to an animal in combination with at least one bacterium selected from the group consisting of bifidobacteria, lactic acid bacteria, saccharifying bacteria, and butyric acid bacteria A method of promoting the expression of a metabolic improving action or an anti-obesity action.
 本発明によれば、血中脂質を効果的に低下させることができ、体重増加を抑制でき、しかも内臓脂肪等の脂肪の蓄積を低減させることができるため、脂質異常症(高脂血症)、肥満、内臓脂肪の蓄積等の脂質代謝異常を効果的に予防、改善又は治療することができる。このため、脂質異常症、肥満等に起因する生活習慣病、メタボリックシンドローム等を効果的に予防、改善又は治療することができる。また、本発明の脂質代謝改善剤、脂質代謝改善作用増強剤、抗肥満剤、抗肥満作用増強剤、脂質代謝改善作用の発現促進剤及び抗肥満作用の発現促進剤は、長期間摂取しても副作用が少なく安全性が高いものである。 According to the present invention, blood lipid can be effectively reduced, weight gain can be suppressed, and accumulation of fat such as visceral fat can be reduced, resulting in dyslipidemia (hyperlipidemia). In addition, abnormalities of lipid metabolism such as obesity and visceral fat accumulation can be effectively prevented, improved or treated. For this reason, lifestyle-related diseases resulting from dyslipidemia, obesity and the like, metabolic syndrome and the like can be effectively prevented, ameliorated or treated. In addition, the lipid metabolism improving agent, lipid metabolism improving action enhancer, anti-obesity agent, anti-obesity action enhancer, lipid metabolism improving action expression promoter and anti-obesity action expression promoter of the present invention are taken for a long time. However, there are few side effects and high safety.
図1は、A~D各群のマウスに、試験飼料を7週間摂餌させたときの体重推移を示す図である。FIG. 1 is a graph showing the change in body weight when mice in groups A to D were fed a test diet for 7 weeks. 図2は、A~D各群のマウスの血漿中性脂肪値を示す図である。FIG. 2 is a graph showing plasma triglyceride levels of mice in groups A to D. 図3は、E~H各群のマウスに、各試験飼料を7週間摂餌させたときの体重推移を示す図である。FIG. 3 is a graph showing changes in body weight when mice of each of E to H groups were fed each test diet for 7 weeks. 図4は、E~H各群のマウスの血漿総コレステロール値を示す図である。FIG. 4 is a graph showing plasma total cholesterol levels in mice of each of E to H groups. 図5は、E~H各群のマウスの血漿中性脂肪値を示す図である。FIG. 5 is a diagram showing plasma triglyceride levels in mice of each of E to H groups. 図6は、E~H各群のマウスの体重に対する子宮周囲脂肪の相対重量を示す図である。FIG. 6 is a graph showing the relative weight of periuterine fat with respect to the body weight of the mice in each of E to H groups. 図7は、I~L各群のマウスに、試験飼料を7週間摂餌させたときの体重推移を示す図である。FIG. 7 is a graph showing changes in body weight when mice in groups I to L were fed a test diet for 7 weeks. 図8は、I~L各群のマウスの血漿中性脂肪値を示す図である。FIG. 8 is a graph showing plasma triglyceride levels in mice of each of the groups IL. 図9は、I~L各群のマウスの体重に対する子宮周囲脂肪の相対重量を示す図である。FIG. 9 is a graph showing the relative weight of periuterine fat with respect to the body weight of mice in each of the groups IL. 図10は、4流路ノズルを有する噴霧乾燥装置におけるノズルエッジ部分の内部構造を示す図である。FIG. 10 is a diagram illustrating an internal structure of a nozzle edge portion in a spray drying apparatus having four flow path nozzles.
 本発明の脂質代謝改善剤は、α-グルコシダーゼ阻害剤を含み、ビフィズス菌、乳酸菌、糖化菌及び酪酸菌からなる群より選ばれる少なくとも1種の菌と組み合わせて投与されるものである。
 前記菌とα-グルコシダーゼ阻害剤とを組み合わせて用いることにより、優れた血中脂質低下作用、内臓脂肪減少作用、内臓脂肪の蓄積の低減作用等の脂質代謝改善作用を発揮することができる。このため、脂質代謝異常を効果的に予防、改善又は治療することができる。
The lipid metabolism improving agent of the present invention contains an α-glucosidase inhibitor and is administered in combination with at least one bacterium selected from the group consisting of bifidobacteria, lactic acid bacteria, saccharifying bacteria, and butyric acid bacteria.
By using a combination of the bacterium and an α-glucosidase inhibitor, it is possible to exert lipid metabolism improving effects such as excellent blood lipid lowering action, visceral fat reducing action, visceral fat accumulation reducing action and the like. Therefore, abnormal lipid metabolism can be effectively prevented, improved or treated.
 本発明において、「予防」には発症を抑制する又は遅延させることが含まれる。「改善」には、症状又は疾病を完全に治癒させることの他、症状を緩和することも含まれる。 In the present invention, “prevention” includes suppressing or delaying the onset. “Improvement” includes alleviation of symptoms as well as complete cure of symptoms or diseases.
 脂質代謝異常は、生体の脂質成分のバランスに異常が認められる状態をいい、例えば脂質異常症(高脂血症)、肥満、内臓脂肪の蓄積等が挙げられる。
 脂質異常症には、例えば血中脂質が高値を示す状態、又は血中HDL(高比重リポ蛋白)コレステロールが低値を示す状態等が含まれる。血中脂質とは、通常、コレステロール、LDLコレステロール、中性脂肪(トリグリセリド)、リン脂質、遊離脂肪酸等である。本発明の脂質代謝改善剤は、コレステロール、LDLコレステロール、中性脂肪(トリグリセリド)等の血中脂質の低下に優れた効果を発揮するものである。このため、本発明の脂質代謝改善剤は、脂質異常症である高コレステロール血症、高LDLコレステロール血症、及び高トリグリセリド血症を効果的に予防、改善又は治療することができる。
An abnormality in lipid metabolism refers to a condition in which an abnormality is found in the balance of lipid components in a living body, and examples thereof include dyslipidemia (hyperlipidemia), obesity, and visceral fat accumulation.
The dyslipidemia includes, for example, a state in which blood lipid has a high value, a state in which blood HDL (high density lipoprotein) cholesterol has a low value, and the like. The blood lipid is usually cholesterol, LDL cholesterol, neutral fat (triglyceride), phospholipid, free fatty acid and the like. The lipid metabolism improving agent of the present invention exhibits an excellent effect in reducing blood lipids such as cholesterol, LDL cholesterol, and neutral fat (triglyceride). For this reason, the lipid metabolism improving agent of the present invention can effectively prevent, ameliorate, or treat hypercholesterolemia, hyper-LDL cholesterolemia, and hypertriglyceridemia that are dyslipidemia.
 脂質代謝異常は、その原因は制限されず、例えば高脂肪食により惹起される場合、又は通常の食生活において年齢、運動不足等により惹起される場合を含む。前記脂質異常症は、動脈硬化症の進行に重大な影響を及ぼし得る。動脈硬化症は、動脈壁の内腔が狭窄や閉塞をきたし、血流の低下を伴って、例えば一過性脳虚血発作、脳梗塞、心筋梗塞、狭心症等を含む種々の病態を引き起こす原因となり得る。
 また、脂質代謝異常は、肥満と関連している。肥満は身体に脂肪が過剰に蓄積した状態をいう。肥満には、内臓脂肪蓄積型肥満が含まれる。本発明の脂質代謝改善剤は、体重増加を抑制する作用を有し、しかも内臓脂肪を減少させる作用、内臓脂肪の蓄積を低下させる作用等を有するものである。従って本発明の脂質代謝改善剤は、肥満を予防、改善又は治療する医薬としても好適に使用し得るものである。
The cause of lipid metabolism abnormalities is not limited, and includes, for example, cases caused by a high fat diet or cases caused by age, lack of exercise, etc. in a normal diet. Said dyslipidemia can have a significant impact on the progression of arteriosclerosis. Arteriosclerosis causes narrowing or occlusion in the lumen of the arterial wall, and with a decrease in blood flow, various pathological conditions including, for example, transient ischemic attack, cerebral infarction, myocardial infarction, angina pectoris, etc. It can be a cause.
In addition, abnormal lipid metabolism is associated with obesity. Obesity is a condition in which fat accumulates excessively in the body. Obesity includes visceral fat accumulation type obesity. The lipid metabolism-improving agent of the present invention has an action of suppressing weight gain, and further has an action of reducing visceral fat, an action of reducing the accumulation of visceral fat, and the like. Therefore, the lipid metabolism improving agent of the present invention can be suitably used as a medicament for preventing, improving or treating obesity.
 α-グルコシダーゼ阻害剤を含み、ビフィズス菌、乳酸菌、糖化菌及び酪酸菌からなる群より選ばれる少なくとも1種の菌と組み合わせて投与される抗肥満剤も、本発明の1つである。 An anti-obesity agent that contains an α-glucosidase inhibitor and is administered in combination with at least one bacterium selected from the group consisting of bifidobacteria, lactic acid bacteria, saccharifying bacteria, and butyric acid bacteria is also one aspect of the present invention.
 脂質異常症及び肥満(特に内臓脂肪蓄積型肥満)は、それぞれ単独でも種々の病態を引き起こし得るが、これらの病気が重複する病態、例えばメタボリックシンドロームにおいては、動脈硬化を促進し、さらには致命的な心筋梗塞、脳梗塞等を起こしやすい。本発明の剤は、前記脂質異常症及び肥満のいずれの疾患をも予防、抑制、改善又は治療できるので、生活習慣病、メタボリックシンドローム等も予防、抑制、改善又は治療し得るものである。 Dyslipidemia and obesity (especially visceral fat accumulation-type obesity) can each cause various pathological conditions, but in conditions where these diseases overlap, such as metabolic syndrome, they promote arteriosclerosis and are fatal. It is easy to cause myocardial infarction, cerebral infarction, etc. Since the agent of the present invention can prevent, suppress, ameliorate or treat any of the above dyslipidemia and obesity diseases, lifestyle-related diseases, metabolic syndrome, etc. can also be prevented, suppressed, ameliorated or treated.
 本発明の脂質代謝改善剤は、ビフィズス菌、乳酸菌、糖化菌、酪酸菌等の菌が有する脂質代謝改善作用及び抗肥満作用を増強させることができるものである。α-グルコシダーゼ阻害剤がビフィズス菌、乳酸菌、糖化菌及び酪酸菌からなる群より選ばれる少なくとも1種の菌と組み合わせて投与されることにより、該菌が有する血中脂質低下作用、内臓脂肪減少作用等の脂質代謝改善作用を特異的に、相乗的に増強することができ、これにより、優れた脂質代謝改善効果及び抗肥満効果が得られる。 The lipid metabolism improving agent of the present invention is capable of enhancing the lipid metabolism improving action and anti-obesity action possessed by bacteria such as bifidobacteria, lactic acid bacteria, saccharifying bacteria, and butyric acid bacteria. When the α-glucosidase inhibitor is administered in combination with at least one bacterium selected from the group consisting of bifidobacteria, lactic acid bacterium, saccharifying bacterium and butyric acid bacterium, the bacterium has a blood lipid lowering action and a visceral fat reducing action. Thus, the lipid metabolism improving action such as the above can be specifically and synergistically enhanced, whereby an excellent lipid metabolism improving effect and anti-obesity effect can be obtained.
 本発明は、α-グルコシダーゼ阻害剤を含み、ビフィズス菌、乳酸菌、糖化菌及び酪酸菌からなる群より選ばれる少なくとも1種の菌と組み合わせて投与される前記菌による脂質代謝改善作用増強剤も包含する。本発明はまた、α-グルコシダーゼ阻害剤を含み、ビフィズス菌、乳酸菌、糖化菌及び酪酸菌からなる群より選ばれる少なくとも1種の菌と組み合わせて投与される前記菌による抗肥満作用増強剤も包含する。 The present invention also includes an agent for improving lipid metabolism by the bacterium, which comprises an α-glucosidase inhibitor and is administered in combination with at least one bacterium selected from the group consisting of bifidobacteria, lactic acid bacterium, saccharifying bacterium and butyric acid bacterium. To do. The present invention also includes an anti-obesity action enhancer by the aforementioned bacterium, which comprises an α-glucosidase inhibitor and is administered in combination with at least one bacterium selected from the group consisting of bifidobacteria, lactic acid bacterium, saccharifying bacterium and butyric acid bacterium. To do.
 松尾らの文献(Am J Clin Nutr. 1992. Vol.55 314S-317S)によると、肥満を特徴とするZucker fattyラットにα-グルコシダーゼ阻害剤であるボグリボースを混餌投与(0.005%:2.1mg/kg/日)して10週間飼育すると、体重増加抑制及び血中中性脂肪低下が認められたとされている。一方、後述する実施例2では、肥満を示すKK-Ayマウスにボグリボースを混餌投与(0.0003%:0.6mg/kg/日)して7週間飼育したとき、体重増加抑制及び中性脂肪低下は認められないものの、この飼料にビフィズス菌を併用することにより7週間の飼育で体重増加抑制及び中性脂肪低下が認められた。このことは、α-グルコシダーゼ阻害剤と乳酸菌などの菌とを併用することにより、α-グルコシダーゼ阻害剤を単独で投与した場合よりも、少量かつ短期間投与で有効な脂質代謝改善効果が得られることを示している。
 本発明においては、α-グルコシダーゼ阻害剤と上記菌とを組み合わせて用いることにより、α-グルコシダーゼ阻害剤の投与量を通常用いられる量より少なくしても、優れた脂質代謝改善作用や抗肥満作用が得られる。このため、α-グルコシダーゼ阻害剤の投与量を少なくして副作用を軽減しつつ、脂質代謝改善作用及び抗肥満作用を効果的に増強させることができる。
According to Matsuo et al. (Am J Clin Nutr. 1992. Vol.55 314S-317S), Zucker fatty rats characterized by obesity were administered with α-glucosidase inhibitor voglibose (0.005%: 2.1 mg / kg). / Day), and after 10 weeks of breeding, suppression of weight gain and reduction of blood neutral fat were observed. On the other hand, in Example 2, which will be described later, when GG-Ay mice showing obesity are fed with boglibose (0.0003%: 0.6 mg / kg / day) and reared for 7 weeks, suppression of weight gain and reduction of triglycerides are observed. Although it was not possible, by using bifidobacteria in combination with this feed, weight gain suppression and triglyceride reduction were observed after 7 weeks of breeding. This is because the combined use of an α-glucosidase inhibitor and a bacterium such as a lactic acid bacterium provides an effective lipid metabolism improving effect in a small amount and in a short period of time compared with the case where the α-glucosidase inhibitor is administered alone. It is shown that.
In the present invention, by using a combination of an α-glucosidase inhibitor and the above-mentioned bacterium, even if the dose of the α-glucosidase inhibitor is smaller than the usual amount, an excellent lipid metabolism improving action and anti-obesity action Is obtained. Therefore, the lipid metabolism improving action and the anti-obesity action can be effectively enhanced while reducing the side effects by reducing the dose of the α-glucosidase inhibitor.
 本発明の脂質代謝改善剤、脂質代謝改善作用増強剤、抗肥満剤及び抗肥満作用増強剤においては、α-グルコシダーゼ阻害剤がビフィズス菌、乳酸菌、糖化菌及び酪酸菌からなる群より選ばれる少なくとも1種の菌と組み合わせて投与されるため、該剤は、さらに、ビフィズス菌、乳酸菌、糖化菌及び酪酸菌からなる群より選ばれる少なくとも1種の菌を含むことが好ましい。 In the lipid metabolism improving agent, lipid metabolism improving agent, anti-obesity agent and anti-obesity agent of the present invention, the α-glucosidase inhibitor is at least selected from the group consisting of bifidobacteria, lactic acid bacteria, saccharifying bacteria and butyric acid bacteria. Since it is administered in combination with one kind of bacteria, the agent preferably further contains at least one kind of bacteria selected from the group consisting of bifidobacteria, lactic acid bacteria, saccharifying bacteria, and butyric acid bacteria.
 ビフィズス菌、乳酸菌、糖化菌及び酪酸菌からなる群より選ばれる少なくとも1種の菌は、α-グルコシダーゼ阻害剤による脂質代謝改善作用や抗肥満作用の発現を促進する作用、α-グルコシダーゼ阻害剤が有する脂質代謝改善作用や抗肥満作用を効果的に増強する作用を有する。
 本発明は、ビフィズス菌、乳酸菌、糖化菌及び酪酸菌からなる群より選ばれる少なくとも1種の菌を含み、α-グルコシダーゼ阻害剤と組み合わせて投与されるα-グルコシダーゼ阻害剤による脂質代謝改善作用増強剤、及び抗肥満作用増強剤も包含する。このような剤も、優れた脂質代謝改善作用及び抗肥満作用を発揮するものである。これらの剤は、さらに、α-グルコシダーゼ阻害剤を含むことが好ましい。
At least one bacterium selected from the group consisting of bifidobacteria, lactic acid bacteria, saccharifying bacteria, and butyric acid bacteria has an action that promotes expression of lipid metabolism and anti-obesity action by an α-glucosidase inhibitor, an α-glucosidase inhibitor It has an action of effectively enhancing the lipid metabolism improving action and anti-obesity action.
The present invention includes at least one bacterium selected from the group consisting of bifidobacteria, lactic acid bacterium, saccharifying bacterium, and butyric acid bacterium, and enhances lipid metabolism improving action by an α-glucosidase inhibitor administered in combination with an α-glucosidase inhibitor An agent and an anti-obesity action enhancer are also included. Such an agent also exhibits an excellent lipid metabolism improving action and anti-obesity action. These agents preferably further contain an α-glucosidase inhibitor.
 本発明において使用されるα-グルコシダーゼ阻害剤としては、例えば、特開昭57-200335号公報、特開昭58-59946号公報、特開昭58-162597号公報、特開昭58-216145号公報、特開昭59-73549号公報、特開昭59-95297号公報、特公平7-2647号公報、特開平11-236337号公報等の明細書に記載の一般式(I) Examples of the α-glucosidase inhibitor used in the present invention include, for example, Japanese Patent Application Laid-Open Nos. 57-200335, 58-59946, 58-162597, and 58-216145. The general formula (I) described in the specifications of JP-A-59-73549, JP-A-59-95297, JP-B-7-2647, JP-A-11-236337, etc.
Figure JPOXMLDOC01-appb-C000009
(式中、Aは、水酸基、フェノキシ、チエニル、フリル、ピリジル、シクロヘキシル、置換されていてもよいフェニル基を有しうる炭素数1~10の鎖状炭化水素基、水酸基、ヒドロキシメチル基、メチル基、アミノ基を有しうる炭素数5又は6員の環状炭化水素基又は糖残基を示す)で表わされるバリオールアミン誘導体が好ましい。
Figure JPOXMLDOC01-appb-C000009
(In the formula, A is a hydroxyl group, phenoxy, thienyl, furyl, pyridyl, cyclohexyl, a chain hydrocarbon group having 1 to 10 carbon atoms which may have an optionally substituted phenyl group, a hydroxyl group, a hydroxymethyl group, methyl Group, a cyclic hydrocarbon group having 5 or 6 carbon atoms which can have an amino group or a sugar residue) is preferable.
 上記一般式(I)におけるAには、例えば、炭素数1~10の直鎖状又は分枝状の飽和又は不飽和脂肪族炭化水素基が含まれ、置換されていてもよいフェニル基には、例えば低級アルキル、低級アルコキシ、ハロゲン、フェニル等により置換されていてもよいフェニル基が含まれる。 A in the general formula (I) includes, for example, a linear or branched saturated or unsaturated aliphatic hydrocarbon group having 1 to 10 carbon atoms. For example, a phenyl group which may be substituted with lower alkyl, lower alkoxy, halogen, phenyl or the like is included.
 糖残基とは糖類の分子から水素原子1個を除いた残りの基を意味し、例えば単糖類、少糖類から導かれた糖残基が挙げられる。 Sugar residue means a remaining group obtained by removing one hydrogen atom from a saccharide molecule, and examples thereof include sugar residues derived from monosaccharides and oligosaccharides.
 上記一般式(I)で表わされるN-置換バリオールアミン誘導体の具体例としては(1)N-フェネチルバリオールアミン、(2)N-(3-フェニルアリル)バイオールアミン、(3)N-フルフリルバイオールアミン、(4)N-チエニルバリオールアミン、(5)N-(3-ピリジルメチル)バリオールアミン、(6)N-(4-ブロモベンジル)バイオールアミン、(7)N-[(R)-β-ヒドロキシフェネチル]バリオールアミン、(8)N-[(S)-β-ヒドロキシフェネチル]バリオールアミン、(9)N-(β-ヒドロキシ-2-メトキシフェネチル)バイオールアミン、(10)N-(3,5-ジ-tert-ブチル-4-ヒドロキシベンジル)バイオールアミン、(11)N-(シクロヘキシルメチル)バリオールアミン、(12)N-ゲラニルバリオールアミン、(13)N-(1,3-ジヒドロキシ-2-プロピル)バリオールアミン、(14)N-(1,3-ジヒドロキシ-1-フェニル-2-プロピル)バリオールアミン、(15)N-[(R)-α-(ヒドロキシメチル)ベンジル]バイオールアミン、(16)N-シクロヘキシルバリオールアミン、(17)N-(2-ヒドロキシシクロヘキシル)バリオールアミン、(18)N-[(1R,2R)-2-ヒドロキシシクロヘキシル]バリオールアミン、(19)N-(2-ヒドロキシシクロペンチル)バリオールアミン、(20)メチル 4-[(1S,2S)-(2,4,5(OH)/3,5)-2,3,4,5-テトラヒドロキシ-5-(ヒドロキシメチル)シクロヘキシル]アミノ-4,6-ジデオキシ-α-D-グルコビラノシド、(21)メチル 4-[(1S,2S)-(2,4,5(OH)/3,5)-2,3,4,5-テトラヒドロキシ-5-(ヒドロキシメチル)シクロヘキシル]アミノ-4-デオキシ-α-D-グルコピラノシド、(22)[(1S,2S)-(2,4,5(OH)/3,5)-2,3,4,5-テトラヒドロキシ-5-(ヒドロキシメチル)シクロヘキシル][(1R,2S)-(2,6/3,4)-4-アミノ-2,3-ジヒドロキシ-6-(ヒドロキシメチル)シクロヘキシル]アミン、(23)N-[(1R,2S)-(2,4/3,5)-2,3,4-トリヒドロキシ-5-(ヒドロキシメチル)シクロヘキシル]バリオールアミン、(24)N-[(1R,2S)-(2,6/3,4)-4-アミノ-2,3-ジヒドロキシ-6-メチルシクロヘキシル]バリオールアミン、(25)N-[(1R,2S)-(2,6/3,4)-2,3,4-トリヒドロキシ-6-メチルシクロヘキシル]バリオールアミン、(26)N-[(1R,2S)-(2,4,6/3)-2,3,4-トリヒドロキシ-6-メチルシクロヘキシル]バリオールアミン、(27)4-O-α-[4-[((1S)-(1,2,4,5(OH)/3,5)-2,3,4,5-テトラヒドロキシ-5-(ヒドロキシメチル)シクロヘキシル)アミノ]-4,6-ジデオキシ-D-グルコピラノシル]-D-グルコピラノース、(28)1,6-アンヒドロ-4-O-α-[4-[((1S)-(1,2,4,5(OH)/3,5)-2,3,4,5-テトラヒドロキシ-5-C-(ヒドロキシメチル)シクロヘキシル)アミノ]-4,6-ジデオキシ-D-グルコピラノシル]-β-D-グルコピラノースなどが挙げられる。 Specific examples of the N-substituted variolamine derivative represented by the above general formula (I) include (1) N-phenethylvariolamine, (2) N- (3-phenylallyl) biolamine, (3) N -Furfuryl violamine, (4) N-thienyl valol amine, (5) N- (3-pyridylmethyl) valol amine, (6) N- (4-bromobenzyl) viol amine, (7) N-[(R) -β-hydroxyphenethyl] variolamine, (8) N-[(S) -β-hydroxyphenethyl] variolamine, (9) N- (β-hydroxy-2-methoxyphenethyl) Biolamine, (10) N- (3,5-di-tert-butyl-4-hydroxybenzyl) biolamine, (11) N- (cyclohexylmethyl) variol (13) N- (1,3-dihydroxy-2-propyl) variolamine, (14) N- (1,3-dihydroxy-1-phenyl-2-amine, Propyl) bariolamine, (15) N-[(R) -α- (hydroxymethyl) benzyl] biolamine, (16) N-cyclohexylvariolamine, (17) N- (2-hydroxycyclohexyl) valyl Allamine, (18) N-[(1R, 2R) -2-hydroxycyclohexyl] variolamine, (19) N- (2-hydroxycyclopentyl) variolamine, (20) methyl 4-[(1S, 2S )-(2,4,5 (OH) / 3,5) -2,3,4,5-tetrahydroxy-5- (hydroxymethyl) cyclohexyl] amino-4, 6-dideoxy-α-D-glucoviranoside, (21) methyl 4-[(1S, 2S)-(2,4,5 (OH) / 3,5) -2,3,4,5-tetrahydroxy-5 -(Hydroxymethyl) cyclohexyl] amino-4-deoxy-α-D-glucopyranoside, (22) [(1S, 2S)-(2,4,5 (OH) / 3,5) -2,3,4, 5-tetrahydroxy-5- (hydroxymethyl) cyclohexyl] [(1R, 2S)-(2,6 / 3,4) -4-amino-2,3-dihydroxy-6- (hydroxymethyl) cyclohexyl] amine, (23) N-[(1R, 2S)-(2,4 / 3,5) -2,3,4-trihydroxy-5- (hydroxymethyl) cyclohexyl] variolamine, (24) N-[( 1R, 2S)-(2,6 / 3,4 ) -4-amino-2,3-dihydroxy-6-methylcyclohexyl] variolamine, (25) N-[(1R, 2S)-(2,6 / 3,4) -2,3,4-tri Hydroxy-6-methylcyclohexyl] bariolamine, (26) N-[(1R, 2S)-(2,4,6 / 3) -2,3,4-trihydroxy-6-methylcyclohexyl] bariolamine , (27) 4-O-α- [4-[((1S)-(1,2,4,5 (OH) / 3,5) -2,3,4,5-tetrahydroxy-5- ( Hydroxymethyl) cyclohexyl) amino] -4,6-dideoxy-D-glucopyranosyl] -D-glucopyranose, (28) 1,6-anhydro-4-O-α- [4-[((1S)-(1 , 2,4,5 (OH) / 3,5) -2,3,4,5-teto Lahydroxy-5-C- (hydroxymethyl) cyclohexyl) amino] -4,6-dideoxy-D-glucopyranosyl] -β-D-glucopyranose.
 中でも、N-(1,3-ジヒドロキシ-2-プロピル)バリオールアミン、すなわち[2-ヒドロキシ-1-(ヒドロキシメチル)エチル]バリオールアミン又は1L(1S)-(1(OH),2,4,5/1,3)-5-[[2-ヒドロキシ-1-(ヒドロキシメチル)エチル]アミノ]-1-C-(ヒドロキシメチル)-1,2,3,4-シクロヘキサンテトロール(一般名:ボグリボース)が特に好ましい。 Among them, N- (1,3-dihydroxy-2-propyl) variolamine, ie [2-hydroxy-1- (hydroxymethyl) ethyl] variolamine or 1L (1S)-(1 (OH), 2, 4,5 / 1,3) -5-[[2-hydroxy-1- (hydroxymethyl) ethyl] amino] -1-C- (hydroxymethyl) -1,2,3,4-cyclohexanetetrol (general Name: Voglibose) is particularly preferred.
 本発明におけるα-グルコシダーゼ阻害剤として、特開昭57-64648号公報等に記載の一般式(II) As the α-glucosidase inhibitor in the present invention, the general formula (II) described in JP-A-57-64648 and the like
Figure JPOXMLDOC01-appb-C000010
Figure JPOXMLDOC01-appb-C000010
(式中、Aは、前記と同義である)で表わされるバリエナミンN-置換誘導体、特開昭57-114554号公報等に記載の一般式(III) (Wherein A has the same meaning as described above), a general formula (III) described in JP-A-57-114554, etc.
Figure JPOXMLDOC01-appb-C000011
Figure JPOXMLDOC01-appb-C000011
(式中、Aは、前記と同義である)で表わされるバリダミンのN-置換誘導体等も好適に使用される。上記一般式(II)で表わされるバリエナミンN-置換誘導体としては、アカルボース(一般名)[BAYg5421、ナツールヴィッセンシャフテン(Naturwissenschaften)、第64巻、535~537頁(1977年)、特公昭54-39474号公報](化学名:O-4,6-ジデオキシ-4-[[(1S,4R,5S,6S)-4,5,6-トリヒドロキシ-3-(ヒドロキシメチル)-2-シクロヘキセン-1-イル]アミノ]-α-D-グルコピラノシル-(1→4)-O-α-D-グルコピラノシル-(1→4)-D-グルコピラノース)が好ましい。 An N-substituted derivative of validadamine represented by the formula (wherein A is as defined above) is also preferably used. As the valienamine N-substituted derivative represented by the above general formula (II), acarbose (generic name) [BAYg5421, Naturwissenschaften, Vol. 64, pp. 535-537 (1977), JP-B-54 -39474] (Chemical name: O-4,6-dideoxy-4-[[(1S, 4R, 5S, 6S) -4,5,6-trihydroxy-3- (hydroxymethyl) -2-cyclohexene] -1-yl] amino] -α-D-glucopyranosyl- (1 → 4) -O-α-D-glucopyranosyl- (1 → 4) -D-glucopyranose) is preferred.
 本発明におけるα-グルコシダーゼ阻害剤として、米国特許第4,639,436号の明細書等に記載されている一般式(IV) As an α-glucosidase inhibitor in the present invention, the general formula (IV) described in the specification of US Pat. No. 4,639,436, etc.
Figure JPOXMLDOC01-appb-C000012
Figure JPOXMLDOC01-appb-C000012
(式中、R及びRは、同一又は異なって、それぞれ水素原子、置換されていてもよい直鎖状、分枝状若しくは環式の飽和又は不飽和脂肪族炭化水素基、置換されていてもよい炭化水素環、芳香環又はヘテロ環であり、Rは、-H、-OH、-OR′、-SH、-SR′、-NH、-NHR′、-N(R′)(R′′)、NHCH-、NHR′-CH-、NR′R′′-CH-、-COOH、-COOR′、HO-CH-、R′CO-NHCH-、R′CO-NR′′CH-、R′SONHCH-、R′SO-NR′′CH-、R′-NH-CO-NH-CH-、R′-NH-CS-NH-CH-R′-O-CO-NH-CH-、-SOH、-CN、-CONH、-CONHR′又は-CONR′R′′であり、R′及びR′′は、同一又は異なって、それぞれRと同義である。Rが-CHOHであり、かつRが水素原子又は-OHである場合;Rが水素原子であり、かつRが水素原子、-OH、-SOH、-CN又は-CH-NHである場合;又はRが-CH-NHであり、かつRが-OHである場合には、Rは、水素原子(-H)でない。)で表わされる3,4,5-トリヒドロキシピペリジンも好適である。 (Wherein R 1 and R 3 are the same or different and each represents a hydrogen atom, an optionally substituted linear, branched or cyclic saturated or unsaturated aliphatic hydrocarbon group, substituted Which may be a hydrocarbon ring, an aromatic ring or a heterocyclic ring, and R 2 is —H, —OH, —OR ′, —SH, —SR ′, —NH 2 , —NHR ′, —N (R ′) (R ″), NH 2 CH 2 —, NHR′—CH 2 —, NR′R ″ —CH 2 —, —COOH, —COOR ′, HO—CH 2 —, R′CO—NHCH 2 —, R′CO—NR ″ CH 2 —, R′SO 2 NHCH 2 —, R′SO 2 —NR ″ CH 2 —, R′—NH—CO—NH—CH 2 —, R′—NH—CS —NH—CH 2 —R′—O—CO—NH—CH 2 —, —SO 3 H, —CN, —CONH 2 , —CON HR ′ or —CONR′R ″, R ′ and R ″ are the same or different and have the same meaning as R 1. R 3 is —CH 2 OH and R 2 is a hydrogen atom or When —OH; R 3 is a hydrogen atom and R 2 is a hydrogen atom, —OH, —SO 3 H, —CN or —CH 2 —NH 2 ; or R 3 is —CH 2 —. In the case of NH 2 and R 2 is —OH, R 1 is not a hydrogen atom (—H).) 3,4,5-trihydroxypiperidine is also suitable.
 一般式(IV)のR及びRにおいて、置換されていてもよい直鎖状、分岐若しくは環式の飽和又は不飽和脂肪族炭化水素基としては、例えば、アルキル基、アルケニル基、アルキニル基等が挙げられる。R、R′及びR′′は、同一又は異なって、好ましくは、炭素数1~30(より好ましくは炭素数1~18、さらに好ましくは炭素数1~10)の置換されていてもよいアルキル基、炭素数2~18の置換されていてもよいアルケニル基、炭素原子、置換されていてもよい炭素数3~10の単環式、二環式又は三環式の脂肪族炭化水素、芳香環、ヘテロ環等である。中でも、置換基を有してもよい炭素数1~10のアルキル基が好ましい。置換基としては、水酸基等が好ましい。Rは、好ましくは、水素原子、-CH、-CHOH、-CH-NH、NHR′-CH-、NR′R′′CH-、R′CONH-CH-、R′CO-NR′′CH-、X-CH-(Xは、ハロゲン原子を表す)、R′O-CH-、R′COOCH-、R′SOO-CH-、R′SONHCH-、R′SO-NR′′CH-、R′NH-CO-NH-CH-、R′NHCS-NH-CH-、R′O-CO-NH-CH-、-CN、-COOH、-COOR′、-CONH、-CONHR′又は-CONR′R′′(R′及びR′′は、同一又は異なって、それぞれ上記と同様に、Rと同義である)である。 In R 1 and R 3 of the general formula (IV), the linear, branched or cyclic saturated or unsaturated aliphatic hydrocarbon group which may be substituted includes, for example, an alkyl group, an alkenyl group, and an alkynyl group. Etc. R 1 , R ′ and R ″ may be the same or different, and may be substituted, preferably having 1 to 30 carbon atoms (more preferably 1 to 18 carbon atoms, more preferably 1 to 10 carbon atoms). An alkyl group, an optionally substituted alkenyl group having 2 to 18 carbon atoms, a carbon atom, an optionally substituted monocyclic, bicyclic or tricyclic aliphatic hydrocarbon having 3 to 10 carbon atoms, An aromatic ring, a heterocyclic ring, and the like. Among these, an alkyl group having 1 to 10 carbon atoms which may have a substituent is preferable. As the substituent, a hydroxyl group and the like are preferable. R 3 is preferably a hydrogen atom, -CH 3, -CH 2 OH, -CH 2 -NH 2, NHR'-CH 2 -, NR'R''CH 2 -, R'CONH-CH 2 -, R′CO—NR ″ CH 2 —, X—CH 2 — (X represents a halogen atom), R′O—CH 2 —, R′COOCH 2 —, R′SO 2 O—CH 2 —, R'SO 2 NHCH 2 -, R'SO 2 -NR''CH 2 -, R'NH-CO-NHCH 2 -, R'NHCS-NHCH 2 -, R'O-CO-NH- CH 2 —, —CN, —COOH, —COOR ′, —CONH 2 , —CONHR ′ or —CONR′R ″ (R ′ and R ″ are the same or different, and R 1 and R Is synonymous with.
 一般式(IV)で表わされる3,4,5-トリヒドロキシピペリジンとしては、Rが-CH-CH-OHであり、Rが水素原子であり、Rが-CH-OHである化合物(一般名:ミグリトール、化学名:(-)-(2R,3R,4R,5S)-1-(2-ヒドロキシメチル)ピペリジン-3,4,5-トリオール)が特に好ましい。 As the 3,4,5-trihydroxypiperidine represented by the general formula (IV), R 1 is —CH 2 —CH 2 —OH, R 2 is a hydrogen atom, and R 3 is —CH 2 —OH. The compound (generic name: miglitol, chemical name: (-)-(2R, 3R, 4R, 5S) -1- (2-hydroxymethyl) piperidine-3,4,5-triol) is particularly preferred.
 さらに、トレスタチン[(trestatin)、ザ・ジャーナル・オブ・アンテイバイオテイクス(J.Antibiotics)第36巻、1157~1175頁(1983年)及び第37巻、182~186頁(1984年)、特開昭54-163511号公報]、アデイポシン[(adiposins)、ザ・ジャーナル・オブ・アンテイバイオテイクス(J.Antibiotics)第35巻、1234~1236頁(1982年);澱粉化学(J.Jap,Soc.Starch Sci.)第26巻、134~144頁(1979年)、第27巻、107~113頁(1980年);特開昭54-106402号公報;特開昭54-106403号公報;特開昭55-64509号公報;特開昭56-123986号公報;特開昭56-125398号公報]、アミロスタチン[(amylostatins)、アグリカルチュラル・アンド・バイオロジカル・ケミストリー(Agric.Biol.Chem.)第46巻、1941~1945頁(1982年);特開昭50-123891号公報;特開昭55-71494号公報;特開昭55-157595号公報]、オリゴスタチン[(oligostatins)、SF-1130X、特開昭53-26398号公報;特開昭56-43294号公報、ザ・ジャーナル・オブ・アンテイバイオテイクス(J.Antibiotics)、第34巻、1424~1433頁(1981年)]、アミノ糖化合物(特開昭54-92909号公報)などが使用できる。なお、上記の化合物を含む微生物起源のα-グルコシダーゼ阻害物質については、エー・トルシヤイト(E.Truscheit)らの総説[アンゲバンテ・ヘミー(Angewandte Chemie)第93巻、738~755頁(1981年)]が報告されている。これらの化合物も、本発明におけるα-グルコシダーゼ阻害剤として使用することができる。 Furthermore, trestatin [(trestatin), The Journal of Antibiotics, Volume 36, pages 1157 to 1175 (1983) and volume 37, pages 182 to 186 (1984), JP No. 54-163511], Adeposins [(adiposins), The Journal of Antibiotics, Vol. 35, pp. 1234-1236 (1982); Starch Chemistry (J. Jap, Soc. Starch Sci.) 26, 134-144 (1979), 27, 107-113 (1980); JP 54-106402; JP 54-106403; JP-A-55-64509; JP-A-56-123986; JP-A-56-125398], amylostatins ((amylostatins), agricultural and biological chemistry (Agric. Biol. Chem.) 46, 1941-1945 (1982); No. 0-123891; JP-A-55-71494; JP-A-55-157595], Oligostatin ((oligostatins), SF-1130X, JP-A-53-26398; JP-A-56-56) No. 43294, The Journal of Antibiotics, Vol. 34, pages 142-1433 (1981)], amino sugar compounds (Japanese Patent Laid-Open No. 54-92909), and the like can be used. . Regarding the α-glucosidase inhibitors derived from microorganisms including the above compounds, a review by E. Truscheit et al. [Angewandte Chemie, Vol. 93, pp. 738-755 (1981)] Has been reported. These compounds can also be used as α-glucosidase inhibitors in the present invention.
 さらにまた、アカルボース(acarbose)及びオリゴスタチンC(oligostatins C)のメタノリシスにより得られるメチル4-[(1S,6S)-(4,6/5)-4,5,6-トリヒドロキシ-3-ヒドロキシメチル-2-シクロヘキセン-1-イル]アミノ-4,6-ジデオキシ-α-D-グルコピラノシド[第182回アメリカ化学会講演要旨集(182nd ACS National meeting Abstracts paper)MEDI 69、1981年8月、ニューヨーク;ザ・ジャーナル・オブ・アンテイバイオテイクス(J.Antibiotics)、第34巻、1429~1433頁(1981年);及び特開昭57-24397号公報]、1-デオキシノジリマイシン[(1-deoxynojirimycin)、ナツ-ルヴィッセンシャフテン(Naturwissenschaften)、第66巻、584~585頁(1979年)]及びそのN-置換誘導体、例えば、BAYo1248[ザ・ジャーナル・オブ・クリニカル・インベスティゲーション(J.Clin.Invest.)、第14巻(2-II)、47(1984);ダイアベトロジア第27巻(2)、288A、346A、323A(1984)]なども、本発明におけるα-グルコシダーゼ阻害剤として使用することができる。 Furthermore, methyl 4-[(1S, 6S)-(4,6 / 5) -4,5,6-trihydroxy-3-hydroxy obtained by methanolysis of acarbose and oligostatins C Methyl-2-cyclohexen-1-yl] amino-4,6-dideoxy-α-D-glucopyranoside [182nd American Chemical Society Abstracts (182nd ACS National meeting Abstracts paper) MEDI 69, August 1981, New York The Journal of Antibiotics (J. Antibiotics), Volume 34, pages 1429 to 1433 (1981); and JP-A-57-24397], 1-deoxynojirimycin [(1-deoxynojirimycin) ), Naturwissenschaften, 66, 584-585 (1979)] and its N-substituted derivatives, such as BAYo1248 [The Journal of Clinical I Investigation (J. Clin. Invest.), Volume 14 (2-II), 47 (1984); Diabetrodia Volume 27 (2), 288A, 346A, 323A (1984)], etc. -It can be used as a glucosidase inhibitor.
 本発明におけるα-グルコシダーゼ阻害剤としては、ボグリボース(一般名)、アカルボース(一般名)又はミグリトール(一般名)がより好ましく、ボグリボース又はアカルボースが特に好ましい。 As the α-glucosidase inhibitor in the present invention, voglibose (generic name), acarbose (generic name) or miglitol (generic name) is more preferable, and voglibose or acarbose is particularly preferable.
 さらに、本発明におけるα-グルコシダーゼ阻害剤としては、上述した化合物以外に、通常飲食品に使用されるα-グルコシダーゼ阻害作用を有する物質も好適である。このような物質として、例えば、マルスエキス、サラシア、桑葉エキス及び茶種エキスの中から選ばれる少なくとも1種を好適に用いることができる。 Furthermore, as the α-glucosidase inhibitor in the present invention, in addition to the compounds described above, substances having an α-glucosidase inhibitory action usually used in foods and drinks are also suitable. As such a substance, for example, at least one selected from Mars extract, Salacia, mulberry leaf extract and tea seed extract can be suitably used.
 マルスエキスは、植物の抽出成分で、α-グルコシダーゼ活性を阻害して、糖質の体外排出を促す作用をする。また、サラシアは、スリランカで自生するニシキギ科のツル性の植物で、成分サラシノールは、インドでは約5000年前から根を茶として飲むことでダイエットに利用していたと言われており、糖尿病に有用なものとされている。茶種(TS)エキスは、お茶の成分の一つで、消化管で糖を吸収するのに必要なグリコシターゼ活性を阻害することにより、糖分(グルコース)の吸収を強力に阻害する。この作用により、糖質からの摂取エネルギーを減少させ、摂取カロリーと消費カロリーのバランスを整える。茶種エキスとしては、茶種(TS)エキス(商品名、タングルウッド社製)等が好ましい。 Malus extract is a plant extract component that inhibits α-glucosidase activity and promotes the in vitro elimination of carbohydrates. Salacia is a vine-like plant that grows naturally in Sri Lanka, and the ingredient Sarasinol is said to have been used for dieting in India by drinking roots as tea for about 5,000 years ago, which is useful for diabetes. It is supposed to be. Tea seed (TS) extract is one of the components of tea and strongly inhibits the absorption of sugar (glucose) by inhibiting the glycosidase activity necessary to absorb sugar in the digestive tract. This action reduces the intake energy from the carbohydrates and balances the intake calorie and the calorie consumption. As the tea seed extract, tea seed (TS) extract (trade name, manufactured by Tanglewood) and the like are preferable.
 本発明において使用される菌は、ビフィズス菌、乳酸菌、糖化菌及び酪酸菌からなる群より選ばれる少なくとも1種の菌であって、具体的には例えば、Bifidobacterium bifidum、B. longum、 B. breve、B. adolescentis、B. infantis、B.pseudolongum、B.thermophilum等のビフィズス菌;例えば、Lactobacillus acidophilus、L. casei、L. gasseri、L. plantarum、L. delbrueckii subsp bulgaricus、L. delbrueckii subsp lactis、L. fermentum、L. helveticus、L. johnsonii、L. paracasei subsp. paracasei、L. reuteri、L. rhamnosus、L. salivarius、L. brevis等の乳酸桿菌;例えば、Leuconostoc mesenteroides、Streptococcus(Enterococcus) faecalis、Streptococcus(Enterococcus) faecium、 Streptococcus(Enterococcus) hirae、Streptococcus thermophilus、 Lactococcus lactis、L. cremoris、Tetragenococcus halophilus、Pediococcus acidilactici、P. pentosaceus、Oenococcus oeni等の乳酸球菌;例えば、Bacillus subtilis、Bacillus mesentericus、Bacillus polyformenticus等の糖化菌;例えば、Bacillus coagulans等の有胞子性乳酸菌; Bacillus toyoi、B.licheniformis、Clostridium butyricum等の酪酸菌;その他の有用菌が挙げられる。
 これらの菌体は、例えばATCC又はIFOなどの機関や財団法人 日本ビフィズス菌センターなどから容易に入手することができる。また、市販されているものを適宜使用することもできる。
The bacterium used in the present invention is at least one bacterium selected from the group consisting of bifidobacteria, lactic acid bacterium, saccharifying bacterium, and butyric acid bacterium. Specifically, for example, Bifidobacterium bifidum, B. longum, B. breve B. adolescentis, B. infantis, B. pseudolongum, B. thermophilum, etc .; for example, Lactobacillus acidophilus, L. casei, L. gasseri, L. plantarum, L. delbrueckii subsp bulgaricus, L. delbrueckii subsp lactis, L. fermentum, L. helveticus, L. johnsonii, L. paracasei subsp. Paracasei, L. reuteri, L. rhamnosus, L. salivarius, L. brevis, and other lactobacilli; for example, Leuconostoc mesenteroides, Streptococcus (Enterococcus) faecalis, Streptococcus (Enterococcus) faecium, Streptococcus (Enterococcus) hirae, Streptococcus thermophilus, Lactococcus lactis, L. cremoris, Tetragenococcus halophilus, Pediococcus acidilactici, P. pentosaceus, Oenococcus oeni, etc. saccharifying bacteria such as acillus mesentericus and Bacillus polyformenticus; for example, sporic lactic acid bacteria such as Bacillus coagulans; Bacillus toyoi, B. et al. Examples include butyric acid bacteria such as licheniformis and Clostridium butyricum; and other useful bacteria.
These cells can be easily obtained from, for example, an organization such as ATCC or IFO or the Japan Bifidobacteria Center. Moreover, what is marketed can also be used suitably.
 本発明で使用される菌は、ビフィズス菌、乳酸菌、糖化菌及び酪酸菌からなる群より選ばれる少なくとも1種の菌であるが、ビフィズス菌、乳酸菌及び糖化菌からなる群より選ばれる少なくとも1種の菌が好ましく、乳酸菌及び/又はビフィズス菌がより好ましい。中でも、ビフィズス菌がより好ましく、Bifidobacterium bifidum、Bifidobacterium longum、Bifidobacterium infantis、Bifidobacterium breveがさらに好ましく、Bifidobacterium bifidum、Bifidobacterium longumが特に好ましい。複数の菌を組み合わせて使用する場合には、ビフィズス菌と乳酸菌と糖化菌、ビフィズス菌と乳酸菌、ビフィズス菌と糖化菌、又は乳酸菌と糖化菌の組み合わせが好ましく、(i)Bifidobacterium bifidum、(ii)Lactobacillus acidophilus、(iii)Lactobacillus gasseri、(iv)Streptococcus(Enterococcus) faecalis、(v)Streptococcus(Enterococcus) faecium、(vi)Bacillus subtilis、(vii)Bacillus mesentericusの(i)~(vii)のうちの2種以上の組み合わせが好ましく、中でも、(i)Bifidobacterium bifidum G9-1、(ii)Lactobacillus acidophilus KS-13、(iii)Lactobacillus gasseri、(iv)Streptococcus(Enterococcus) faecalis 129 BIO 3B、(v)Streptococcus(Enterococcus) faecium、(vi)Bacillus subtilis 129 BIO H(α)、(vii)Bacillus mesentericusの(i)~(vii)のうちの2種以上の組み合わせがより好ましい。本発明における菌として、Bifidobacterium bifidum G9-1、Lactobacillus acidophilus KS-13、Streptococcus(Enterococcus) faecalis 129 BIO 3B、及びBacillus subtilis 129 BIO H(α)からなる群より選択される1又は2以上がさらに好ましく、Bifidobacterium bifidum G9-1、Streptococcus(Enterococcus) faecalis 129 BIO 3B、及びBacillus subtilis 129 BIO H(α)からなる群より選択される1又は2以上が特に好ましい。ビフィズス菌、乳酸菌、糖化菌及び酪酸菌のうちの2種以上を組み合わせて用いる場合の配合比率は特に限定されない。 The bacterium used in the present invention is at least one bacterium selected from the group consisting of bifidobacteria, lactic acid bacterium, saccharifying bacterium and butyric acid bacterium, but at least one selected from the group consisting of bifidobacteria, lactic acid bacterium and saccharifying bacterium. Are preferred, and lactic acid bacteria and / or bifidobacteria are more preferred. Among them, bifidobacteria are more preferable, Bifidobacterium bifidum, Bifidobacterium umlongum, Bifidobacterium infantis, and Bifidobacterium breve are more preferable, and Bifidobacterium bifidum and Bifidobacterium longum are particularly preferable. When a plurality of bacteria are used in combination, bifidobacteria and lactic acid bacteria and saccharifying bacteria, bifidobacteria and lactic acid bacteria, bifidobacteria and saccharifying bacteria, or a combination of lactic acid bacteria and saccharifying bacteria are preferred, (i) Bifidobacterium bifidum, (ii) (Iii) Lactobacillus Enter acidophilus, (iii) Lactobacillus Strgasseri, (iv) Streptococcus (Enterococcus) faecalis, (v) Streptococcus (Enterococcus) faecium, (vi) Bacillus subtilis, (vi) Bacillus mesentericus (i) to (i) to (i) Combinations of more than one species are preferred, among which (i) Bifidobacterium bifidum G9-1, (ii) Lactobacillus acidophilus KS-13, (iii) Lactobacillus gasseri, (iv) Streptococcus (Enterococcus) faecalis 129 BIO 3B, (v) Streptococcus ( Enterococcus) faecium, (vi) Bacillus subtilis 129 BIO H (α), (vii) two of Bacillus mesentericus (i) to (vii) Combination of the above is more preferable. As the bacterium in the present invention, one or more selected from the group consisting of Bifidobacterium bifidum G9-1, Lactobacillus acidophilus KS-13, Streptococcus (Enterococcus) faecalis 129 BIO 3B, and Bacillus subtilis 129 BIO H (α) is more preferable. Particularly preferred is one or more selected from the group consisting of Bifidobacterium id bifidum G9-1, Streptococcus (Enterococcus) faecalis 129 BIO 3B, and Bacillus subtilis 129 BIO H (α). The blending ratio in the case of using two or more of Bifidobacteria, lactic acid bacteria, saccharifying bacteria, and butyric acid bacteria in combination is not particularly limited.
 上記菌体は、公知の条件又はそれに準じる条件で培養することにより得ることができる。例えば、ビフィズス菌又は乳酸菌の場合は、通常、グルコ-ス、酵母エキス、及びペプトン等を含む液体培地で前記ビフィズス菌や乳酸菌の1種又は2種以上を通常約25~45℃程度で約4~72時間程度、好気又は嫌気培養し、培養液から菌体を集菌し、洗浄し、湿菌体を得る。また、糖化菌の場合は、通常、肉エキス、カゼイン製ペプトン、塩化ナトリウム等を含む寒天培地で1種又は2種以上を通常約25~45℃程度で約4~72時間程度、好気培養し、培地から菌体を集菌し、洗浄し、湿菌体を得る。 The above-mentioned cells can be obtained by culturing under known conditions or similar conditions. For example, in the case of bifidobacteria or lactic acid bacteria, a liquid medium containing glucose, yeast extract, peptone, etc. is usually used, and one or more of the bifidobacteria and lactic acid bacteria are usually about 4 at about 25 to 45 ° C. Cultivate aerobically or anaerobically for about 72 hours, collect bacterial cells from the culture, and wash to obtain wet bacterial cells. In the case of saccharified bacteria, aerobic culture is usually performed at about 25 to 45 ° C. for about 4 to 72 hours in one or two or more agar media containing meat extract, casein peptone, sodium chloride and the like. Then, the cells are collected from the medium and washed to obtain wet cells.
 本発明において用いられるビフィズス菌、乳酸菌、糖化菌及び酪酸菌からなる群より選ばれる少なくとも1種の菌としては、生菌が好ましいが、菌の処理物を用いてもよい。菌の処理物とは、ビフィズス菌、乳酸菌、糖化菌及び酪酸菌からなる群より選ばれる少なくとも1種の菌に何らかの処理を加えたものをいい、その処理は特に限定されない。該処理物として具体的には、該菌体の超音波などによる破砕液、該菌体の培養液又は培養上清、それらを濾過又は遠心分離など固液分離手段によって分離した固体残渣などが挙げられる。また、細胞壁を酵素又は機械的手段により除去した処理液、トリクロロ酢酸処理又は塩析処理などして得られるタンパク質複合体(タンパク質、リポタンパク質、糖タンパク質など)又はペプチド複合体(ペプチド、糖ペプチド等)なども該処理物として挙げられる。さらに、これらの濃縮物、これらの希釈物又はこれらの乾燥物なども該処理物に含まれる。また、該菌体の超音波などによる破砕液、該細胞の培養液又は培養上清などに対し、例えば各種クロマトグラフィーによる分離などの処理をさらに加えたものも本発明における該処理物に含まれる。ビフィズス菌、乳酸菌、糖化菌及び酪酸菌からなる群より選ばれる少なくとも1種の菌の死菌体も本発明における該処理物に含まれる。前記死菌体は、例えば、酵素処理、約100℃程度の熱をかける加熱処理、抗生物質などの薬物による処理、ホルマリンなどの化学物質による処理、γ線などの放射線による処理などにより得ることができる。 As the at least one bacterium selected from the group consisting of bifidobacteria, lactic acid bacterium, saccharifying bacterium, and butyric acid bacterium used in the present invention, a viable bacterium is preferable, but a processed product of the bacterium may be used. The treated product of the bacterium refers to a product obtained by adding some treatment to at least one bacterium selected from the group consisting of bifidobacteria, lactic acid bacterium, saccharifying bacterium, and butyric acid bacterium, and the treatment is not particularly limited. Specific examples of the treated product include a disruption solution of the microbial cells by ultrasonic waves, a culture solution or a culture supernatant of the microbial cells, and a solid residue obtained by separating them by solid-liquid separation means such as filtration or centrifugation. It is done. In addition, a treatment solution obtained by removing a cell wall by an enzyme or mechanical means, a protein complex (protein, lipoprotein, glycoprotein, etc.) or a peptide complex (peptide, glycopeptide, etc.) obtained by trichloroacetic acid treatment or salting-out treatment, etc. ) Etc. are also mentioned as the treated product. Furthermore, these concentrates, these dilutions, or these dried products are also included in the treated product. In addition, the treated product in the present invention includes those obtained by further adding, for example, various chromatographic separations to the disrupted solution of the bacterial cells by ultrasonic waves, the cell culture solution or the culture supernatant. . A dead cell of at least one bacterium selected from the group consisting of bifidobacteria, lactic acid bacteria, saccharifying bacteria, and butyric acid bacteria is also included in the treated product in the present invention. The dead cells can be obtained by, for example, enzyme treatment, heat treatment at about 100 ° C., treatment with drugs such as antibiotics, treatment with chemicals such as formalin, treatment with radiation such as γ rays. it can.
 本発明において使用される菌は、乾燥物(菌体乾燥物)であってもよく、菌体乾燥物としては、シングルミクロンの菌体乾燥物が好ましい。菌体乾燥物とは、通常は乾燥された個々の菌体又は乾燥された菌体の集合物をいう。また、シングルミクロンとは、小数第1位を四捨五入して1~10μmをいう。本発明に使用されるビフィズス菌、乳酸菌、糖化菌及び酪酸菌からなる群より選ばれる少なくとも1種の菌として、シングルミクロンの菌体乾燥物を使用すると、製剤中の生菌率が上がるため、脂質代謝改善作用増強効果が高まる結果、脂質異常症、肥満等の生活習慣病の予防及び改善効果が高くなる。 The fungus used in the present invention may be a dried product (bacterial cell dried product), and the dried cell product is preferably a single micron dried cell product. The dried microbial cell usually refers to a dried individual microbial cell or a collection of dried microbial cells. Single micron means 1 to 10 μm by rounding off the first decimal place. As at least one type of bacteria selected from the group consisting of bifidobacteria, lactic acid bacteria, saccharifying bacteria, and butyric acid bacteria used in the present invention, when a single micron dried cell product is used, the viable cell rate in the preparation increases. As a result of enhancing the effect of improving lipid metabolism, the effect of preventing and improving lifestyle diseases such as dyslipidemia and obesity is enhanced.
 菌体乾燥物の好ましい製造方法について説明する。上記菌体を溶媒に分散して菌体液とする。溶媒は、当業界で用いられる公知の溶媒を用いてよいが、水が好ましい。また、所望によりエタノールを加えてよい。エタノールを加えることによって、最初にエタノールが気化し、ついで水が気化するから、段階的な乾燥が可能となる。さらに、菌体液は、懸濁液であってもよい。溶媒は上記で示したものと同じでよい。また、懸濁させる際、懸濁剤、例えばアルギン酸ナトリウム等を使用してもよい。
 また、上記菌体液には、さらに保護剤、賦形剤、結合剤、崩壊剤、又は静電気防止剤など当業界で一般に用いられている添加剤を通常の配合割合で添加してもよい。
A preferred method for producing a dried microbial cell product will be described. The said microbial cell is disperse | distributed to a solvent and it is set as a microbial cell liquid. As the solvent, a known solvent used in the art may be used, but water is preferable. If desired, ethanol may be added. By adding ethanol, ethanol is vaporized first, and then water is vaporized, so that stepwise drying is possible. Further, the bacterial cell liquid may be a suspension. The solvent may be the same as shown above. When suspending, a suspending agent such as sodium alginate may be used.
Moreover, you may add the additive generally used in this industry, such as a protective agent, an excipient | filler, a binder, a disintegrating agent, or an antistatic agent, to the said microbial cell liquid by a normal compounding ratio.
 上記菌体液を、菌体乾燥物を製造するために噴霧乾燥装置による乾燥操作に付する。噴霧乾燥装置は、シングルミクロンの噴霧液滴を形成できる微粒化装置を備えた噴霧乾燥装置が好ましい。非常に粒径の小さな噴霧液滴にすると、噴霧液滴の単位質量あたりの表面積が大きくなり、乾燥温風との接触が効率よく行われるため、生産性が向上する。
 ここでシングルミクロンの液滴とは、噴霧液滴の粒径が小数第1位を四捨五入して1~10μmであるものをいう。
The bacterial cell liquid is subjected to a drying operation by a spray dryer in order to produce a dried bacterial cell product. The spray drying apparatus is preferably a spray drying apparatus equipped with a atomizing apparatus capable of forming single micron spray droplets. When spray droplets having a very small particle diameter are used, the surface area per unit mass of the spray droplets is increased, and contact with dry hot air is efficiently performed, so that productivity is improved.
Here, the single-micron droplet means a spray droplet having a particle size of 1 to 10 μm rounded to the first decimal place.
 噴霧乾燥装置には、微粒化装置が、例えばロータリーアトマイザー(回転円盤)、加圧ノズル、又は圧縮気体の力を利用した2流体ノズルや4流体ノズルである噴霧乾燥装置が挙げられる。
 噴霧乾燥装置は、シングルミクロンの噴霧液滴を形成できるものであれば、上記形式のいずれの噴霧乾燥装置であってもよいが、4流体ノズルを有する噴霧乾燥装置を使用するのが好ましい。
Examples of the spray drying device include a spray drying device in which the atomization device is, for example, a rotary atomizer (rotary disk), a pressurized nozzle, or a two-fluid nozzle or a four-fluid nozzle using the force of compressed gas.
The spray drying apparatus may be any spray drying apparatus of the above type as long as it can form single micron spray droplets, but it is preferable to use a spray drying apparatus having a four-fluid nozzle.
 4流体ノズルを有する噴霧乾燥装置では、4流体ノズルの構造としては、気体流路と液体流路とを1系統として、これを2系統ノズルエッジにおいて対称に設けたもので、ノズルエッジに流体流動面となる斜面を構成している。
 また、ノズルエッジの先端の衝突焦点に向かって、両サイドから圧縮気体と液体を一点に集合させる外部混合方式の装置がよい。この方式であれば、ノズル詰まりがなく長時間噴霧することが可能となる。
In a spray drying apparatus having a four-fluid nozzle, the four-fluid nozzle has a gas flow channel and a liquid flow channel as one system, which are provided symmetrically at the two-system nozzle edge. It constitutes the slope that becomes the surface.
Also, an external mixing type apparatus that gathers compressed gas and liquid from one side toward the collision focus at the tip of the nozzle edge is preferable. With this method, it is possible to spray for a long time without nozzle clogging.
 4流路ノズルを有する噴霧乾燥装置について図10を用いてさらに詳しく説明する。4流路ノズルのノズルエッジにおいて、液体流路3又は4から湧き出るように出た菌体液が、気体流路1又は2から出た高速気体流により流体流動面5で薄く引き伸ばされ、引き伸ばされた液体はノズルエッジ先端の衝突焦点6で発生する衝撃波で微粒化させることにより、シングルミクロンの噴霧液滴7を形成する。 The spray drying apparatus having a four-channel nozzle will be described in more detail with reference to FIG. At the nozzle edge of the four-channel nozzle, the bacterial cell liquid that springed out from the liquid channel 3 or 4 was thinly stretched and stretched on the fluid flow surface 5 by the high-speed gas flow exiting from the gas channel 1 or 2. The liquid is atomized by a shock wave generated at the collision focal point 6 at the tip of the nozzle edge to form a single micron spray droplet 7.
 圧縮気体としては、例えば、空気、炭酸ガス、窒素ガス又はアルゴンガス等の不活性ガス等を用いることができる。とくに、酸化されやすいもの等を噴霧乾燥させる場合は、炭酸ガス、窒素ガス又はアルゴンガス等の不活性ガスを用いるのが好ましい。
 圧縮気体の圧力としては、通常約1~15kg重/cm、好ましくは約3~8kg重/cmである。
 ノズルにおける気体量は、ノズルエッジ1mmあたり、通常約1~100L/分、好ましくは約10~20L/分である。
As the compressed gas, for example, an inert gas such as air, carbon dioxide, nitrogen gas, or argon gas can be used. In particular, when spray-drying a material that is easily oxidized, it is preferable to use an inert gas such as carbon dioxide, nitrogen gas, or argon gas.
The pressure of the compressed gas is usually about 1 to 15 kgf / cm 2 , preferably about 3 to 8 kgf / cm 2 .
The amount of gas in the nozzle is usually about 1 to 100 L / min, preferably about 10 to 20 L / min per 1 mm of the nozzle edge.
 通常、その後、乾燥室において、その噴霧液滴に乾燥温風を接触させることで水分を蒸発させ菌体乾燥物を得る。
 乾燥室の入り口温度は、通常約2~400℃、好ましくは約5~250℃、より好ましくは約5~150℃である。入り口温度が約200~400℃の高温であっても、水分の蒸発による気化熱により乾燥室内の温度はそれほど高くならず、また、乾燥室内の滞留時間を短くすることにより、生菌の死滅や損傷をある程度抑えることができる。
 出口温度は、通常約0~120℃、好ましくは約5~90℃、より好ましくは約5~70℃である。
Usually, after that, in the drying chamber, the sprayed droplets are brought into contact with dry hot air to evaporate the water and obtain a dried bacterial cell product.
The inlet temperature of the drying chamber is usually about 2 to 400 ° C., preferably about 5 to 250 ° C., more preferably about 5 to 150 ° C. Even when the inlet temperature is about 200 to 400 ° C., the temperature in the drying chamber is not so high due to the heat of vaporization due to the evaporation of moisture, and by reducing the residence time in the drying chamber, Damage can be suppressed to some extent.
The outlet temperature is usually about 0 to 120 ° C., preferably about 5 to 90 ° C., more preferably about 5 to 70 ° C.
 4流路ノズルを有する噴霧乾燥装置では、液体流路が2流路あるので、異なった2種の菌体液又は菌体液と他の溶液若しくは懸濁液をそれぞれの液体流路から、同時に噴霧することにより、これらが混合された菌体乾燥物を製造できる。
 例えば、異なった2種類の菌体の菌体液を同時に噴霧することにより、該2種の菌体を含有する菌体乾燥物が得られる。
In the spray drying apparatus having a four-channel nozzle, since there are two liquid channels, two different types of bacterial cell liquids or bacterial cell liquids and other solutions or suspensions are sprayed simultaneously from the respective liquid channels. Thus, a dried microbial cell product in which these are mixed can be produced.
For example, by simultaneously spraying two different types of bacterial cell solutions, a dried bacterial cell product containing the two types of bacterial cells can be obtained.
 上記のように菌体乾燥物の粒径を小さくすることにより、生菌率が上がり、生菌率の多い製剤を提供できるという利点がある。
 すなわち、シングルミクロンの菌体乾燥物を得るためにはシングルミクロンの噴霧液滴を噴霧するのが好ましい。噴霧液滴の粒径を小さくすると、噴霧液滴の単位質量あたりの表面積が大きくなるので、乾燥温風との接触が効率よく行われ、乾燥温風の熱による菌体の死滅又は損傷を極力抑えることができる。その結果として、生菌率が上がり生菌数の多い菌体乾燥物が得られる。
By reducing the particle size of the dried bacterial cell as described above, there is an advantage that the viable cell rate is increased and a preparation having a high viable cell rate can be provided.
That is, it is preferable to spray single micron spray droplets in order to obtain a single micron dried cell. When the particle size of the spray droplets is reduced, the surface area per unit mass of the spray droplets increases, so that contact with the dry hot air is performed efficiently, and killing or damaging the cells due to the heat of the dry hot air as much as possible. Can be suppressed. As a result, the viable cell rate is increased and a dried cell body having a large number of viable cells is obtained.
 本発明におけるビフィズス菌、乳酸菌、糖化菌及び酪酸菌からなる群より選ばれる少なくとも1種の菌と、α-グルコシダーゼ阻害剤との組み合わせは特に限定されないが、例えば、α-グルコシダーゼ阻害剤が上記一般式(I)で表わされる化合物(好ましくは、ボグリボース(一般名))の場合、ビフィズス菌、乳酸菌及び糖化菌からなる群より選択される少なくとも1種を用いることが好ましく、中でも、ビフィズス菌が特に好ましく、ビフィズス菌と共に、乳酸菌及び/又は糖化菌を用いることも好ましい。α-グルコシダーゼ阻害剤が上記一般式(II)で表される化合物(好ましくは、アカルボース(一般名))の場合、乳酸菌、糖化菌及びビフィズス菌からなる群より選択される少なくとも1種を用いることが好ましく、中でも、ビフィズス菌及び/又は乳酸菌がより好ましく、ビフィズス菌が特に好ましい。ビフィズス菌と共に、乳酸菌及び糖化菌を用いてもよい。α-グルコシダーゼ阻害剤及び菌をこのような組み合わせで用いると、α-グルコシダーゼ阻害剤及び/又は該菌の脂質代謝改善作用及び抗肥満作用を顕著に増強させることができるため、優れた脂質代謝改善作用及び抗肥満作用が得られる。 The combination of at least one bacterium selected from the group consisting of bifidobacteria, lactic acid bacterium, saccharifying bacterium and butyric acid bacterium and an α-glucosidase inhibitor in the present invention is not particularly limited. In the case of the compound represented by the formula (I) (preferably voglibose (generic name)), it is preferable to use at least one selected from the group consisting of bifidobacteria, lactic acid bacteria, and saccharifying bacteria. Preferably, it is also preferable to use lactic acid bacteria and / or saccharifying bacteria together with bifidobacteria. When the α-glucosidase inhibitor is a compound represented by the above general formula (II) (preferably acarbose (generic name)), at least one selected from the group consisting of lactic acid bacteria, saccharifying bacteria and bifidobacteria should be used. Among them, bifidobacteria and / or lactic acid bacteria are more preferable, and bifidobacteria are particularly preferable. Along with bifidobacteria, lactic acid bacteria and saccharified bacteria may be used. When an α-glucosidase inhibitor and a bacterium are used in such a combination, the α-glucosidase inhibitor and / or the lipid metabolism improving action and the anti-obesity action of the bacterium can be remarkably enhanced, and thus excellent lipid metabolism improvement. Action and anti-obesity effect are obtained.
 例えば、ボグリボースを含むビフィズス菌による脂質代謝改善作用増強剤、アカルボースを含むビフィズス菌又は乳酸菌による脂質代謝改善作用増強剤、ビフィズス菌を含むボグリボース又はアカルボースによる脂質代謝改善作用増強剤、乳酸菌を含むアカルボースによる脂質代謝改善作用増強剤等は、本発明の好ましい実施態様の1つである。
 ボグリボース又はアカルボースを含み、ビフィズス菌と組み合わせて投与される脂質代謝改善剤、抗肥満剤及び抗肥満作用増強剤も、本発明の好ましい実施態様の1つである。
 アカルボースを含み、乳酸菌と組み合わせて投与される脂質代謝改善剤、抗肥満剤及び抗肥満作用増強剤も、本発明の好ましい実施態様の1つである。
For example, an agent for improving lipid metabolism by bifidobacteria containing voglibose, an agent for improving lipid metabolism by bifidobacteria containing acarbose or lactic acid bacteria, an agent for improving lipid metabolism by voglibose containing bifidobacteria or acarbose, an acarbose containing lactic acid bacteria A lipid metabolism improving agent or the like is one of the preferred embodiments of the present invention.
Lipid metabolism improving agents, anti-obesity agents, and anti-obesity action enhancing agents that contain voglibose or acarbose and are administered in combination with bifidobacteria are also preferred embodiments of the present invention.
A lipid metabolism improving agent, an anti-obesity agent and an anti-obesity effect-enhancing agent which contain acarbose and are administered in combination with lactic acid bacteria are also one preferred embodiment of the present invention.
 ビフィズス菌を含み、ボグリボース又はアカルボースと組み合わせて投与される脂質代謝改善剤、抗肥満剤及び抗肥満作用増強剤も、本発明の好ましい実施態様の1つである。
 乳酸菌を含み、アカルボースと組み合わせて投与される脂質代謝改善剤、抗肥満剤及び抗肥満作用増強剤も、本発明の好ましい実施態様の1つである。
A lipid metabolism improving agent, an anti-obesity agent and an anti-obesity effect-enhancing agent containing bifidobacteria and administered in combination with voglibose or acarbose are also one preferred embodiment of the present invention.
A lipid metabolism improving agent, an anti-obesity agent and an anti-obesity effect-enhancing agent which contain lactic acid bacteria and are administered in combination with acarbose are also one preferred embodiment of the present invention.
 本発明のα-グルコシダーゼ阻害剤を含む脂質代謝改善剤、前記菌による脂質代謝改善作用増強剤、抗肥満剤及び抗肥満作用増強剤は、上記α-グルコシダーゼ阻害剤と、他の成分とを混合することにより容易に製造される。ビフィズス菌、乳酸菌、糖化菌及び酪酸菌からなる群より選ばれる少なくとも1種の菌を含むα-グルコシダーゼ阻害剤による脂質代謝改善作用増強剤及び抗肥満作用増強剤は、前記菌と、他の成分とを混合することにより容易に製造される。他の成分は、本発明の効果を奏する限り特に限定されない。本発明の脂質代謝改善剤、脂質代謝改善作用増強剤、抗肥満剤及び抗肥満作用増強剤は、医薬品、医薬部外品、飲食品、飼料等の形態として用いることができる。このような、本発明の脂質代謝改善剤、脂質代謝改善作用増強剤、抗肥満剤又は抗肥満作用増強剤を含む医薬品も、本発明の1つである。 The lipid metabolism improving agent comprising the α-glucosidase inhibitor of the present invention, the lipid metabolism improving effect enhancer by the fungus, the anti-obesity agent and the anti-obesity effect enhancer are a mixture of the α-glucosidase inhibitor and other components. Is easily manufactured. Lipid metabolism improving action enhancer and anti-obesity action enhancer by α-glucosidase inhibitor containing at least one bacterium selected from the group consisting of bifidobacteria, lactic acid bacterium, saccharifying bacterium and butyric acid bacterium, the bacterium and other components It is easily manufactured by mixing. Other components are not particularly limited as long as the effects of the present invention are exhibited. The lipid metabolism improving agent, lipid metabolism improving action enhancer, anti-obesity agent and anti-obesity action enhancer of the present invention can be used in the form of pharmaceuticals, quasi drugs, food and drink, feeds and the like. Such a pharmaceutical comprising the lipid metabolism improving agent, lipid metabolism improving action enhancer, anti-obesity agent or anti-obesity action enhancer of the present invention is also one aspect of the present invention.
 本発明において、α-グルコシダーゼ阻害剤とビフィズス菌、乳酸菌、糖化菌及び酪酸菌からなる群より選ばれる少なくとも1種の菌とを組み合せて投与する方法としては、本発明の効果を奏する限り特に限定されず、例えば、α-グルコシダーゼ阻害剤を含有する製剤(組成物)と、ビフィズス菌、乳酸菌、糖化菌及び酪酸菌からなる群より選ばれる少なくとも1種の菌を含有する製剤(組成物)とを別々に調製し、両製剤を同時に、又は時を異にして投与する方法、α-グルコシダーゼ阻害剤及びビフィズス菌、乳酸菌、糖化菌及び酪酸菌からなる群より選ばれる少なくとも1種の菌の双方を含有する製剤(組成物)を投与する方法が挙げられるが、両成分を含有する製剤を調製して投与することが好ましい。 In the present invention, the method of administering a combination of an α-glucosidase inhibitor and at least one bacterium selected from the group consisting of bifidobacteria, lactic acid bacteria, saccharifying bacteria and butyric acid bacteria is not particularly limited as long as the effects of the present invention are exhibited. For example, a preparation (composition) containing an α-glucosidase inhibitor and a preparation (composition) containing at least one bacterium selected from the group consisting of bifidobacteria, lactic acid bacteria, saccharifying bacteria, and butyric acid bacteria A method in which both preparations are administered separately or at the same time, both α-glucosidase inhibitors and at least one bacterium selected from the group consisting of bifidobacteria, lactic acid bacteria, saccharifying bacteria, and butyric acid bacteria Can be mentioned, but it is preferable to prepare and administer a preparation containing both components.
 (A)α-グルコシダーゼ阻害剤、及び(B)ビフィズス菌、乳酸菌、糖化菌及び酪酸菌からなる群より選ばれる少なくとも1種の菌のそれぞれを単独で含有する製剤、両者を同時に含有する複合剤の剤形は、それぞれの成分の物理化学的性質、生物学的性質等を考慮して投与に好適な剤形とすればよい。医薬品の場合には、経口投与に適しており、内服剤とすることが好ましい。内服剤の剤型としては、例えば、錠剤、ペレット、細粒剤、散剤、顆粒剤、丸剤、チュアブル剤、トローチ剤、液剤、懸濁剤等が挙げられる。中でも、錠剤又は散剤が好ましい。さらに、それぞれの製剤は、α-グルコシダーゼ阻害剤及び/又はビフィズス菌、乳酸菌、糖化菌及び酪酸菌からなる群より選ばれる少なくとも1種の菌の他に、賦形剤(例えば、乳糖、デンプン、結晶セルロース又はリン酸ナトリウム等)、結合剤(例えば、デンプン、ゼラチン、カルメロースナトリウム、メチルセルロース、ヒドロキシプロピルメチルセルロース、ヒドロキシプロピルセルロース、ポリビニルピロリドン等)、崩壊剤(例えばデンプン、カルメロースナトリウム等)、滑沢剤(例えばタルク、ステアリン酸マグネシウム、ステアリン酸カルシウム、マクロゴール、ショ糖脂肪酸エステル等)、安定剤(亜硫酸水素ナトリウム、チオ硫酸ナトリウム、エデト酸ナトリウム、クエン酸ナトリウム、アスコルビン酸、ジブチルヒドロキシトルエン等)、着色剤、賦香剤、光沢剤等、当業界で使用される公知の添加剤等を適宜含有していてもよい。製剤中に含まれるα-グルコシダーゼ阻害剤の量は、通常、最終製剤中に約0.0001~99質量%の範囲から適宜選択して決定することができる。製剤中に含まれるビフィズス菌、乳酸菌、糖化菌及び酪酸菌からなる群より選ばれる少なくとも1種の菌の量は、通常、最終製剤中に約0.000001~99質量%の範囲から適宜選択して決定することができる。 (A) an α-glucosidase inhibitor, and (B) a preparation containing each of at least one bacterium selected from the group consisting of bifidobacteria, lactic acid bacteria, saccharifying bacteria, and butyric acid bacteria, and a composite agent containing both at the same time The dosage form may be a dosage form suitable for administration in consideration of the physicochemical properties and biological properties of each component. In the case of a pharmaceutical, it is suitable for oral administration and is preferably an internal preparation. Examples of the internal dosage form include tablets, pellets, fine granules, powders, granules, pills, chewables, troches, liquids, suspensions and the like. Among these, tablets or powders are preferable. Furthermore, each preparation is prepared by adding an excipient (for example, lactose, starch, etc.) in addition to an α-glucosidase inhibitor and / or at least one bacterium selected from the group consisting of bifidobacteria, lactic acid bacteria, saccharifying bacteria, and butyric acid bacteria. Crystalline cellulose or sodium phosphate), binders (eg starch, gelatin, carmellose sodium, methylcellulose, hydroxypropylmethylcellulose, hydroxypropylcellulose, polyvinylpyrrolidone, etc.), disintegrants (eg starch, carmellose sodium, etc.), Reagents (eg talc, magnesium stearate, calcium stearate, macrogol, sucrose fatty acid ester, etc.), stabilizers (sodium bisulfite, sodium thiosulfate, sodium edetate, sodium citrate, ascorbic acid, dibutyl Mud carboxymethyl toluene), colorants, Fukozai, brighteners, etc., known additives such as a may contain appropriately used in the art. The amount of the α-glucosidase inhibitor contained in the preparation can be usually determined by appropriately selecting from the range of about 0.0001 to 99% by mass in the final preparation. The amount of at least one bacterium selected from the group consisting of bifidobacteria, lactic acid bacteria, saccharifying bacteria, and butyric acid bacteria contained in the preparation is usually appropriately selected from the range of about 0.000001 to 99% by mass in the final preparation. Can be determined.
 α-グルコシダーゼ阻害剤とビフィズス菌、乳酸菌、糖化菌及び酪酸菌からなる群より選ばれる少なくとも1種の菌とを含有する組成物の調製は、製剤の常法によって両成分を混合し、製造することができるが、その場合、該組成物におけるα-グルコシダーゼ阻害剤と、ビフィズス菌、乳酸菌、糖化菌及び酪酸菌からなる群より選ばれる少なくとも1種の菌の配合比率は、α-グルコシダーゼ阻害剤約0.05~500mgに対し、該菌を約10~1012個とすることが好ましく、α-グルコシダーゼ阻害剤約0.01~300mgに対し、該菌を約10~1011個とすることが特に好ましい。 Preparation of a composition containing an α-glucosidase inhibitor and at least one bacterium selected from the group consisting of bifidobacteria, lactic acid bacteria, saccharifying bacteria, and butyric acid bacteria is performed by mixing both components according to a conventional method of preparation. In that case, the combination ratio of the α-glucosidase inhibitor in the composition and at least one bacterium selected from the group consisting of bifidobacteria, lactic acid bacterium, saccharifying bacterium, and butyric acid bacterium is an α-glucosidase inhibitor. About 10 3 to 10 12 bacteria are preferable for about 0.05 to 500 mg, and about 10 5 to 10 11 bacteria for about 0.01 to 300 mg of the α-glucosidase inhibitor. It is particularly preferable to do this.
 なお、ビフィズス菌、乳酸菌、糖化菌及び酪酸菌からなる群より選ばれる少なくとも1種の菌は、一般に嫌気性で乾燥状態では空気又は酸素に対して弱く、また、高温と湿気に弱いため、組成物の製剤化に際してはできるだけ、不活性ガスの存在下又は真空、低温下で、処理することが好ましい。 In addition, at least one bacterium selected from the group consisting of bifidobacteria, lactic acid bacterium, saccharifying bacterium, and butyric acid bacterium is generally anaerobic and weak against air or oxygen in a dry state, and is also resistant to high temperature and humidity. When formulating a product, it is preferable to treat it in the presence of an inert gas or in a vacuum at a low temperature as much as possible.
 α-グルコシダーゼ阻害剤とビフィズス菌、乳酸菌、糖化菌及び酪酸菌からなる群より選ばれる少なくとも1種の菌とを含有する組成物を固形製剤にする場合、乾燥法によって、単に粉末同士を混合してもよいし、またその粉末を圧縮して顆粒にしたり、錠剤にしたりしてもよい。湿式法により顆粒、錠剤を製造する場合は、結合剤の水溶液を用いて練合、乾燥し、目的の固形剤とすることができる。さらに、この様にして得られた粉末又は顆粒をカプセルに充填して、カプセル剤とすることもできる。 When a composition containing an α-glucosidase inhibitor and at least one bacterium selected from the group consisting of bifidobacteria, lactic acid bacteria, saccharifying bacteria, and butyric acid bacteria is made into a solid preparation, powders are simply mixed by a drying method. Alternatively, the powder may be compressed into granules or tablets. When granules and tablets are produced by a wet method, they can be kneaded and dried using an aqueous solution of a binder to obtain a desired solid agent. Furthermore, the powder or granule obtained in this way can be filled into a capsule to form a capsule.
 例えば、錠剤を製造する場合は、公知の打錠機を用いるとよい。該打錠機としては、例えば単発式打錠機又はロータリー型打錠機等が挙げられる。また、丸剤、チュアブル剤又はトローチ剤の製造方法は、公知の方法に従って行われてよく、例えば錠剤を製造するのと同じ手段で作ることができる。 For example, when manufacturing tablets, a known tableting machine may be used. Examples of the tableting machine include a single-shot tableting machine and a rotary tableting machine. Moreover, the manufacturing method of a pill, a chewable agent, or a troche agent may be performed in accordance with a well-known method, for example, can be made with the same means as manufacturing a tablet.
 微量の有効成分(α-グルコシダーゼ阻害剤及び/又はビフィズス菌、乳酸菌、糖化菌及び酪酸菌からなる群より選ばれる少なくとも1種の菌)を大量の他の粉末と混合し均一な混合物を得るためには、いわゆる段階的混合法を採るのがよい。例えば、有効成分をその100~200容量倍の粉末と混合して均一な粉末を得、これを残りの粉末と混合すると均一な粉末を得ることができる。
 含水物からの乾燥には、L-乾燥、凍結乾燥、噴霧乾燥などの手段をとることができる。ビフィズス菌、乳酸菌、糖化菌及び酪酸菌からなる群より選ばれる少なくとも1種の菌の乾燥菌体(菌体乾燥物)を得るには、適当な安定剤、例えばグルタミン酸モノナトリウム塩、アドニトールなどを加えた中性の緩衝液に菌を懸濁させておき、自体公知の方法で乾燥することもできる。
In order to obtain a uniform mixture by mixing a small amount of an active ingredient (α-glucosidase inhibitor and / or at least one bacterium selected from the group consisting of bifidobacteria, lactic acid bacteria, saccharifying bacteria, and butyric acid bacteria) with a large amount of other powders. For this, a so-called stepwise mixing method is preferably employed. For example, the active ingredient can be mixed with 100 to 200 times its volume of powder to obtain a uniform powder, and this can be mixed with the remaining powder to obtain a uniform powder.
For drying from the water-containing material, means such as L-drying, freeze-drying and spray-drying can be employed. In order to obtain a dry cell (dry cell) of at least one bacterium selected from the group consisting of bifidobacteria, lactic acid bacterium, saccharification bacterium and butyric acid bacterium, an appropriate stabilizer such as monosodium glutamate, adonitol, etc. Bacteria can be suspended in the added neutral buffer and dried by a method known per se.
 本発明において、α-グルコシダーゼ阻害剤の投与量は、通常約0.001~500mg/大人/回、好ましくは約0.001~100mg/大人/回、より好ましくは約0.002~100mg/大人/回であり、これを通常1日2回~4回食前1時間~食後2時間の間に経口投与するのが好ましい。特にα-グルコシダーゼ阻害剤が上記一般式(I)で表わされるバイオールアミン誘導体である場合は、該化合物を通常約0.001~20mg/大人/回(より好ましくは約0.002~20mg/大人/回)、1日2~4回の投与であり、これを好ましくは食前1時間~食後2時間の間の適当な時期に経口投与するのが効果的である。 In the present invention, the dose of the α-glucosidase inhibitor is usually about 0.001 to 500 mg / adult / dose, preferably about 0.001 to 100 mg / adult / dose, more preferably about 0.002 to 100 mg / adult. It is preferably administered orally between 2 to 4 times a day, usually 1 hour before meal to 2 hours after meal. In particular, when the α-glucosidase inhibitor is a violamine derivative represented by the above general formula (I), the compound is usually about 0.001 to 20 mg / adult / dose (more preferably about 0.002 to 20 mg / day). Adults / dose) 2-4 times a day, and it is effective to orally administer this at an appropriate time between 1 hour before meal and 2 hours after meal.
 本発明において、ビフィズス菌、乳酸菌、糖化菌及び酪酸菌からなる群より選ばれる少なくとも1種の菌の投与量は、生菌を用いる場合には、生菌の菌数にして通常約10~1012個/大人/回、好ましくは10~1010個/大人/回、より好ましくは10~1010個/大人/回を含む製剤を、通常1日2~4回、好ましくは食前約1時間~食後約2時間の間に経口投与するのが効果的である。ここで、製剤中の生菌数の測定は菌体によって異なるが、例えば日本薬局方外医薬品規格に記載されたそれぞれの菌体の定量方法により容易に測定できる。 In the present invention, the dose of at least one bacterium selected from the group consisting of bifidobacteria, lactic acid bacterium, saccharifying bacterium, and butyric acid bacterium is usually about 10 3 to 10 in terms of the number of viable bacteria. A preparation containing 10 12 / adult / time, preferably 10 5 to 10 10 / adult / time, more preferably 10 6 to 10 10 / adult / time, usually 2 to 4 times a day, preferably before meals It is effective to administer orally between about 1 hour and about 2 hours after meal. Here, the measurement of the number of viable bacteria in the preparation varies depending on the bacterial cells, but can be easily measured by, for example, each bacterial cell quantification method described in the Japanese Pharmacopoeia Pharmaceutical Standards.
 本発明の脂質代謝改善剤、脂質代謝改善作用増強剤、抗肥満剤及び抗肥満作用増強剤は、例えば、脂質異常症、循環器疾患、心臓疾患等の生活習慣病又はそのおそれのある個体(動物)に好適に適用することができる。また、肥満又は肥満予備軍の減量を必要とする個体も、好適な対象である。さらに、肥満を中心として脂質異常症等を併発(メタボリックシンドローム)した個体又はそのおそれのある個体がより好適である。中でも、肥満及び/又は脂質異常症を発症した個体又はそのおそれのある個体がより好適であり、肥満及び/又は脂質異常症を発症した個体がさらに好適であり、肥満及び高脂血症を発症した個体が特に好適である。個体としてはヒト、マウス、ラット、ウサギ、イヌ、ネコ、ウシ、ウマ、ブタ、サル等の哺乳類が好ましく、特にヒトが好ましい。 The lipid metabolism-improving agent, lipid metabolism-improving action enhancer, anti-obesity agent and anti-obesity action enhancer of the present invention are, for example, lifestyle-related diseases such as dyslipidemia, cardiovascular disease, heart disease and the like ( Animal). Individuals in need of obesity or obesity reserve weight loss are also suitable subjects. Furthermore, an individual who has dyslipidemia or the like (metabolic syndrome) mainly in obesity or an individual who is likely to do so is more preferable. Among them, an individual who develops obesity and / or dyslipidemia or an individual at risk thereof is more preferable, an individual who develops obesity and / or dyslipidemia is more preferable, and develops obesity and hyperlipidemia. Individuals are particularly preferred. As the individual, mammals such as humans, mice, rats, rabbits, dogs, cats, cows, horses, pigs and monkeys are preferable, and humans are particularly preferable.
 本発明の脂質代謝改善剤、脂質代謝改善作用増強剤、抗肥満剤及び抗肥満作用増強剤は、少量の使用でも、α-グルコシダーゼ阻害剤とビフィズス菌、乳酸菌、糖化菌及び酪酸菌からなる群より選ばれる少なくとも1種の菌との併用によって、前記菌及び/又はα-グルコシダーゼ阻害剤の脂質代謝改善作用が相乗的に増強されるので、肥満、脂質異常症等の予防、改善又は治療に有効なものであり、投与の方法も簡単で、しかも副作用がほとんどないものである。 The lipid metabolism-improving agent, lipid metabolism-improving action enhancer, anti-obesity agent and anti-obesity action enhancer of the present invention are a group consisting of an α-glucosidase inhibitor and bifidobacteria, lactic acid bacteria, saccharifying bacteria, and butyric acid bacteria, even in small amounts. The combined use with at least one bacterium selected from the above synergistically enhances the lipid metabolism improving action of the bacterium and / or the α-glucosidase inhibitor, so that it can be used for the prevention, improvement or treatment of obesity, dyslipidemia, etc. It is effective, easy to administer, and has few side effects.
 本発明の脂質代謝改善剤、脂質代謝改善作用増強剤、抗肥満剤及び抗肥満作用増強剤は、上述した医薬品として用いることができるほか、機能性食品、特定保健用食品又はドリンク剤などの飲食品として用いることができるものである。本発明の脂質代謝改善剤を含む脂質代謝改善用飲食品組成物も、本発明の1つである。前記α-グルコシダーゼ阻害剤を含む脂質代謝改善作用増強剤を含む、ビフィズス菌、乳酸菌、糖化菌及び酪酸菌からなる群より選ばれる少なくとも1種の菌による脂質代謝改善作用増強用飲食品組成物も、本発明の1つである。前記菌を含む脂質代謝改善作用増強剤を含む、α-グルコシダーゼ阻害剤による脂質代謝改善作用増強用飲食品組成物も、本発明の1つである。本発明の抗肥満剤を含む肥満改善用飲食品組成物も、本発明の1つである。前記α-グルコシダーゼ阻害剤を含む抗肥満作用増強剤を含む、ビフィズス菌、乳酸菌、糖化菌及び酪酸菌からなる群より選ばれる少なくとも1種の菌による肥満改善作用増強用飲食品組成物も、本発明の1つである。前記菌を含む抗肥満作用増強剤を含む、α-グルコシダーゼ阻害剤による肥満改善作用増強用飲食品組成物も、本発明の1つである。本発明に係る飲食品組成物を、肥満、脂質異常症等の生活習慣病若しくはメタボリックシンドローム、又はそのおそれのあるヒトを含む哺乳動物に摂取させることにより、該生活習慣病等を予防又は改善することができる。飲食品組成物中に含まれるα-グルコシダーゼ阻害剤の量は、通常、最終組成物中に約0.0001~99質量%の範囲から適宜選択して決定することができる。飲食品組成物中に含まれるビフィズス菌、乳酸菌、糖化菌及び酪酸菌からなる群より選ばれる少なくとも1種の菌の量は、通常、最終組成物中に約0.000001~99質量%の範囲から適宜選択して決定することができる。 The lipid metabolism-improving agent, lipid metabolism-improving action enhancer, anti-obesity agent and anti-obesity action enhancer of the present invention can be used as the above-mentioned pharmaceuticals, as well as food and drink such as functional foods, foods for specified health use or drinks. It can be used as a product. The food / beverage composition for lipid metabolism improvement containing the lipid metabolism improving agent of this invention is also one of this invention. A food / beverage composition for enhancing lipid metabolism improving action by at least one bacterium selected from the group consisting of bifidobacteria, lactic acid bacteria, saccharifying bacteria and butyric acid bacteria, comprising the lipid metabolism improving action enhancing agent containing the α-glucosidase inhibitor. This is one of the present inventions. A food / beverage food composition for enhancing lipid metabolism improving action by an α-glucosidase inhibitor, which includes the lipid metabolism improving action enhancing agent containing the bacterium, is also one aspect of the present invention. The food / beverage composition for obesity improvement containing the anti-obesity agent of this invention is also one of this invention. A food / beverage composition for enhancing obesity-improving action by at least one bacterium selected from the group consisting of bifidobacteria, lactic acid bacteria, saccharifying bacteria and butyric acid bacteria, comprising the anti-obesity action enhancing agent containing the α-glucosidase inhibitor is also provided. It is one of the inventions. A food / beverage composition for enhancing obesity-improving action by an α-glucosidase inhibitor, comprising the anti-obesity action-enhancing agent containing the above-mentioned bacteria, is also one aspect of the present invention. Preventing or improving the lifestyle-related diseases and the like by ingesting the food and beverage composition according to the present invention into mammals including lifestyle-related diseases such as obesity and dyslipidemia or metabolic syndrome, or humans who are likely to have it. be able to. The amount of the α-glucosidase inhibitor contained in the food / beverage product composition can usually be determined by appropriately selecting from the range of about 0.0001 to 99% by mass in the final composition. The amount of at least one bacterium selected from the group consisting of bifidobacteria, lactic acid bacteria, saccharifying bacteria, and butyric acid bacteria contained in the food and drink composition is usually in the range of about 0.000001 to 99% by mass in the final composition. It can be selected and determined as appropriate.
 本発明において、α-グルコシダーゼ阻害剤とビフィズス菌、乳酸菌、糖化菌及び酪酸菌からなる群より選ばれる少なくとも1種の菌とを摂取させる方法としては、本発明の効果を奏する限り特に限定されず、例えば、α-グルコシダーゼ阻害剤を含有する組成物と、ビフィズス菌、乳酸菌、糖化菌及び酪酸菌からなる群より選ばれる少なくとも1種の菌を含有する組成物とを別々に調製し、両組成物を同時に、又は時を異にして摂取させる方法、α-グルコシダーゼ阻害剤及びビフィズス菌、乳酸菌、糖化菌及び酪酸菌からなる群より選ばれる少なくとも1種の菌の双方を含有する組成物を摂取させる方法が挙げられるが、両成分を含有する組成物を調製して摂取させることが好ましい。 In the present invention, the method for ingesting an α-glucosidase inhibitor and at least one bacterium selected from the group consisting of bifidobacteria, lactic acid bacteria, saccharifying bacteria, and butyric acid bacteria is not particularly limited as long as the effects of the present invention are exhibited. For example, a composition containing an α-glucosidase inhibitor and a composition containing at least one bacterium selected from the group consisting of bifidobacteria, lactic acid bacteria, saccharifying bacteria, and butyric acid bacteria are prepared separately. Ingesting a composition containing both an α-glucosidase inhibitor and at least one bacterium selected from the group consisting of bifidobacteria, lactic acid bacteria, saccharifying bacteria, and butyric acid bacteria However, it is preferable to prepare and ingest a composition containing both components.
 本発明の剤を飲食品組成物として用いる場合、その形態は特に限定されない。また、飲食品組成物は、自然流動食、半消化態栄養食若しくは成分栄養食、又はドリンク剤等の加工形態とすることもできる。さらに、本発明にかかる飲食品組成物は、アルコール飲料又はミネラルウォーターに用時添加する易溶性製剤としてもよい。より具体的には、本発明に係る飲食品組成物は、例えばビスケット、クッキー、ケーキ、キャンディー、チョコレート、チューインガム、和菓子などの菓子類;パン、麺類、米飯又はその加工品;清酒、薬用酒などの発酵食品;ヨーグルト、ハム、ベーコン、ソーセージ、マヨネーズなどの畜農食品;果汁飲料、清涼飲料、スポーツ飲料、アルコール飲料、茶などの飲料等の形態とすることができる。 When using the agent of the present invention as a food or drink composition, the form is not particularly limited. Moreover, food-drinks compositions can also be made into processing forms, such as a natural liquid food, a semi-digested nutrient food, a component nutrient food, or a drink agent. Furthermore, the food-drinks composition concerning this invention is good also as an easily soluble formulation added to an alcoholic beverage or mineral water at the time of use. More specifically, the food / beverage composition according to the present invention includes, for example, confectionery such as biscuits, cookies, cakes, candy, chocolate, chewing gum, Japanese confectionery; bread, noodles, cooked rice or processed products thereof; sake, medicinal liquor, etc. Fermented foods; livestock farming foods such as yogurt, ham, bacon, sausage, mayonnaise; beverages such as fruit juice drinks, soft drinks, sports drinks, alcoholic drinks, and tea.
 また、本発明に係る飲食品組成物は、例えば、医師の食事箋に基づく栄養士の管理の下に、病院給食の調理の際に任意の食品に本発明の飲食品組成物を加え、その場で調製した食品の形態で患者に与えることもできる。本発明の飲食品組成物は、液状であっても、粉末や顆粒などの固形状であってもよい。 In addition, the food / beverage composition according to the present invention, for example, under the control of a dietitian based on a doctor's meal, adds the food / beverage composition of the present invention to any food at the time of cooking in a hospital meal, It can also be given to patients in the form of food prepared in The food / beverage composition of the present invention may be liquid or solid such as powder or granule.
 本発明に係る飲食品組成物は、食品分野で慣用の補助成分を含んでいてもよい。前記補助成分としては、例えば乳糖、ショ糖、液糖、蜂蜜、ステアリン酸マグネシウム、オキシプロピルセルロース、各種ビタミン類、微量元素、クエン酸、リンゴ酸、香料、無機塩などが挙げられる。 The food / beverage composition according to the present invention may contain auxiliary components commonly used in the food field. Examples of the auxiliary component include lactose, sucrose, liquid sugar, honey, magnesium stearate, oxypropylcellulose, various vitamins, trace elements, citric acid, malic acid, fragrance, and inorganic salt.
 本発明に係る飲食品組成物の摂取量は、摂取する哺乳動物の生活習慣病の状態、年齢、性別などによって異なるので、一概には言えないが、α-グルコシダーゼ阻害剤及びビフィズス菌、乳酸菌、糖化菌及び酪酸菌からなる群より選ばれる少なくとも1種の菌を、それぞれ上述した医薬品の場合と同様の量摂取させることが好ましい。 The amount of intake of the food and beverage composition according to the present invention varies depending on the lifestyle-related disease state, age, sex, etc. of the mammal to be ingested, and cannot be generally stated, but it is not possible to say generally, α-glucosidase inhibitors and bifidobacteria, lactic acid bacteria, It is preferable to ingest at least one type of bacteria selected from the group consisting of saccharifying bacteria and butyric acid bacteria in the same amount as in the case of the above-described pharmaceuticals.
 本発明は、ビフィズス菌、乳酸菌、糖化菌及び酪酸菌からなる群より選ばれる少なくとも1種の菌を含み、α-グルコシダーゼ阻害剤と組み合わせて投与されるα-グルコシダーゼ阻害剤による脂質代謝改善作用又は抗肥満作用の発現促進剤も包含する。α-グルコシダーゼ阻害剤と前記菌とを併用することにより、α-グルコシダーゼ阻害剤の投与量を、該阻害剤がその血中脂質低下作用等の脂質代謝改善作用や抗肥満作用を発揮させる目的で単独で使用される場合より少量としても、該阻害剤を単独で通常使用される量使用した場合と比較して短期間の投与で有効な脂質代謝改善効果や抗肥満作用を得ることができる。従って、前記菌とα-グルコシダーゼ阻害剤とを併用すると、α-グルコシダーゼ阻害剤の使用量を少なくしても、該阻害剤による脂質代謝改善作用及び/又は抗肥満作用を短期間で効果的に発現させることができる。 The present invention includes at least one bacterium selected from the group consisting of bifidobacteria, lactic acid bacterium, saccharifying bacterium, and butyric acid bacterium, and an action of improving lipid metabolism by an α-glucosidase inhibitor administered in combination with an α-glucosidase inhibitor or An agent for promoting the expression of anti-obesity action is also included. By using an α-glucosidase inhibitor in combination with the above-mentioned bacteria, the dose of the α-glucosidase inhibitor can be adjusted so that the inhibitor exerts its lipid metabolism improving action such as blood lipid lowering action and anti-obesity action. Even when the amount of the inhibitor is smaller than when used alone, an effective lipid metabolism improving effect and anti-obesity effect can be obtained by administration in a short period of time compared to the case where the inhibitor is used in an amount usually used alone. Therefore, when the bacterium and the α-glucosidase inhibitor are used in combination, even if the amount of the α-glucosidase inhibitor used is reduced, the lipid metabolism improving action and / or anti-obesity action by the inhibitor can be effectively achieved in a short period of time. Can be expressed.
 α-グルコシダーゼ阻害剤とビフィズス菌、乳酸菌、糖化菌及び酪酸菌からなる群より選ばれる少なくとも1種の菌とを併用すると、例えば、α-グルコシダーゼ阻害剤の投与量を1回につき約0.02~100mgとし、この量を1日2~4回食前に経口投与すると、投与開始から約4~8週間後に有効な脂質代謝改善作用が得られる。このため、血中脂質及び内臓脂肪を減少させ、体重増加を抑制することができる。ビフィズス菌、乳酸菌、糖化菌及び酪酸菌からなる群より選ばれる少なくとも1種の菌の好ましい使用量は、上述した脂質代謝改善増強剤における使用量と同じである。本発明のα-グルコシダーゼ阻害剤による脂質代謝改善作用又は抗肥満作用の発現促進剤及びその好ましい態様は、上述したα-グルコシダーゼ阻害剤による脂質代謝改善増強剤と同様である。 When an α-glucosidase inhibitor is used in combination with at least one bacterium selected from the group consisting of bifidobacteria, lactic acid bacteria, saccharifying bacteria, and butyric acid bacteria, for example, the dose of the α-glucosidase inhibitor is about 0.02 at a time. When this amount is orally administered 2 to 4 times a day before meals, an effective lipid metabolism improving effect is obtained about 4 to 8 weeks after the start of administration. For this reason, blood lipid and visceral fat can be reduced and weight gain can be suppressed. The preferred amount of use of at least one bacterium selected from the group consisting of bifidobacteria, lactic acid bacteria, saccharifying bacteria and butyric acid bacteria is the same as the amount used in the lipid metabolism improving agent described above. The expression promoter of lipid metabolism improving action or anti-obesity action by the α-glucosidase inhibitor of the present invention and preferred embodiments thereof are the same as the lipid metabolism improving enhancer by the α-glucosidase inhibitor described above.
 本発明の脂質代謝改善作用又は抗肥満作用の発現促進剤は、上述した脂質代謝改善増強剤等と同様に医薬とすることができるほか、飲食品として用いることもできるものである。
 脂質代謝改善作用又は抗肥満作用の発現促進剤におけるα-グルコシダーゼ阻害剤と前記菌との好ましい組み合わせも、上述した脂質代謝改善剤と同様である。例えば、ビフィズス菌を含むボグリボース又はアカルボースによる脂質代謝改善作用又は抗肥満作用の発現促進剤、乳酸菌を含むアカルボースによる脂質代謝改善作用又は抗肥満作用の発現促進剤は、本発明の好ましい実施態様の1つである。
The expression promoter for lipid metabolism improving action or anti-obesity action of the present invention can be used as a drug as well as the above-described lipid metabolism improving enhancer, and can also be used as food and drink.
The preferred combination of the α-glucosidase inhibitor and the bacterium in the expression promoting agent for improving lipid metabolism or anti-obesity is the same as that for the lipid metabolism improving agent described above. For example, a lipid metabolism improving action or anti-obesity action promoting agent by voglibose or acarbose containing bifidobacteria, and a lipid metabolism improving action or anti-obesity action promoting agent by acarbose containing lactic acid bacteria are preferred embodiments of the present invention. One.
 本発明は、α-グルコシダーゼ阻害剤を、ビフィズス菌、乳酸菌、糖化菌及び酪酸菌からなる群より選ばれる少なくとも1種の菌と組み合わせて動物に投与する脂質代謝改善方法も包含する。
 本発明はまた、α-グルコシダーゼ阻害剤を、ビフィズス菌、乳酸菌、糖化菌及び酪酸菌からなる群より選ばれる少なくとも1種の菌と組み合わせて動物に投与する前記菌による脂質代謝改善作用を増強する方法も包含する。
 本発明はさらに、α-グルコシダーゼ阻害剤を、ビフィズス菌、乳酸菌、糖化菌及び酪酸菌からなる群より選ばれる少なくとも1種の菌と組み合わせて動物に投与する肥満の改善又は治療方法も包含する。
 本発明はさらに、α-グルコシダーゼ阻害剤を、ビフィズス菌、乳酸菌、糖化菌及び酪酸菌からなる群より選ばれる少なくとも1種の菌と組み合わせて動物に投与する前記菌による肥満の改善作用を増強する方法も包含する。
The present invention also includes a method for improving lipid metabolism, wherein an α-glucosidase inhibitor is administered to an animal in combination with at least one bacterium selected from the group consisting of bifidobacteria, lactic acid bacteria, saccharifying bacteria, and butyric acid bacteria.
The present invention also enhances the lipid metabolism-improving action of the above-mentioned bacteria administered to animals by combining an α-glucosidase inhibitor with at least one bacterium selected from the group consisting of bifidobacteria, lactic acid bacteria, saccharifying bacteria, and butyric acid bacteria. Methods are also encompassed.
The present invention further includes a method for improving or treating obesity, wherein an α-glucosidase inhibitor is administered to an animal in combination with at least one bacterium selected from the group consisting of bifidobacteria, lactic acid bacteria, saccharifying bacteria, and butyric acid bacteria.
The present invention further enhances the obesity-improving action of the above-mentioned bacteria administered to animals by combining an α-glucosidase inhibitor with at least one bacteria selected from the group consisting of bifidobacteria, lactic acid bacteria, saccharifying bacteria and butyric acid bacteria. Methods are also encompassed.
 本発明は、ビフィズス菌、乳酸菌、糖化菌及び酪酸菌からなる群より選ばれる少なくとも1種の菌を、α-グルコシダーゼ阻害剤と組み合わせて動物に投与するα-グルコシダーゼ阻害剤による脂質代謝改善作用を増強させる方法も包含する。
 本発明は、ビフィズス菌、乳酸菌、糖化菌及び酪酸菌からなる群より選ばれる少なくとも1種の菌を、α-グルコシダーゼ阻害剤と組み合わせて動物に投与するα-グルコシダーゼ阻害剤による肥満の改善作用を増強する方法も包含する。
 本発明は、ビフィズス菌、乳酸菌、糖化菌及び酪酸菌からなる群より選ばれる少なくとも1種の菌を、α-グルコシダーゼ阻害剤と組み合わせて動物に投与するα-グルコシダーゼ阻害剤による脂質代謝改善作用の発現又は抗肥満作用を促進する方法も包含する。
The present invention provides an effect of improving lipid metabolism by an α-glucosidase inhibitor administered to an animal in combination with an α-glucosidase inhibitor at least one bacterium selected from the group consisting of bifidobacteria, lactic acid bacteria, saccharifying bacteria and butyric acid bacteria. A method of enhancing is also included.
The present invention provides an obesity-improving action by an α-glucosidase inhibitor that is administered to an animal in combination with an α-glucosidase inhibitor at least one bacterium selected from the group consisting of bifidobacteria, lactic acid bacteria, saccharifying bacteria, and butyric acid bacteria. A method of enhancing is also included.
The present invention relates to an action of improving lipid metabolism by an α-glucosidase inhibitor administered to an animal in combination with an α-glucosidase inhibitor at least one bacterium selected from the group consisting of bifidobacteria, lactic acid bacteria, saccharifying bacteria and butyric acid bacteria Also included are methods of promoting expression or anti-obesity effects.
 本発明の方法における動物としては、上述した脂質異常症等の生活習慣病又はそのおそれのある個体(動物);肥満又は肥満予備軍の減量を必要とする個体;肥満を中心として高脂血症等を併発(メタボリックシンドローム)した個体又はそのおそれのある個体等が好適である。ビフィズス菌、乳酸菌、糖化菌及び酪酸菌からなる群より選ばれる少なくとも1種の菌、並びにα-グルコシダーゼ阻害剤の投与方法、投与量等は、上述した脂質代謝改善剤における投与方法等と同じである。 Examples of the animal in the method of the present invention include the above-mentioned lifestyle-related diseases such as dyslipidemia or individuals (animals) that may be there; obesity or individuals who need to reduce weight of the obesity reserve army; hyperlipidemia mainly in obesity It is preferable to use an individual having metabolic syndrome (metabolic syndrome) or an individual having such a possibility. The administration method, dosage, etc. of at least one bacterium selected from the group consisting of bifidobacteria, lactic acid bacteria, saccharification bacteria, and butyric acid bacteria, and the α-glucosidase inhibitor are the same as those in the lipid metabolism improving agent described above. is there.
 以下実施例を示してさらに詳しく説明を行うが、本発明はこれによりなんら制限されるものではない。本実施例中、「%」は、特に断らない限り「質量%」を意味する。 Hereinafter, the present invention will be described in more detail with reference to examples, but the present invention is not limited thereby. In this example, “%” means “% by mass” unless otherwise specified.
<実施例1>
(ビフィズス菌菌体乾燥物の調製及び該菌体乾燥物中の生菌数の測定)
1.菌(BBG9-1:Bifidobacterium bifidum G9-1)の調製方法
 BBG9-1の菌体乾燥物の調製は以下のように行った。すなわち、BBG9-1の凍結保存菌株(ビオフェルミン製薬社保存菌株)を37℃で24時間静置培養後、ビフィズス菌試験用液体培地(1)(日本薬局方外医薬品規格「ビフィズス菌」の項に記載)にこの培養菌液をビフィズス菌試験用液体培地(1)100に対して1の割合(容量比)で接種し、37℃で18時間静置培養した。得られた培養菌液を遠心分離し、水で3回洗浄後、適量の水を加え、湿菌体1kgに対し、グルタミン酸塩0.1kg及びデキストリン0.5kgの割合で加えて噴霧乾燥装置にて菌体乾燥物とした。なお、ビフィズス菌BBG9-1株は、医療用医薬品のビオフェルミン錠剤(商品名、ビオフェルミン製薬社製)等の成分として含まれており、該錠剤等から通常行われる方法で精製することによって入手可能である。
<Example 1>
(Preparation of dried Bifidobacterium cells and measurement of the number of viable cells in the dried cells)
1. Preparation Method of Bacteria (BBG9-1: Bifidobacterium bifidum G9-1) BBG9-1 was prepared as follows. That is, after the BBG9-1 cryopreserved strain (Biofermin Pharmaceutical Co., Ltd.) was allowed to stand at 37 ° C. for 24 hours, the Bifidobacterium test liquid medium (1) (in Japanese Pharmacopoeia Pharmaceutical Standards “Bifidobacterium” This culture was inoculated at a ratio (volume ratio) of 1 with respect to the liquid medium for bifidobacterial test (1) 100, followed by stationary culture at 37 ° C. for 18 hours. The obtained culture solution is centrifuged, washed three times with water, an appropriate amount of water is added, and 0.1 kg of glutamate and 0.5 kg of dextrin are added to 1 kg of wet cells, and the mixture is added to the spray drying apparatus. The cells were dried. The Bifidobacterium BBG9-1 strain is contained as a component of a biopharmaceutical drug Biofermin tablet (trade name, manufactured by Biofermin Pharmaceutical Co., Ltd.), and can be obtained by purification from the tablet or the like by a usual method. is there.
 上記ビフィズス菌試験用液体培地(1)は、日本薬局方外医薬品規格「ビフィズス菌」の項に記載された方法に従い、下記成分を混合し、高圧蒸気滅菌器を用いて121℃で10分間加熱して滅菌して調製した。
  牛肉・肝臓浸出液     1000mL
  カゼイン製ペプトン      10g
  ブドウ糖           10g
  ポリソルベート80       1g
  L-シスチン        0.5g
(あらかじめ2mLの希塩酸に溶かして添加した。)
  pH 7.0~7.2
The liquid medium (1) for testing the Bifidobacterium is mixed with the following components according to the method described in the Japanese Pharmacopoeia Pharmaceutical Standards “Bifidobacterium”, and heated at 121 ° C. for 10 minutes using a high-pressure steam sterilizer. And prepared by sterilization.
1000mL of beef / liver exudate
Casein peptone 10g
Glucose 10g
Polysorbate 80 1g
L-cystine 0.5g
(Previously dissolved in 2 mL of dilute hydrochloric acid and added.)
pH 7.0-7.2
2.菌体乾燥物中の生菌数の測定
 日本薬局方外医薬品規格「ビフィズス菌」の項に記載されているビフィズス菌の定量法に準じて測定した。すなわち、菌体乾燥物5gを精密に量り、希釈液(2)30mL中に加え、強く振り混ぜ、更に同希釈液を加えて正確に50mLとし、よく振り混ぜ、この菌液1mLを正確に量り、別に正確に分注した同希釈液9mL中に加える操作(10倍希釈法)を繰り返し、1mL中の生菌数が20~200個となるよう希釈した。この液1mLをペトリ皿にとり、ここに50℃に保ったビフィズス菌試験用カンテン培地を20mL加えてすばやく混和し、固化させた。これを37℃で48~72時間嫌気培養し、出現したコロニー数及び希釈倍率から菌体乾燥物中の生菌数を求めた。これにより求めた上記1.で得られた菌体乾燥物の菌数は、生菌数3.4×1011CFU/gであった。
2. Measurement of the number of viable bacteria in the dried microbial cell body The measurement was performed according to the method for quantifying bifidobacteria described in the section of the Japanese Pharmacopoeia Pharmaceutical Standards “Bifidobacteria”. That is, weigh accurately 5 g of the dried bacterial cell product, add it to 30 mL of diluent (2), shake vigorously, add the same diluent to make exactly 50 mL, shake well, and accurately measure 1 mL of this bacterial solution. Then, the operation (10-fold dilution method) of adding to 9 mL of the same diluted solution accurately dispensed was repeated, and diluted so that the number of viable bacteria in 1 mL was 20 to 200. 1 mL of this solution was placed in a Petri dish, and 20 mL of an agar medium for bifidobacteria test maintained at 50 ° C. was added thereto and quickly mixed to solidify. This was anaerobically cultured at 37 ° C. for 48 to 72 hours, and the number of viable cells in the dried microbial cell was determined from the number of colonies that appeared and the dilution rate. The above-described 1. The cell count of the dried microbial cell product obtained in (1) was 3.4 × 10 11 CFU / g viable count.
 実施例中で用いた希釈液(2)の調製方法を、以下に示す。
希釈液(2)の調製方法
 日本薬局方外医薬品規格「ビフィズス菌」の項に記載された方法に従い、下記の成分を混合し、高圧蒸気滅菌器を用いて121℃で15分間加熱して滅菌して調製した。
  無水リン酸一水素ナトリウム  6.0g
  リン酸二水素カリウム     4.5g
  ポリソルベート80      0.5g
  L-塩酸システイン      0.5g
  カンテン           1.0g
  精製水           1000mL
  pH 6.8~7.0
The preparation method of the diluent (2) used in the examples is shown below.
Preparation of Diluent (2) According to the method described in the Japanese Pharmacopoeia Pharmaceutical Standards “Bifidobacteria”, the following components are mixed and sterilized by heating at 121 ° C. for 15 minutes using a high-pressure steam sterilizer Prepared.
Anhydrous sodium monohydrogen phosphate 6.0 g
4.5g potassium dihydrogen phosphate
Polysorbate 80 0.5g
L-cysteine hydrochloride 0.5g
Kang 1.0g
Purified water 1000mL
pH 6.8-7.0
 上記ビフィズス菌試験用カンテン培地の調製方法を、以下に示す。
 日本薬局方外医薬品規格「ビフィズス菌」の項に記載された方法に従い、下記成分を混合し、高圧蒸気滅菌器を用いて121℃で15分間加熱して滅菌した後、使用した。
  豚肝臓浸出液     1000mL
  カゼイン製ペプトン    20g
  乳糖           20g
  ブドウ糖         10g
  塩化ナトリウム       5g
  リン酸二水素カリウム    4g
  L-グルタミン酸ナトリウム 2g
  L-シスチン 2g(あらかじめ10%の水酸化ナトリウム溶液に溶かして添加した)
  カンテン  15g
  pH 6.7~6.9
A method for preparing the agar medium for testing the Bifidobacterium is shown below.
The following components were mixed according to the method described in the Japanese Pharmacopoeia drug standard “Bifidobacteria”, sterilized by heating at 121 ° C. for 15 minutes using a high-pressure steam sterilizer, and then used.
Pig liver leachate 1000mL
Casein peptone 20g
Lactose 20g
Glucose 10g
Sodium chloride 5g
4g potassium dihydrogen phosphate
Sodium L-glutamate 2g
2 g of L-cystine (preliminarily dissolved in 10% sodium hydroxide solution)
Kanten 15g
pH 6.7 to 6.9
<実施例2>
(ビフィズス菌及びα-グルコシダーゼ阻害剤併用による脂質低下及び抗肥満増強作用)
 乳酸菌として実施例1の方法によって得たBBG9-1の乾燥菌体を、α-グルコシダーゼ阻害剤としてボグリボースを、それぞれ用いた。ボグリボースとしては、ベイスン(登録商標)錠0.2(武田薬品工業社製)を粉砕したものを用いた。
<Example 2>
(Lipid lowering and anti-obesity enhancing action by combined use of bifidobacteria and α-glucosidase inhibitor)
BBG9-1 dried cells obtained by the method of Example 1 were used as lactic acid bacteria, and voglibose was used as an α-glucosidase inhibitor. As voglibose, pulverized Basin (registered trademark) 0.2 (manufactured by Takeda Pharmaceutical Company Limited) was used.
 雌性KK-Aマウス(系統名KK-A/TaJcl)を8週齢で購入後(日本クレア社より購入)、個別ケージにて2週間の予備飼育を行った。KK-Aマウスは、糖尿病のモデルマウスである。予備飼育期間中は市販の粉末飼料(CE-2:日本クレア社製)及び上水道水を自由摂取させた。実験開始日には経口糖負荷試験(OGTT)を実施した。すなわち、OGTT実施の前日より絶食とし、実施当日グルコース溶液(2g/5mL/kg)を経口投与した。負荷前ならびに負荷後15、30、60及び120分後に尾静脈から血液を漏出させ、漏出血液中のグルコース濃度を市販の自己検査用グルコース測定器(商品名:アキュチェックアビバ、ロシュ・ダイアグノスティックス社製)を用いて測定した。このときの血糖値の曲線下面積(AUC)を算出し、これを指標にして以下のA~Dの4群(8匹/群)に群分けし、各試験飼料を自由摂取させた。 Female KK-A y mice (strain name KK-A y / TaJcl) were purchased at 8 weeks of age (purchased from Clea Japan) and then preliminarily reared for 2 weeks in individual cages. The KK-A y mouse is a model mouse for diabetes. During the preliminary breeding period, commercially available powdered feed (CE-2: manufactured by CLEA Japan, Inc.) and tap water were freely ingested. An oral glucose tolerance test (OGTT) was performed on the day of the experiment. That is, fasting was performed from the day before OGTT was performed, and a glucose solution (2 g / 5 mL / kg) was orally administered on the day of implementation. Blood was leaked from the tail vein before loading and 15, 30, 60 and 120 minutes after loading, and the glucose concentration in the leaked blood was measured using a commercially available glucose measuring instrument (trade name: Accucheck Aviva, Roche Diagnostics) The measurement was performed using The area under the curve (AUC) of the blood glucose level at this time was calculated, and this was used as an index to divide into the following 4 groups A to D (8 animals / group), and each test feed was freely ingested.
A群:デキストリンを10%の割合で混合したCE-2を混餌投与するグループ。
B群:実施例1の方法によって得たBBG9-1の乾燥菌体(3.4×1011/g)を10%の割合で混合したCE-2を混餌投与するグループ。
C群:ボグリボースを0.0003%、デキストリンを10%の割合で混合したCE-2を混餌投与するグループ。
D群:実施例1の方法によって得たBBG9-1の乾燥菌体(3.4×1011/g)を10%、ボグリボースを0.0003%の割合で混合したCE-2を混餌投与するグループ。
Group A: a group to which CE-2 mixed with 10% dextrin is administered as a diet.
Group B: a group to which CE-2 mixed with 10% of dry BBG9-1 cells (3.4 × 10 11 / g) obtained by the method of Example 1 was fed.
Group C: a group to which CE-2 mixed with 0.0003% voglibose and 10% dextrin is administered as a diet.
Group D: CE-2 mixed with 10% dry BBG9-1 cells obtained by the method of Example 1 (3.4 × 10 11 / g) and voglibose at a ratio of 0.0003% is fed as a diet. group.
 各群について7週間、上記飼料を摂取させたときの体重推移を測定した。さらに、試験終了時に全採血を行い、得られた血漿中の中性脂肪値を測定した。A群に対する各群の有意差はDunnett検定を、2群間の有意差はt検定を用いて評価した。 For each group, the body weight change was measured when the feed was ingested for 7 weeks. Furthermore, whole blood was collected at the end of the test, and the neutral plasma level of the obtained plasma was measured. The significant difference between each group relative to the A group was evaluated using Dunnett test, and the significant difference between the two groups was evaluated using t test.
(結果)
 A~D群のマウスに、各試験飼料を7週間摂餌させたときの体重推移を図1に示した。図2に、試験終了時に測定した血漿中性脂肪値(mg/dL)を示す。図1から明らかなように、BBG9-1単独(B群)及びボグリボース単独(C群)では、いずれも体重の増加抑制が認められなかったが、BBG9-1及びボグリボースの併用は体重の増加を有意に抑制した(D群)。図2から明らかなように、BBG9-1単独(B群)及びボグリボース単独(C群)では、いずれも血漿中の中性脂肪値の上昇を抑制しなかったが、BBG9-1及びボグリボースの併用は中性脂肪値の上昇を有意に抑制した(D群)。
(result)
FIG. 1 shows the change in body weight when mice in groups A to D were fed each test diet for 7 weeks. FIG. 2 shows the plasma triglyceride value (mg / dL) measured at the end of the test. As is clear from FIG. 1, neither BBG9-1 alone (group B) nor voglibose alone (group C) was found to suppress body weight gain, but the combination of BBG9-1 and voglibose increased body weight. Significantly suppressed (Group D). As is clear from FIG. 2, neither BBG9-1 alone (group B) nor voglibose alone (group C) suppressed the increase in plasma triglycerides, but BBG9-1 and voglibose were used in combination. Significantly suppressed the increase in triglyceride level (Group D).
 図1及び2について詳細に説明する。
 図1中の各点は、8個体の平均±標準誤差(SE)を表す。折れ線グラフにおいて、白丸はデキストリンを10%の割合で混合したCE-2を混餌投与したマウスである(A群)。白四角は実施例1の方法によって得たBBG9-1の乾燥菌体(3.4×1011/g)を10%の割合で混合したCE-2を混餌投与したマウスである(B群)。白三角はボグリボースを0.0003%、及びデキストリンを10%の割合で混合したCE-2を混餌投与したマウスである(C群)。黒四角は実施例1の方法によって得たBBG9-1の乾燥菌体(3.4×1011/g)を10%、及びボグリボースを0.0003%の割合で混合したCE-2を混餌投与したマウスである(D群)。*、#及び$はそれぞれ、デキストリンを10%の割合で混合したCE-2を混餌投与したマウス(A群)からの有意差(*:p<0.01、**:p<0.01、***:p<0.001)、実施例1の方法によって得たBBG9-1の乾燥菌体(3.4×1011/g)を10%の割合で混合したCE-2を混餌投与したマウス(B群)からの有意差(#:p<0.05、##:p<0.01)及びボグリボースを0.0003%、デキストリンを10%の割合で混合したCE-2を混餌投与したマウス(C群)からの有意差($:p<0.05、$$:p<0.01)を表す。
1 and 2 will be described in detail.
Each point in FIG. 1 represents the mean ± standard error (SE) of 8 individuals. In the line graph, open circles are mice administered with a diet containing CE-2 mixed with 10% dextrin (Group A). Open squares are mice fed with CE-2 mixed with 10% of dry BBG9-1 cells (3.4 × 10 11 / g) obtained by the method of Example 1 (Group B). . White triangles represent mice fed with CE-2 mixed with 0.003% voglibose and 10% dextrin (Group C). The black square is fed with 10% dry BBG9-1 cells (3.4 × 10 11 / g) obtained by the method of Example 1 and CE-2 mixed with voglibose at a rate of 0.0003%. Mice (Group D). *, #, And $ are significant differences (*: p <0.01, **: p <0.01) from mice (group A) fed with CE-2 mixed with dextrin at a ratio of 10%, respectively. ***, p <0.001), mixed with CE-2 mixed with 10% of dry BBG9-1 cells (3.4 × 10 11 / g) obtained by the method of Example 1 Significant difference (#: p <0.05, ##: p <0.01) and CE-2 mixed with voglibose 0.0003% and dextrin 10% from the administered mice (group B) The significant difference ($: p <0.05, $$: p <0.01) from the mouse | mouth (Group C) administered with diet is represented.
 図2中の棒グラフの値は、8個体の平均±標準誤差(SE)を表す。棒グラフにおいて、白はデキストリンを10%の割合で混合したCE-2を混餌投与したマウスである(A群)。灰色は実施例1の方法によって得たBBG9-1の乾燥菌体(3.4×1011/g)を10%の割合で混合したCE-2を混餌投与したマウスである(B群)。斜線はボグリボースを0.0003%、及びデキストリンを10%の割合で混合したCE-2を混餌投与したマウスである(C群)。黒は実施例1の方法によって得たBBG9-1の乾燥菌体(3.4×1011/g)を10%、及びボグリボースを0.0003%の割合で混合したCE-2を混餌投与したマウスである(D群)。*及び$はそれぞれ、デキストリンを10%の割合で混合したCE-2を混餌投与したマウス(A群)からの有意差(**:p<0.01)、及びボグリボースを0.0003%、デキストリンを10%の割合で混合したCE-2を混餌投与したマウス(C群)からの有意差($:p<0.05)を表す。 The values in the bar graph in FIG. 2 represent the mean ± standard error (SE) of 8 individuals. In the bar graph, white is a mouse fed with CE-2 mixed with dextrin at a ratio of 10% (Group A). Gray is a mouse fed with CE-2 mixed with 10% of dry BBG9-1 cells (3.4 × 10 11 / g) obtained by the method of Example 1 (Group B). The slanted lines are mice fed with CE-2 mixed with voglibose 0.0003% and dextrin 10% (group C). Black was fed with CE-2 mixed with 10% dry BBG9-1 cells obtained by the method of Example 1 (3.4 × 10 11 / g) and voglibose at a ratio of 0.0003%. Mice (Group D). * And $ are significant differences (**: p <0.01) from mice fed with CE-2 mixed with dextrin at a rate of 10% (Group A), and voglibose 0.0003%, A significant difference ($: p <0.05) from a mouse (Group C) fed with CE-2 mixed with dextrin at a ratio of 10% is shown.
<実施例3>
(ビフィズス菌及びα-グルコシダーゼ阻害剤併用による脂質低下及び抗肥満増強作用)
 乳酸菌として実施例1の方法によって得たBBG9-1の乾燥菌体を、α-グルコシダーゼ阻害剤としてアカルボースを、それぞれ用いた。アカルボースとしては、グルコバイ(登録商標)錠100mg(バイエル薬品製)を粉砕したものを用いた。
<Example 3>
(Lipid lowering and anti-obesity enhancing action by combined use of bifidobacteria and α-glucosidase inhibitor)
BBG9-1 dry cells obtained by the method of Example 1 were used as lactic acid bacteria, and acarbose was used as an α-glucosidase inhibitor. As acarbose, pulverized glucobay (registered trademark) 100 mg (manufactured by Bayer Yakuhin) was used.
 雌性KK-Aマウス(系統名KK-A/TaJcl)を8週齢で購入後(日本クレア社より購入)、個別ケージにて2週間の予備飼育を行った。KK-Aマウスは、糖尿病のモデルマウスである。予備飼育期間中は市販の粉末飼料(CE-2:日本クレア社製)及び上水道水を自由摂取させた。実験開始日には経口糖負荷試験(OGTT)を実施した。すなわち、OGTT実施の前日より絶食とし、実施当日グルコース溶液(2g/5mL/kg)を経口投与した。負荷前ならびに負荷後15、30、60及び120分後に尾静脈から血液を漏出させ、漏出血液中のグルコース濃度を市販の自己検査用グルコース測定器(商品名:アキュチェックアビバ、ロシュ・ダイアグノスティックス社製)を用いて測定した。このときの血糖値の曲線下面積(AUC)を算出し、これを指標にして以下のE~Hの4群(9匹/群)に群分けし、各試験飼料を自由摂取させた。 Female KK-A y mice (strain name KK-A y / TaJcl) were purchased at 8 weeks of age (purchased from Clea Japan) and then preliminarily reared for 2 weeks in individual cages. The KK-A y mouse is a model mouse for diabetes. During the preliminary breeding period, commercially available powdered feed (CE-2: manufactured by CLEA Japan, Inc.) and tap water were freely ingested. An oral glucose tolerance test (OGTT) was performed on the day of the experiment. That is, fasting was performed from the day before OGTT was performed, and a glucose solution (2 g / 5 mL / kg) was orally administered on the day of implementation. Blood was leaked from the tail vein before loading and 15, 30, 60 and 120 minutes after loading, and the glucose concentration in the leaked blood was measured using a commercially available glucose measuring instrument (trade name: Accucheck Aviva, Roche Diagnostics) The measurement was performed using The area under the curve (AUC) of the blood glucose level at this time was calculated and divided into the following 4 groups (9 animals / group) of E to H using this as an index, and each test feed was freely ingested.
E群:デキストリンを10%の割合で混合したCE-2を混餌投与するグループ。
F群:実施例1の方法によって得たBBG9-1の乾燥菌体(3.4×1011/g)を10%の割合で混合したCE-2を混餌投与するグループ。
G群:アカルボースを0.1%、デキストリンを10%の割合で混合したCE-2を混餌投与するグループ。
H群:実施例1の方法によって得たBBG9-1の乾燥菌体(3.4×1011/g)を10%、アカルボースを0.1%の割合で混合したCE-2を混餌投与するグループ。
Group E: a group to which CE-2 mixed with 10% dextrin is administered as a diet.
Group F: A group to which CE-2 mixed with 10% of dry BBG9-1 cells (3.4 × 10 11 / g) obtained by the method of Example 1 was fed.
Group G: Group administered with CE-2 mixed with 0.1% acarbose and 10% dextrin.
Group H: Feeding CE-2 mixed with 10% dry BBG9-1 cells (3.4 × 10 11 / g) obtained by the method of Example 1 and 0.1% acarbose group.
 各群について7週間、上記飼料を摂取させたときの体重推移を測定した。さらに、試験終了時に全採血を行い、得られた血漿中の総コレステロール値及び中性脂肪値を測定した。また子宮周囲脂肪を摘出し、体重あたりの相対重量を比較した。E群に対する各群の有意差はDunnett検定を、2群間の有意差はt検定を用いて評価した。 For each group, the body weight change was measured when the feed was ingested for 7 weeks. Furthermore, whole blood was collected at the end of the test, and the total cholesterol level and neutral fat level in the obtained plasma were measured. Periuterine fat was removed and the relative weight per body weight was compared. The significant difference between each group with respect to the E group was evaluated using Dunnett test, and the significant difference between the two groups was evaluated using t test.
(結果)
 E~H群のマウスに、各試験飼料を7週間摂餌させたときの体重推移を図3に示した。図4及び図5に、試験終了時に測定した血漿中の総コレステロール値(mg/dL)及び血漿中の中性脂肪値(mg/dL)をそれぞれ示す。図6に、試験終了時の体重に対する子宮周囲脂肪の相対重量(体脂肪率(%))を示す。図3から明らかなように、BBG9-1単独(F群)及びアカルボース単独(G群)では、いずれも体重の増加抑制が認められなかったが、BBG9-1及びアカルボースの併用は体重の増加を有意に抑制した(H群)。図4から明らかなように、BBG9-1単独では総コレステロール値の上昇を抑制せず(F群)、アカルボース単独では有意に抑制したが(G群)、BBG9-1及びボグリボースの併用は総コレステロール値の上昇を相乗的に有意に抑制した(H群)。図5から明らかなように、BBG9-1単独(F群)及びアカルボース単独(G群)では、いずれも中性脂肪値の上昇を抑制しなかったが、BBG9-1及びアカルボースの併用は中性脂肪値の上昇を抑制する傾向を示した(H群)。図6から明らかなように、BBG9-1単独(F群)及びアカルボース単独(G群)では、いずれも子宮周囲脂肪の相対重量の上昇を抑制しなかったが、BBG9-1及びアカルボースの併用は子宮周囲脂肪の相対重量の上昇を有意に抑制した(H群)。このように、BBG9-1とα-グルコシダーゼ阻害剤とを組み合わせて投与することにより体重増加が有意に抑制されたが、これは内臓脂肪の減少を伴うものであることが示された。
(result)
FIG. 3 shows the changes in body weight when the mice in groups E to H were fed each test diet for 7 weeks. 4 and 5 show the total cholesterol level (mg / dL) in plasma and the neutral fat level (mg / dL) in plasma measured at the end of the test, respectively. FIG. 6 shows the relative weight of periuterine fat (body fat percentage (%)) relative to the body weight at the end of the test. As is clear from FIG. 3, BBG9-1 alone (Group F) and acarbose alone (Group G) did not suppress body weight gain, but the combination of BBG9-1 and acarbose increased body weight. Significantly suppressed (H group). As is clear from FIG. 4, BBG9-1 alone did not suppress the increase in total cholesterol level (Group F), but acarbose alone significantly suppressed (Group G), but the combined use of BBG9-1 and voglibose was not effective in total cholesterol. The increase in value was synergistically significantly suppressed (Group H). As is clear from FIG. 5, neither BBG9-1 alone (F group) nor acarbose alone (G group) suppressed the increase in triglyceride, but the combined use of BBG9-1 and acarbose was neutral. The tendency which suppressed the raise of a fat value was shown (H group). As is clear from FIG. 6, neither BBG9-1 alone (Group F) nor acarbose alone (Group G) suppressed the increase in the relative weight of periuterine fat, but the combined use of BBG9-1 and acarbose was The increase in the relative weight of peritoneal fat was significantly suppressed (Group H). As described above, administration of BBG9-1 and an α-glucosidase inhibitor in combination suppressed the increase in body weight significantly, which was shown to be accompanied by a decrease in visceral fat.
 図3~6について詳細に示す。
 図3中の各点は、9個体の平均±標準誤差(SE)を表す。折れ線グラフにおいて、白丸はデキストリンを10%の割合で混合したCE-2を混餌投与したマウスである(E群)。白四角は実施例1の方法によって得たBBG9-1の乾燥菌体(3.4×1011/g)を10%の割合で混合したCE-2を混餌投与したマウスである(F群)。白三角はアカルボースを0.1%、及びデキストリンを10%の割合で混合したCE-2を混餌投与したマウスである(G群)。黒四角は実施例1の方法によって得たBBG9-1の乾燥菌体(3.4×1011/g)を10%、及びアカルボースを0.1%の割合で混合したCE-2を混餌投与したマウスである(H群)。*、#及び$はそれぞれ、デキストリンを10%の割合で混合したCE-2を混餌投与したマウス(E群)からの有意差(*:p<0.01、**:p<0.01、***:p<0.001)、実施例1の方法によって得たBBG9-1の乾燥菌体(3.4×1011/g)を10%の割合で混合したCE-2を混餌投与したマウス(F群)からの有意差(#:p<0.05、##:p<0.01)及びアカルボースを0.1%、デキストリンを10%の割合で混合したCE-2を混餌投与したマウス(G群)からの有意差($:p<0.05)を表す。
3 to 6 will be described in detail.
Each point in FIG. 3 represents the mean ± standard error (SE) of 9 individuals. In the line graph, open circles are mice administered with CE-2 mixed with 10% dextrin (Group E). Open squares are mice fed with CE-2 mixed with 10% of dry BBG9-1 cells (3.4 × 10 11 / g) obtained by the method of Example 1 (Group F). . White triangles represent mice administered with dietary CE-2 mixed with 0.1% acarbose and 10% dextrin (group G). The black square is fed with CE-2 mixed with 10% dry BBG9-1 cells (3.4 × 10 11 / g) obtained by the method of Example 1 and 0.1% acarbose. Mice (Group H). *, # And $ are significant differences (*: p <0.01, **: p <0.01) from mice (group E) fed with CE-2 mixed with 10% dextrin. ***, p <0.001), mixed with CE-2 mixed with 10% of dry BBG9-1 cells (3.4 × 10 11 / g) obtained by the method of Example 1 Significant difference (#: p <0.05, ##: p <0.01) from the administered mice (F group) and CE-2 mixed with 0.1% acarbose and 10% dextrin The significant difference ($: p <0.05) from the mouse | mouth (Group G) administered with diet is represented.
 図4中の棒グラフの値は、9個体の平均±標準誤差(SE)を表す。棒グラフにおいて、白はデキストリンを10%の割合で混合したCE-2を混餌投与したマウスである(E群)。灰色は実施例1の方法によって得たBBG9-1の乾燥菌体(3.4×1011/g)を10%の割合で混合したCE-2を混餌投与したマウスである(F群)。斜線はアカルボースを0.1%、及びデキストリンを10%の割合で混合したCE-2を混餌投与したマウスである(G群)。黒は実施例1の方法によって得たBBG9-1の乾燥菌体(3.4×1011/g)を10%、及びアカルボースを0.1%の割合で混合したCE-2を混餌投与したマウスである(H群)。*、#及び$はそれぞれ、デキストリンを10%の割合で混合したCE-2を混餌投与したマウス(E群)からの有意差(***:p<0.001)、実施例1の方法によって得たBBG9-1の乾燥菌体(3.4×1011/g)を10%の割合で混合したCE-2を混餌投与したマウス(F群)からの有意差(###:p<0.001)及びアカルボースを0.1%、デキストリンを10%の割合で混合したCE-2を混餌投与したマウス(G群)からの有意差($:p<0.05)を表す。 The values in the bar graph in FIG. 4 represent the mean ± standard error (SE) of 9 individuals. In the bar graph, white is a mouse fed with CE-2 mixed with dextrin at a ratio of 10% (Group E). Gray is a mouse fed with CE-2 mixed with 10% of dry BBG9-1 cells (3.4 × 10 11 / g) obtained by the method of Example 1 (Group F). The hatched lines are mice administered with CE-2 mixed with 0.1% acarbose and 10% dextrin (Group G). Black is fed with CE-2 mixed with 10% dry BBG9-1 cells (3.4 × 10 11 / g) obtained by the method of Example 1 and 0.1% acarbose. Mice (Group H). *, # And $ are significant differences (***: p <0.001) from mice (group E) fed with CE-2 mixed with 10% dextrin, respectively, the method of Example 1 Significant difference (###: p) from mice (group F) fed with CE-2 mixed with 10% of dry BBG9-1 cells (3.4 × 10 11 / g) obtained by <0.001) and a significant difference ($: p <0.05) from mice (Group G) fed with CE-2 mixed with 0.1% acarbose and 10% dextrin.
 図5中の棒グラフの値は、9個体の平均±標準誤差(SE)を表す。棒グラフにおいて、白はデキストリンを10%の割合で混合したCE-2を混餌投与したマウスである(E群)。灰色は実施例1の方法によって得たBBG9-1の乾燥菌体(3.4×1011/g)を10%の割合で混合したCE-2を混餌投与したマウスである(F群)。斜線はアカルボースを0.1%、及びデキストリンを10%の割合で混合したCE-2を混餌投与したマウスである(G群)。黒は実施例1の方法によって得たBBG9-1の乾燥菌体(3.4×1011/g)を10%、及びアカルボースを0.1%の割合で混合したCE-2を混餌投与したマウスである(H群)。 The values in the bar graph in FIG. 5 represent the mean ± standard error (SE) of 9 individuals. In the bar graph, white is a mouse fed with CE-2 mixed with dextrin at a ratio of 10% (Group E). Gray is a mouse fed with CE-2 mixed with 10% of dry BBG9-1 cells (3.4 × 10 11 / g) obtained by the method of Example 1 (Group F). The hatched lines are mice administered with CE-2 mixed with 0.1% acarbose and 10% dextrin (Group G). Black is fed with CE-2 mixed with 10% dry BBG9-1 cells (3.4 × 10 11 / g) obtained by the method of Example 1 and 0.1% acarbose. Mice (Group H).
 図6中の棒グラフの値は、9個体の平均±標準誤差(SE)を表す。棒グラフにおいて、白はデキストリンを10%の割合で混合したCE-2を混餌投与したマウスである(E群)。灰色は実施例1の方法によって得たBBG9-1の乾燥菌体(3.4×1011/g)を10%の割合で混合したCE-2を混餌投与したマウスである(F群)。斜線はアカルボースを0.1%、及びデキストリンを10%の割合で混合したCE-2を混餌投与したマウスである(G群)。黒は実施例1の方法によって得たBBG9-1の乾燥菌体(3.4×1011/g)を10%、及びアカルボースを0.1%の割合で混合したCE-2を混餌投与したマウスである(H群)。*、#及び$はそれぞれ、デキストリンを10%の割合で混合したCE-2を混餌投与したマウス(E群)からの有意差(***:p<0.001)、実施例1の方法によって得たBBG9-1の乾燥菌体(3.4×1011/g)を10%の割合で混合したCE-2を混餌投与したマウス(F群)からの有意差(###:p<0.001)及びアカルボースを0.1%、デキストリンを10%の割合で混合したCE-2を混餌投与したマウス(G群)からの有意差($:p<0.05)を表す。
 なお、実施例2~3においてBBG9-1以外のビフィズス菌、乳酸菌、糖化菌又は酪酸菌を用いても、上記と同様の結果が得られる。また、ボグリボース及びアカルボース以外のα-グルコシダーゼ阻害剤を用いても、上記と同様の結果が得られる。
The values in the bar graph in FIG. 6 represent the mean ± standard error (SE) of 9 individuals. In the bar graph, white is a mouse fed with CE-2 mixed with dextrin at a ratio of 10% (Group E). Gray is a mouse fed with CE-2 mixed with 10% of dry BBG9-1 cells (3.4 × 10 11 / g) obtained by the method of Example 1 (Group F). The hatched lines are mice administered with CE-2 mixed with 0.1% acarbose and 10% dextrin (Group G). Black is fed with CE-2 mixed with 10% dry BBG9-1 cells (3.4 × 10 11 / g) obtained by the method of Example 1 and 0.1% acarbose. Mice (Group H). *, # And $ are significant differences (***: p <0.001) from mice (group E) fed with CE-2 mixed with 10% dextrin, respectively, the method of Example 1 Significant difference (###: p) from mice (group F) fed with CE-2 mixed with 10% of dry BBG9-1 cells (3.4 × 10 11 / g) obtained by <0.001) and a significant difference ($: p <0.05) from mice (Group G) fed with CE-2 mixed with 0.1% acarbose and 10% dextrin.
In Examples 2 to 3, the same results as above can be obtained by using bifidobacteria, lactic acid bacteria, saccharifying bacteria or butyric acid bacteria other than BBG9-1. In addition, the same results as above can be obtained by using an α-glucosidase inhibitor other than voglibose and acarbose.
 <実施例4>
(乳酸菌菌体乾燥物の調製及び該菌体乾燥物中の生菌数の測定)
1.菌(3B:Streptococcus faecalis 129 BIO 3B)の調製方法
 3Bの菌体乾燥物の調製は以下のように行った。すなわち、3Bの凍結保存菌株(ビオフェルミン製薬社保存菌株)を37℃で24時間静置培養後、ラクトミン試験用液体培地(2)(日本薬局方外医薬品規格「ラクトミン」の項に記載)にこの培養菌液をラクトミン試験用液体培地(2)100に対して1の割合(容量比)で接種し、37℃で18時間静置培養した。得られた培養菌液を遠心分離し、水で3回洗浄後、適量の水を加え、湿菌体1kgに対し、グルタミン酸塩0.1kg及びデキストリン0.5kgの割合で加えて噴霧乾燥装置にて菌体乾燥物とした。なお、3B株は、医療用医薬品のビオフェルミン(商品名、ビオフェルミン製薬社製)等の成分として含まれており、該錠剤等から通常行われる方法で精製することによって入手可能である。
<Example 4>
(Preparation of dried lactic acid bacteria and measurement of the number of viable bacteria in the dried bacteria)
1. Preparation Method of Bacteria (3B: Streptococcus faecalis 129 BIO 3B) The dry cell product of 3B was prepared as follows. That is, after the 3B cryopreserved strain (Biofermin Pharmaceutical Co., Ltd.) was allowed to stand at 37 ° C. for 24 hours, this was added to the liquid medium for lactamine test (2) (described in the Japanese Pharmacopoeia Pharmaceutical Standards “Lactamine” section). The cultured bacterial solution was inoculated at a ratio (volume ratio) of 1 with respect to the liquid medium for lactamine test (2) 100, followed by stationary culture at 37 ° C. for 18 hours. The obtained culture solution is centrifuged, washed three times with water, an appropriate amount of water is added, and 0.1 kg of glutamate and 0.5 kg of dextrin are added to 1 kg of wet cells, and the mixture is added to the spray drying apparatus. The cells were dried. In addition, 3B stock | strain is contained as components, such as biopharmaceuticals of biopharmaceuticals (brand name, Biofermin Pharmaceutical Co., Ltd.), and can be obtained by refine | purifying with the method performed normally from this tablet.
 上記ラクトミン試験用液体培地(2)は、日本薬局方外医薬品規格「ラクトミン」の項に記載された方法に従い、下記の成分を混合し、高圧蒸気滅菌器を用いて121℃で15分間加熱して滅菌して調製した。
  酵母エキス           5g
  カゼイン製ペプトン      20g
  ブドウ糖           20g
  肉エキス           15g
  トマトジュース      200mL
  ポリソルベート80       3g
  L-塩酸システイン       1g
  精製水          800mL
  pH 6.8±0.1
 トマトジュースは、トマトジュースに等量の精製水を加え、時々かき混ぜながら煮沸した後、pHを6.8に調整し、ろ過したものを使用した。
The above-mentioned liquid medium for lactamine test (2) is mixed with the following components according to the method described in the section of the Japanese Pharmacopoeia Standard “Lactamine”, and heated at 121 ° C. for 15 minutes using a high-pressure steam sterilizer. And prepared by sterilization.
Yeast extract 5g
Casein peptone 20g
Glucose 20g
Meat extract 15g
Tomato juice * 200mL
Polysorbate 80 3g
L-cysteine hydrochloride 1g
800 mL of purified water
pH 6.8 ± 0.1
Tomato juice * was prepared by adding an equal amount of purified water to tomato juice, boiled with occasional stirring, adjusted to pH 6.8, and filtered.
2.菌体乾燥物中の生菌数の測定
 日本薬局方外医薬品規格「ラクトミン」の項に記載されているラクトミンの定量法に準じて測定した。すなわち、菌体乾燥物5gを精密に量り、希釈液(2)30mL中に加え、強く振り混ぜ、更に同希釈液を加えて正確に50mLとし、よく振り混ぜ、この菌液1mLを正確に量り、別に正確に分注した同希釈液9mL中に加える操作(10倍希釈法)を繰り返し、1mL中の生菌数が20~200個となるよう希釈した。この液1mLをペトリ皿にとり、ここに50℃に保ったラクトミン試験用カンテン培地(2)を20mL加えてすばやく混和し、固化させた。これを37℃で24~48時間好気培養し、出現したコロニー数及び希釈倍率から菌体乾燥物中の生菌数を求めた。これにより求めた上記1.で得られた菌体乾燥物の菌数は、生菌数7.0×1011CFU/gであった。
2. Measurement of the number of viable bacteria in the dried microbial cell body The measurement was performed according to the lactamine determination method described in the section of the Japanese Pharmacopoeia Pharmaceutical Standards “Lactamine”. That is, weigh accurately 5 g of the dried bacterial cell product, add it to 30 mL of diluent (2), shake vigorously, add the same diluent to make exactly 50 mL, shake well, and accurately measure 1 mL of this bacterial solution. Then, the operation (10-fold dilution method) of adding to 9 mL of the same diluted solution accurately dispensed was repeated, and diluted so that the number of viable bacteria in 1 mL was 20 to 200. 1 mL of this solution was placed in a Petri dish, and 20 mL of a lactamine test agar medium (2) maintained at 50 ° C. was added thereto and quickly mixed to solidify. This was subjected to aerobic culture at 37 ° C. for 24-48 hours, and the number of viable bacteria in the dried microbial cells was determined from the number of colonies that appeared and the dilution rate. The above-described 1. The cell count of the dried microbial cell product obtained in (1) was 7.0 × 10 11 CFU / g viable cells.
 上記ラクトミン試験用カンテン培地(2)は、上記ラクトミン試験用液体培地(2)にカンテン20gを加え、高圧蒸気滅菌器を用いて121℃で15分間加熱して滅菌して調製した。 The agar medium for lactamine test (2) was prepared by adding 20 g of agar to the liquid medium for lactamine test (2) and sterilizing by heating at 121 ° C. for 15 minutes using a high-pressure steam sterilizer.
<実施例5>
(乳酸菌及びα-グルコシダーゼ阻害剤併用による脂質低下及び抗肥満増強作用)
 乳酸菌として実施例4の方法によって得た3Bの乾燥菌体を、α-グルコシダーゼ阻害剤としてアカルボースを、それぞれ用いた。アカルボースとしては、グルコバイ(登録商標)錠100mg(バイエル薬品製)を粉砕したものを用いた。
<Example 5>
(Lipid lowering and anti-obesity enhancing action by combined use of lactic acid bacteria and α-glucosidase inhibitor)
3B dried cells obtained by the method of Example 4 were used as lactic acid bacteria, and acarbose was used as an α-glucosidase inhibitor. As acarbose, pulverized glucobay (registered trademark) 100 mg (manufactured by Bayer Yakuhin) was used.
 雌性KK-Aマウス(系統名KK-A/TaJcl)を8週齢で購入後(日本クレア社より購入)、個別ケージにて2週間の予備飼育を行った。KK-Aマウスは、糖尿病のモデルマウスである。予備飼育期間中は市販の粉末飼料(CE-2:日本クレア社製)及び上水道水を自由摂取させた。実験開始日には経口糖負荷試験(OGTT)を実施した。すなわち、OGTT実施の前日より絶食とし、実施当日グルコース溶液(2g/5mL/kg)を経口投与した。負荷前ならびに負荷後15、30、60及び120分後に尾静脈から血液を漏出させ、漏出血液中のグルコース濃度を市販の自己検査用グルコース測定器(商品名:アキュチェックアビバ、ロシュ・ダイアグノスティックス社製)を用いて測定した。このときの血糖値の曲線下面積(AUC)を算出し、これを指標にして以下のI~Lの4群(9匹/群)に群分けし、各試験飼料を自由摂取させた。 Female KK-A y mice (strain name KK-A y / TaJcl) were purchased at 8 weeks of age (purchased from Clea Japan) and then preliminarily reared for 2 weeks in individual cages. The KK-A y mouse is a model mouse for diabetes. During the preliminary breeding period, commercially available powdered feed (CE-2: manufactured by CLEA Japan, Inc.) and tap water were freely ingested. An oral glucose tolerance test (OGTT) was performed on the day of the experiment. That is, fasting was performed from the day before OGTT was performed, and a glucose solution (2 g / 5 mL / kg) was orally administered on the day of implementation. Blood was leaked from the tail vein before loading and 15, 30, 60 and 120 minutes after loading, and the glucose concentration in the leaked blood was measured using a commercially available glucose measuring instrument (trade name: Accucheck Aviva, Roche Diagnostics) The measurement was performed using The area under the curve (AUC) of the blood glucose level at this time was calculated and divided into 4 groups (9 animals / group) of the following I to L using this as an index, and each test feed was freely ingested.
I群:デキストリンを10%の割合で混合したCE-2を混餌投与するグループ。
J群:実施例4の方法によって得た3Bの乾燥菌体(7.0×1011/g)を10%の割合で混合したCE-2を混餌投与するグループ。
K群:アカルボースを0.1%、デキストリンを10%の割合で混合したCE-2を混餌投与するグループ。
L群:実施例4の方法によって得た3Bの乾燥菌体(7.0×1011/g)を10%、アカルボースを0.1%の割合で混合したCE-2を混餌投与するグループ。
Group I: a group to which CE-2 mixed with 10% dextrin is administered as a diet.
Group J: A group to which CE-2 mixed with 10% of 3B dry cells (7.0 × 10 11 / g) obtained by the method of Example 4 was fed.
Group K: Group administered with CE-2 mixed with 0.1% acarbose and 10% dextrin.
Group L: A group to which CE-2 mixed with 10% of dry 3B cells (7.0 × 10 11 / g) obtained by the method of Example 4 and acarbose at a ratio of 0.1% was administered as a diet.
 各群について7週間、上記飼料を摂取させたときの体重推移を測定した。さらに、試験終了時に全採血を行い、得られた血漿中の中性脂肪値を測定した。また子宮周囲脂肪を摘出し、体重あたりの相対重量を比較した。I群に対する各群の有意差はDunnett検定を、2群間の有意差はt検定を用いて評価した。 For each group, the body weight change was measured when the feed was ingested for 7 weeks. Furthermore, whole blood was collected at the end of the test, and the neutral plasma level of the obtained plasma was measured. Periuterine fat was removed and the relative weight per body weight was compared. The significant difference between each group relative to the group I was evaluated using Dunnett test, and the significant difference between the two groups was evaluated using t test.
(結果)
 I~L群のマウスに、各試験飼料を7週間摂餌させたときの体重推移を図7に示した。図8に、試験終了時に測定した血漿中の中性脂肪値(mg/dL)を示す。図9に、試験終了時の体重に対する子宮周囲脂肪の相対重量(体脂肪率(%))を示す。図7から明らかなように、3B単独(J群)及びアカルボース単独(K群)では、いずれも体重の増加抑制が認められなかったが、3B及びアカルボースの併用は体重の増加を有意に抑制した(L群)。図8から明らかなように、3B単独(J群)及びアカルボース単独(K群)では、いずれも中性脂肪値の上昇を抑制しなかったが、3B及びアカルボースの併用は中性脂肪値の上昇を抑制する傾向を示した(L群)。図9から明らかなように、3B単独(J群)及びアカルボース単独(K群)では、いずれも子宮周囲脂肪の相対重量の上昇を抑制しなかったが、3B及びアカルボースの併用は子宮周囲脂肪の相対重量の上昇を3B単独と比較して有意に抑制した(L群)。このように、3Bとα-グルコシダーゼ阻害剤とを組み合わせて投与することにより体重増加が有意に抑制されたが、これは内臓脂肪の減少を伴うものであることが示された。
(result)
FIG. 7 shows changes in body weight when mice in groups I to L were fed each test diet for 7 weeks. FIG. 8 shows the neutral fat level (mg / dL) in plasma measured at the end of the test. FIG. 9 shows the relative weight of periuterine fat (body fat percentage (%)) relative to the body weight at the end of the test. As is clear from FIG. 7, 3B alone (group J) and acarbose alone (group K) did not suppress the increase in body weight, but the combined use of 3B and acarbose significantly suppressed the increase in body weight. (L group). As is clear from FIG. 8, neither 3B alone (group J) nor acarbose alone (group K) suppressed the increase in triglyceride level, but the combined use of 3B and acarbose increased the triglyceride level. (L group). As is clear from FIG. 9, neither 3B alone (group J) nor acarbose alone (group K) suppressed the increase in the relative weight of peritoneal fat. The increase in relative weight was significantly suppressed compared with 3B alone (Group L). Thus, administration of 3B in combination with an α-glucosidase inhibitor significantly suppressed body weight gain, which was shown to be accompanied by a decrease in visceral fat.
 図7~9について詳細に示す。
 図7中の各点は、9個体の平均±標準誤差(SE)を表す。折れ線グラフにおいて、白丸はデキストリンを10%の割合で混合したCE-2を混餌投与したマウスである(I群)。白四角は実施例4の方法によって得た3Bの乾燥菌体(7.0×1011/g)を10%の割合で混合したCE-2を混餌投与したマウスである(J群)。白三角はアカルボースを0.1%、及びデキストリンを10%の割合で混合したCE-2を混餌投与したマウスである(K群)。黒四角は実施例4の方法によって得た3Bの乾燥菌体(7.0×1011/g)を10%及び、アカルボースを0.1%の割合で混合したCE-2を混餌投与したマウスである(L群)。*及び#はそれぞれ、デキストリンを10%の割合で混合したCE-2を混餌投与したマウス(I群)からの有意差(*:p<0.01、**:p<0.01)及び、実施例4の方法によって得た3Bの乾燥菌体(7.0×1011/g)を10%の割合で混合したCE-2を混餌投与したマウス(J群)からの有意差(#:p<0.05、##:p<0.01)を表す。
7 to 9 will be described in detail.
Each point in FIG. 7 represents the mean ± standard error (SE) of 9 individuals. In the line graph, open circles are mice administered with a diet containing CE-2 mixed with 10% dextrin (group I). White squares are mice fed with CE-2 mixed with 10% of 3B dry cells (7.0 × 10 11 / g) obtained by the method of Example 4 (Group J). White triangles represent mice administered with dietary CE-2 mixed with 0.1% acarbose and 10% dextrin (group K). Black squares represent mice fed with CE-2 mixed with 10% of 3B dry cells (7.0 × 10 11 / g) obtained by the method of Example 4 and 0.1% of acarbose. (Group L). * And # are significant differences (*: p <0.01, **: p <0.01) from mice (group I) fed with CE-2 mixed with dextrin at a ratio of 10%, respectively. Significant difference from mice (group J) fed with CE-2 mixed with 10% of 3B dry cells (7.0 × 10 11 / g) obtained by the method of Example 4 (# : P <0.05, ##: p <0.01).
 図8中の棒グラフの値は、9個体の平均±標準誤差(SE)を表す。棒グラフにおいて、白はデキストリンを10%の割合で混合したCE-2を混餌投与したマウスである(I群)。灰色は実施例4の方法によって得た3Bの乾燥菌体(7.0×1011/g)を10%の割合で混合したCE-2を混餌投与したマウスである(J群)。斜線はアカルボースを0.1%、及びデキストリンを10%の割合で混合したCE-2を混餌投与したマウスである(K群)。黒は実施例4の方法によって得た3Bの乾燥菌体(7.0×1011/g)を10%、及びアカルボースを0.1%の割合で混合したCE-2を混餌投与したマウスである(L群)。 The values in the bar graph in FIG. 8 represent the mean ± standard error (SE) of 9 individuals. In the bar graph, white is a mouse fed with CE-2 mixed with dextrin at a ratio of 10% (group I). The gray color represents mice fed with CE-2 mixed with 10% of 3B dry cells (7.0 × 10 11 / g) obtained by the method of Example 4 (Group J). The hatched lines are mice administered with CE-2 mixed with 0.1% acarbose and 10% dextrin (group K). Black is a mouse fed with CE-2 mixed with 10% of 3B dry cells (7.0 × 10 11 / g) obtained by the method of Example 4 and 0.1% of acarbose. Yes (group L).
 図9中の棒グラフの値は、9個体の平均±標準誤差(SE)を表す。棒グラフにおいて、白はデキストリンを10%の割合で混合したCE-2を混餌投与したマウスである(I群)。灰色は実施例4の方法によって得た3Bの乾燥菌体(7.0×1011/g)を10%の割合で混合したCE-2を混餌投与したマウスである(J群)。斜線はアカルボースを0.1%、及びデキストリンを10%の割合で混合したCE-2を混餌投与したマウスである(K群)。黒は実施例4の方法によって得た3Bの乾燥菌体(7.0×1011/g)を10%、及びアカルボースを0.1%の割合で混合したCE-2を混餌投与したマウスである(L群)。#は、実施例4の方法によって得た3Bの乾燥菌体(7.0×1011/g)を10%の割合で混合したCE-2を混餌投与したマウス(J群)からの有意差(#:p<0.05)を表す。 The values in the bar graph in FIG. 9 represent the mean ± standard error (SE) of 9 individuals. In the bar graph, white is a mouse fed with CE-2 mixed with dextrin at a ratio of 10% (group I). The gray color represents mice fed with CE-2 mixed with 10% of 3B dry cells (7.0 × 10 11 / g) obtained by the method of Example 4 (Group J). The hatched lines are mice administered with CE-2 mixed with 0.1% acarbose and 10% dextrin (group K). Black is a mouse fed with CE-2 mixed with 10% of 3B dry cells (7.0 × 10 11 / g) obtained by the method of Example 4 and 0.1% of acarbose. Yes (group L). #: Significant difference from mice (group J) fed with CE-2 mixed with 10% of 3B dry cells (7.0 × 10 11 / g) obtained by the method of Example 4 (#: P <0.05).
 なお、実施例5において3B以外のビフィズス菌、乳酸菌、糖化菌又は酪酸菌を用いても、上記と同様の結果が得られる。また、アカルボース以外のα-グルコシダーゼ阻害剤を用いても、上記と同様の結果が得られる。 In Example 5, the same results as above can be obtained even if bifidobacteria, lactic acid bacteria, saccharifying bacteria or butyric acid bacteria other than 3B are used. In addition, the same result as above can be obtained by using an α-glucosidase inhibitor other than acarbose.
 本発明は、肥満、脂質異常症等を予防、改善又は治療できることから、生活習慣病、メタボリックシンドローム等の予防、改善又は治療に有用である。 Since the present invention can prevent, improve or treat obesity, dyslipidemia, etc., it is useful for the prevention, improvement or treatment of lifestyle-related diseases, metabolic syndrome and the like.
1、2 圧縮気体が供給される気体流路
3、4 被乾燥体を含む液体が供給される液体流路
5   流体流動面
6   衝突焦点
7   噴霧液滴
DESCRIPTION OF SYMBOLS 1, 2 Gas flow path 3 to which compressed gas is supplied, 4 Liquid flow path to which the liquid containing a to-be-dried body is supplied 5 Fluid flow surface 6 Collision focus 7 Spray droplet

Claims (24)

  1.  α-グルコシダーゼ阻害剤を含み、ビフィズス菌、乳酸菌、糖化菌及び酪酸菌からなる群より選ばれる少なくとも1種の菌と組み合わせて投与されることを特徴とする脂質代謝改善剤。 An agent for improving lipid metabolism, comprising an α-glucosidase inhibitor and administered in combination with at least one bacterium selected from the group consisting of bifidobacteria, lactic acid bacteria, saccharifying bacteria, and butyric acid bacteria.
  2.  さらに、ビフィズス菌、乳酸菌、糖化菌及び酪酸菌からなる群より選ばれる少なくとも1種の菌を含む請求項1に記載の脂質代謝改善剤。 The lipid metabolism improving agent according to claim 1, further comprising at least one bacterium selected from the group consisting of bifidobacteria, lactic acid bacteria, saccharifying bacteria, and butyric acid bacteria.
  3.  α-グルコシダーゼ阻害剤が、一般式(I)
    Figure JPOXMLDOC01-appb-C000001
    (式中、Aは、水酸基、フェノキシ、チエニル、フリル、ピリジル、シクロヘキシル、置換されていてもよいフェニル基を有しうる炭素数1~10の鎖状炭化水素基、水酸基、ヒドロキシメチル基、メチル基、アミノ基を有しうる炭素数5又は6員の環状炭化水素基又は糖残基を示す)で表わされるバリオールアミン誘導体、一般式(II)
    Figure JPOXMLDOC01-appb-C000002
    (式中、Aは、前記と同義である)で表わされるバリエナミンN-置換誘導体、一般式(III)
    Figure JPOXMLDOC01-appb-C000003
    (式中、Aは、前記と同義である)で表わされるバリダミンのN-置換誘導体、又は一般式(IV)
    Figure JPOXMLDOC01-appb-C000004
    (式中、R及びRは、同一又は異なって、それぞれ水素原子、置換されていてもよい直鎖状、分枝状若しくは環式の飽和又は不飽和脂肪族炭化水素基、置換されていてもよい炭化水素環、芳香環又はヘテロ環であり、Rは、-H、-OH、-OR′、-SH、-SR′、-NH、-NHR′、-N(R′)(R′′)、NHCH-、NHR′-CH-、NR′R′′-CH-、-COOH、-COOR′、HO-CH-、R′CO-NHCH-、R′CO-NR′′CH-、R′SONHCH-、R′SO-NR′′CH-、R′-NH-CO-NH-CH-、R′-NH-CS-NH-CH-R′-O-CO-NH-CH-、-SOH、-CN、-CONH、-CONHR′又は-CONR′R′′であり、R′及びR′′は、同一又は異なって、それぞれRと同義である。Rが-CHOHであり、かつRが水素原子又は-OHである場合;Rが水素原子であり、かつRが水素原子、-OH、-SOH、-CN又は-CH-NHである場合;又はRが-CH-NHであり、かつRが-OHである場合には、Rは、水素原子でない。)で表わされる3,4,5-トリヒドロキシピペリジンである請求項1又は2に記載の脂質代謝改善剤。
    The α-glucosidase inhibitor has the general formula (I)
    Figure JPOXMLDOC01-appb-C000001
    (In the formula, A is a hydroxyl group, phenoxy, thienyl, furyl, pyridyl, cyclohexyl, a chain hydrocarbon group having 1 to 10 carbon atoms which may have an optionally substituted phenyl group, a hydroxyl group, a hydroxymethyl group, methyl , A variolamine derivative represented by the general formula (II): a cyclic hydrocarbon group having 5 or 6 carbon atoms or a sugar residue which may have an amino group)
    Figure JPOXMLDOC01-appb-C000002
    (Wherein A is as defined above), a valienamine N-substituted derivative represented by the general formula (III)
    Figure JPOXMLDOC01-appb-C000003
    (Wherein A is as defined above) or an N-substituted derivative of validamine, represented by the general formula (IV)
    Figure JPOXMLDOC01-appb-C000004
    (Wherein R 1 and R 3 are the same or different and each represents a hydrogen atom, an optionally substituted linear, branched or cyclic saturated or unsaturated aliphatic hydrocarbon group, substituted Which may be a hydrocarbon ring, an aromatic ring or a heterocyclic ring, and R 2 is —H, —OH, —OR ′, —SH, —SR ′, —NH 2 , —NHR ′, —N (R ′) (R ″), NH 2 CH 2 —, NHR′—CH 2 —, NR′R ″ —CH 2 —, —COOH, —COOR ′, HO—CH 2 —, R′CO—NHCH 2 —, R′CO—NR ″ CH 2 —, R′SO 2 NHCH 2 —, R′SO 2 —NR ″ CH 2 —, R′—NH—CO—NH—CH 2 —, R′—NH—CS —NH—CH 2 —R′—O—CO—NH—CH 2 —, —SO 3 H, —CN, —CONH 2 , —CON HR ′ or —CONR′R ″, R ′ and R ″ are the same or different and have the same meaning as R 1. R 3 is —CH 2 OH and R 2 is a hydrogen atom or When —OH; R 3 is a hydrogen atom and R 2 is a hydrogen atom, —OH, —SO 3 H, —CN or —CH 2 —NH 2 ; or R 3 is —CH 2 —. The lipid metabolism according to claim 1 or 2, wherein NH 2 is 3,4,5-trihydroxypiperidine represented by the following formula: when NH 2 and R 2 is -OH, R 1 is not a hydrogen atom. Improver.
  4.  α-グルコシダーゼ阻害剤を含み、ビフィズス菌、乳酸菌、糖化菌及び酪酸菌からなる群より選ばれる少なくとも1種の菌と組み合わせて投与されることを特徴とする前記菌による脂質代謝改善作用増強剤。 An agent for improving lipid metabolism by the bacterium, comprising an α-glucosidase inhibitor and administered in combination with at least one bacterium selected from the group consisting of bifidobacteria, lactic acid bacterium, saccharifying bacterium and butyric acid bacterium.
  5.  α-グルコシダーゼ阻害剤を含み、ビフィズス菌、乳酸菌、糖化菌及び酪酸菌からなる群より選ばれる少なくとも1種の菌と組み合わせて投与されることを特徴とする抗肥満剤。 An anti-obesity agent comprising an α-glucosidase inhibitor and administered in combination with at least one bacterium selected from the group consisting of bifidobacteria, lactic acid bacteria, saccharifying bacteria, and butyric acid bacteria.
  6.  α-グルコシダーゼ阻害剤を含み、ビフィズス菌、乳酸菌、糖化菌及び酪酸菌からなる群より選ばれる少なくとも1種の菌と組み合わせて投与されることを特徴とする前記菌による抗肥満作用増強剤。 An anti-obesity effect enhancer by the aforementioned bacterium, which comprises an α-glucosidase inhibitor and is administered in combination with at least one bacterium selected from the group consisting of bifidobacteria, lactic acid bacterium, saccharifying bacterium and butyric acid bacterium.
  7.  さらに、ビフィズス菌、乳酸菌、糖化菌及び酪酸菌からなる群より選ばれる少なくとも1種の菌を含む請求項4~6のいずれか一項に記載の剤。 The agent according to any one of claims 4 to 6, further comprising at least one bacterium selected from the group consisting of bifidobacteria, lactic acid bacteria, saccharifying bacteria, and butyric acid bacteria.
  8.  ビフィズス菌、乳酸菌、糖化菌及び酪酸菌からなる群より選ばれる少なくとも1種の菌を含み、α-グルコシダーゼ阻害剤と組み合わせて投与されることを特徴とするα-グルコシダーゼ阻害剤による脂質代謝改善作用増強剤。 Lipid metabolism improving action by an α-glucosidase inhibitor characterized by comprising at least one bacterium selected from the group consisting of bifidobacteria, lactic acid bacteria, saccharifying bacteria and butyric acid bacteria, and being administered in combination with an α-glucosidase inhibitor Enhancer.
  9.  ビフィズス菌、乳酸菌、糖化菌及び酪酸菌からなる群より選ばれる少なくとも1種の菌を含み、α-グルコシダーゼ阻害剤と組み合わせて投与されることを特徴とするα-グルコシダーゼ阻害剤による抗肥満作用増強剤。 An anti-obesity effect enhanced by an α-glucosidase inhibitor, comprising at least one bacterium selected from the group consisting of bifidobacteria, lactic acid bacteria, saccharifying bacteria, and butyric acid bacteria, and administered in combination with an α-glucosidase inhibitor Agent.
  10.  ビフィズス菌、乳酸菌、糖化菌及び酪酸菌からなる群より選ばれる少なくとも1種の菌を含み、α-グルコシダーゼ阻害剤と組み合わせて投与されることを特徴とするα-グルコシダーゼ阻害剤による脂質代謝改善作用又は抗肥満作用の発現促進剤。 Lipid metabolism improving action by an α-glucosidase inhibitor characterized by comprising at least one bacterium selected from the group consisting of bifidobacteria, lactic acid bacteria, saccharifying bacteria and butyric acid bacteria, and being administered in combination with an α-glucosidase inhibitor Alternatively, an agent for promoting the expression of anti-obesity action.
  11.  請求項1~10のいずれか一項に記載の剤を含むことを特徴とする医薬品。 A pharmaceutical comprising the agent according to any one of claims 1 to 10.
  12.  請求項1~3のいずれか一項に記載の脂質代謝改善剤を含むことを特徴とする脂質代謝改善用飲食品組成物。 A lipid metabolism improving food or drink composition comprising the lipid metabolism improving agent according to any one of claims 1 to 3.
  13.  請求項4に記載の脂質代謝改善作用増強剤を含むことを特徴とするビフィズス菌、乳酸菌、糖化菌及び酪酸菌からなる群より選ばれる少なくとも1種の菌による脂質代謝改善作用増強用飲食品組成物。 A food / beverage composition for enhancing lipid metabolism improving action by at least one bacterium selected from the group consisting of bifidobacteria, lactic acid bacteria, saccharifying bacteria and butyric acid bacteria, comprising the lipid metabolism improving action enhancing agent according to claim 4. object.
  14.  請求項5に記載の抗肥満剤を含むことを特徴とする肥満改善用飲食品組成物。 An obesity-improving food / beverage composition comprising the anti-obesity agent according to claim 5.
  15.  請求項6に記載の抗肥満作用増強剤を含むことを特徴とするビフィズス菌、乳酸菌、糖化菌及び酪酸菌からなる群より選ばれる少なくとも1種の菌による肥満改善作用増強用飲食品組成物。 A food / beverage composition for enhancing obesity-improving action by at least one bacterium selected from the group consisting of bifidobacteria, lactic acid bacteria, saccharifying bacteria, and butyric acid bacteria, comprising the anti-obesity action enhancing agent according to claim 6.
  16.  請求項8に記載の脂質代謝改善作用増強剤を含むことを特徴とするα-グルコシダーゼ阻害剤による脂質代謝改善作用増強用飲食品組成物。 A food or drink composition for enhancing lipid metabolism improving action by an α-glucosidase inhibitor, comprising the lipid metabolic improving action enhancing agent according to claim 8.
  17.  請求項9に記載の抗肥満作用増強剤を含むことを特徴とするα-グルコシダーゼ阻害剤による肥満改善作用増強用飲食品組成物。 A food / beverage composition for enhancing obesity-improving action by an α-glucosidase inhibitor, comprising the anti-obesity action-enhancing agent according to claim 9.
  18.  α-グルコシダーゼ阻害剤を、ビフィズス菌、乳酸菌、糖化菌及び酪酸菌からなる群より選ばれる少なくとも1種の菌と組み合わせて動物に投与することを特徴とする脂質代謝改善方法。 A method for improving lipid metabolism, comprising administering an α-glucosidase inhibitor to an animal in combination with at least one bacterium selected from the group consisting of bifidobacteria, lactic acid bacteria, saccharifying bacteria, and butyric acid bacteria.
  19.  α-グルコシダーゼ阻害剤を、ビフィズス菌、乳酸菌、糖化菌及び酪酸菌からなる群より選ばれる少なくとも1種の菌と組み合わせて動物に投与することを特徴とする前記菌による脂質代謝改善作用を増強する方法。 An α-glucosidase inhibitor is administered to an animal in combination with at least one bacterium selected from the group consisting of bifidobacteria, lactic acid bacteria, saccharifying bacteria, and butyric acid bacteria, and enhances the lipid metabolism improving action by the bacteria Method.
  20.  α-グルコシダーゼ阻害剤を、ビフィズス菌、乳酸菌、糖化菌及び酪酸菌からなる群より選ばれる少なくとも1種の菌と組み合わせて動物に投与することを特徴とする肥満の改善又は治療方法。 A method for improving or treating obesity, comprising administering an α-glucosidase inhibitor to an animal in combination with at least one bacterium selected from the group consisting of bifidobacteria, lactic acid bacteria, saccharifying bacteria, and butyric acid bacteria.
  21.  α-グルコシダーゼ阻害剤を、ビフィズス菌、乳酸菌、糖化菌及び酪酸菌からなる群より選ばれる少なくとも1種の菌と組み合わせて動物に投与することを特徴とする前記菌による肥満の改善作用を増強する方法。 An α-glucosidase inhibitor is administered to an animal in combination with at least one bacterium selected from the group consisting of bifidobacteria, lactic acid bacterium, saccharifying bacterium, and butyric acid bacterium, and enhances the obesity improving action by the bacterium Method.
  22.  ビフィズス菌、乳酸菌、糖化菌及び酪酸菌からなる群より選ばれる少なくとも1種の菌を、α-グルコシダーゼ阻害剤と組み合わせて動物に投与することを特徴とするα-グルコシダーゼ阻害剤による脂質代謝改善作用を増強させる方法。 Lipid metabolism improving action by α-glucosidase inhibitor, characterized in that at least one bacterium selected from the group consisting of bifidobacteria, lactic acid bacteria, saccharifying bacteria and butyric acid bacteria is administered to animals in combination with α-glucosidase inhibitors How to strengthen.
  23.  ビフィズス菌、乳酸菌、糖化菌及び酪酸菌からなる群より選ばれる少なくとも1種の菌を、α-グルコシダーゼ阻害剤と組み合わせて動物に投与することを特徴とするα-グルコシダーゼ阻害剤による肥満の改善作用を増強する方法。 An obesity-improving action by an α-glucosidase inhibitor, characterized in that at least one bacterium selected from the group consisting of bifidobacteria, lactic acid bacteria, saccharifying bacteria and butyric acid bacteria is administered to an animal in combination with an α-glucosidase inhibitor How to strengthen.
  24.  α-グルコシダーゼ阻害剤を、ビフィズス菌、乳酸菌、糖化菌及び酪酸菌からなる群より選ばれる少なくとも1種の菌と組み合わせて動物に投与することを特徴とするα-グルコシダーゼ阻害剤による脂質代謝改善作用又は抗肥満作用の発現を促進する方法。 Lipid metabolism improving action by α-glucosidase inhibitor, comprising administering α-glucosidase inhibitor to an animal in combination with at least one bacterium selected from the group consisting of bifidobacteria, lactic acid bacteria, saccharifying bacteria and butyric acid bacteria Or a method of promoting the development of an anti-obesity effect.
PCT/JP2010/062314 2010-07-22 2010-07-22 Lipid metabolism improving agent, agent for enhancing lipid metabolism improving action, anti-obesity agent, and agent for enhancing anti-obesity action WO2012011174A1 (en)

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Cited By (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2018034047A1 (en) * 2016-08-16 2018-02-22 株式会社ゲノム創薬研究所 Lactic acid bacteria, hypoglycemic agent derived from same, therapeutic agent for diabetes, and food or beverage
JP2019089815A (en) * 2013-12-05 2019-06-13 インセルム(インスティチュート ナショナル デ ラ サンテ エ デ ラ リシェルシェ メディカル) BACTERIAL INFLUENCE ON REGULATION OF APPETITE VIA ClpB PROTEIN MIMICRY OF α-MSH
WO2020262414A1 (en) * 2019-06-25 2020-12-30 株式会社ヤクルト本社 Method for promoting growth of bacteria of genus bifidobacterium
CN114703105A (en) * 2022-04-29 2022-07-05 善恩康生物科技(苏州)有限公司 Application of composite probiotics in reducing blood fat or relieving obesity

Citations (8)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JPS5446786A (en) * 1977-08-27 1979-04-12 Bayer Ag Novel 3*4*55trihydroxypiperidine compound* its manufacture and use for medicine
JPS5764648A (en) * 1980-10-06 1982-04-19 Takeda Chem Ind Ltd N-substituted derivative of valienamine, its preparation, and alpha-glucosidase inhibitor
JPS57114554A (en) * 1981-01-05 1982-07-16 Takeda Chem Ind Ltd N-substituted derivative of validamine, its preparation, and alpha-glucosidase inhibiting agent
JPS57200335A (en) * 1981-06-02 1982-12-08 Takeda Chem Ind Ltd N-substituted derivative of valiolamine, its preparation and use
JPS5984825A (en) * 1982-11-05 1984-05-16 Yakult Honsha Co Ltd Antilipemic agent
JPS61205215A (en) * 1985-03-08 1986-09-11 Takeda Chem Ind Ltd Saccharide digestion inhibitor and composition thereof
JPS61271223A (en) * 1985-05-24 1986-12-01 Biofuerumin Seiyaku Kk Improver for blood lipid
JP2007031291A (en) * 2005-07-22 2007-02-08 Ace Bio Product Kk Body weight increase-inhibiting agent and body weight increase-inhibiting drink

Family Cites Families (6)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JP2004113068A (en) * 2002-09-25 2004-04-15 Sanwa Kosan Kk Growth promoter for intestinal bifidobacterium
US7108869B2 (en) * 2002-11-07 2006-09-19 Access Business Group International Llc Nutritional supplement containing alpha-glucosidase and alpha-amylase inhibitors
JP4463525B2 (en) * 2003-10-23 2010-05-19 ビオフェルミン製薬株式会社 Desensitization therapy agent
CN101057847A (en) * 2006-04-21 2007-10-24 中国医学科学院药物研究所 Polyhydroxy piperidines compound and preparation method and application thereof
JP5405793B2 (en) * 2008-10-09 2014-02-05 ビオフェルミン製薬株式会社 Preventive or therapeutic agent for nonspecific hypersensitivity of mucous membrane
SG10201400931RA (en) * 2009-03-26 2014-07-30 Biofermin Pharmaceutical Co Ltd Agent for enhancing hypoglycemic activity

Patent Citations (8)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JPS5446786A (en) * 1977-08-27 1979-04-12 Bayer Ag Novel 3*4*55trihydroxypiperidine compound* its manufacture and use for medicine
JPS5764648A (en) * 1980-10-06 1982-04-19 Takeda Chem Ind Ltd N-substituted derivative of valienamine, its preparation, and alpha-glucosidase inhibitor
JPS57114554A (en) * 1981-01-05 1982-07-16 Takeda Chem Ind Ltd N-substituted derivative of validamine, its preparation, and alpha-glucosidase inhibiting agent
JPS57200335A (en) * 1981-06-02 1982-12-08 Takeda Chem Ind Ltd N-substituted derivative of valiolamine, its preparation and use
JPS5984825A (en) * 1982-11-05 1984-05-16 Yakult Honsha Co Ltd Antilipemic agent
JPS61205215A (en) * 1985-03-08 1986-09-11 Takeda Chem Ind Ltd Saccharide digestion inhibitor and composition thereof
JPS61271223A (en) * 1985-05-24 1986-12-01 Biofuerumin Seiyaku Kk Improver for blood lipid
JP2007031291A (en) * 2005-07-22 2007-02-08 Ace Bio Product Kk Body weight increase-inhibiting agent and body weight increase-inhibiting drink

Non-Patent Citations (5)

* Cited by examiner, † Cited by third party
Title
HARISA GI ET AL.: "Oral administration of Lactobacillus acidophilus restores nitric oxide level in diabetic rats", AUSTRALIAN JOURNAL OF BASIC AND APPLIED SCIENCES, vol. 3, no. 3, 2009, pages 2963 - 2969 *
KYOICHI KOBASHI: "Therapies of hyperlipemia and cholelithiasis by administering viable bacterial preparations", BIOMEDICINE & THERAPEUTICS, vol. 14, no. 5, 1985, pages 673 - 674 *
MAKI SHIMAKAWA ET AL.: "Effects of the Combination of Bifidobacterium bifidum G9-1 and a-glucosidase Inhibitor on Impaired Glucose Tolerance and Lipid Metabolism in Obese Diabetic KK-Ay Mice", JOURNAL OF INTESTINAL MICROBIOLOGY, vol. 24, no. 2, April 2010 (2010-04-01), pages 99 *
NAGAO TOTANI ET AL.: "Bifidus-kin no Himan Tonyobyo Shikkan Model Dobutsu ni Taisuru Koka", IGAKU NO AYUMI, vol. 205, no. 4, April 2003 (2003-04-01), pages 273 - 274 *
PAIK HD ET AL.: "Effects of Bacillus polyfermenticus SCD on Lipid and Antioxidant Metabolisms in Rats Fed a High-Fat and High- Cholesterol Diet", BIOLOGICAL & PHARMACEUTICAL BULLETIN, vol. 28, no. 7, 2005, pages 1270 - 1274 *

Cited By (8)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JP2019089815A (en) * 2013-12-05 2019-06-13 インセルム(インスティチュート ナショナル デ ラ サンテ エ デ ラ リシェルシェ メディカル) BACTERIAL INFLUENCE ON REGULATION OF APPETITE VIA ClpB PROTEIN MIMICRY OF α-MSH
WO2018034047A1 (en) * 2016-08-16 2018-02-22 株式会社ゲノム創薬研究所 Lactic acid bacteria, hypoglycemic agent derived from same, therapeutic agent for diabetes, and food or beverage
JPWO2018034047A1 (en) * 2016-08-16 2019-06-13 株式会社ゲノム創薬研究所 Lactic acid bacteria, hypoglycemic agent derived from said lactic acid bacteria, medicine for treating diabetes, and food and drink
JP7054111B2 (en) 2016-08-16 2022-04-13 株式会社ゲノム創薬研究所 Lactic acid bacteria, hypoglycemic agents derived from the lactic acid bacteria, diabetes therapeutic agents, and foods and drinks
WO2020262414A1 (en) * 2019-06-25 2020-12-30 株式会社ヤクルト本社 Method for promoting growth of bacteria of genus bifidobacterium
CN114026218A (en) * 2019-06-25 2022-02-08 株式会社益力多本社 Method for promoting proliferation of bacterium belonging to the genus Bifidobacterium
CN114703105A (en) * 2022-04-29 2022-07-05 善恩康生物科技(苏州)有限公司 Application of composite probiotics in reducing blood fat or relieving obesity
CN114703105B (en) * 2022-04-29 2022-12-27 善恩康生物科技(苏州)有限公司 Application of composite probiotics in reducing blood fat or relieving obesity

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