JP5769710B2 - Lipid metabolism improving agent, lipid metabolism improving agent, anti-obesity agent and anti-obesity agent - Google Patents

Description

  The present invention relates to a composition having an action of improving lipid metabolism, an action of enhancing lipid metabolism improvement action by bacteria such as lactic acid bacteria, an anti-obesity action and an action of enhancing 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.

  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.

  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.

  In order to prevent an increase in blood lipid level, restriction of energy intake, exercise, etc. are effective, but it is necessary to change the lifestyle of many years, and it is often not easy. For this reason, research has been conducted on pharmaceuticals or foods having an action of improving lipid metabolism.

Patent Document 1 discloses a dead cell of Lactobacillus fermentum SBT10534 strain (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). According to Non-Patent Document 3, 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.

JP 2010-132580 A

Totani, N., Ishihara, Y. History of effect medicine for obesity / diabetic disease model animals, Vol.205 (4), 273-274, 2003, Ohno H et.al. Effects of Bifidobacterium bifidum G9-1 on Hypercholesterolemic and Obese Diabetic Animal Models. Bioscience and Microflora. Vol.23 (3), 109-117, 2004 Japanese Society of Agricultural Chemistry 2010 (March 28, 2010) (Abstract 47 pages) Title # 2Aka09 Shizuki Kondo et al. “Anti-metabolic syndrome effect of bifidobacteria in obese mice”, title number 2Aka10 Takumi Sato et al. “Mechanistic analysis of anti-metabolic syndrome effect of bifidobacteria in obese mice” Kazuo Mimura et al., Clinical and Research, 1992, 69: 919

  In view of the above-described situation, the present invention is a lipid metabolism improving agent capable of reducing blood lipids such as cholesterol and neutral fat, and effectively preventing, improving or treating 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 research in view of the above problems, and as a result of examining lipid metabolism improving action and anti-obesity action for various substances, α-glucosidase (disaccharide-degrading enzyme) inhibitors and bacteria such as lactic acid bacteria have been used as animals. It was found that the lipid concentration in blood can be significantly reduced by the specific synergistic effect of a combination of an α-glucosidase inhibitor and a bacterium such as lactic acid bacteria. Further, it has also been found that when an α-glucosidase inhibitor and a bacterium such as lactic acid bacteria are administered in combination, weight gain can be suppressed and fat in the body (particularly visceral fat) can be reduced. An 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 an α-glucosidase inhibitor (voglibose) lowers blood lipids (Mimura) Kazuo et al., Clinical and Research, 1992, 69: 919). Although this document reports that blood triglyceride is significantly decreased and HDL-cholesterol is increased, the effect of oral administration of Basin (registered trademark) 0.2 mg 3 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 a bacterium such as lactic acid bacteria. -It has been found that the combined use of a glucosidase inhibitor and a bacterium such as a lactic acid bacterium exhibits a blood lipid lowering effect earlier than when only an α-glucosidase inhibitor is administered.

In addition, it is known that blood lipid concentration is reduced by lactic acid bacteria, but when α-glucosidase inhibitor and bacteria such as lactic acid bacteria are used in combination, compared with the case where bacteria such as 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.

That is, the present invention relates to the following (1) to (24).
(1) A lipid metabolism improving 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.
(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)

(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 a phenyl group which may be substituted, 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)

(Wherein A is as defined above), a valienamine N-substituted derivative represented by the general formula (III)

(Wherein A is as defined above), an N-substituted derivative of validamine, or a general formula (IV)

(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 And R ² may be —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-NHCH 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 antiobesity 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) An anti-obesity effect enhancement by said bacteria characterized by including an α-glucosidase inhibitor and being administered in combination with at least one bacteria selected from the group consisting of bifidobacteria, lactic acid bacteria, saccharifying bacteria and butyric acid bacteria Agent.
(7) The agent according to any one of (4) to (6), further including at least one kind of bacteria selected from the group consisting of bifidobacteria, lactic acid bacteria, saccharifying bacteria, and butyric acid bacteria.
(8) A lipid 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 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 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 beverage 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 and beverage composition for enhancing obesity-improving action by an α-glucosidase inhibitor, comprising the anti-obesity action potentiator 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 of improving lipid metabolism 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 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 above-mentioned fungus, characterized in that an α-glucosidase inhibitor is administered to an animal in combination with at least one fungus 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.

  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.

FIG. 1 is a graph showing changes in body weight when mice in groups A to D were fed a test diet for 7 weeks. FIG. 2 is a diagram showing plasma triglyceride levels of mice in groups A to D. FIG. 3 is a graph showing changes in body weight when mice in each of the groups E to H are fed each test feed for 7 weeks. FIG. 4 is a diagram showing plasma total cholesterol levels in mice of each of E to H groups. FIG. 5 is a diagram showing plasma triglyceride values of mice of each of E to H groups. FIG. 6 is a diagram showing the relative weight of periuterine fat with respect to the body weight of the mice in each of the E to H groups. FIG. 7 is a graph showing changes in body weight when mice in each of the groups I to L are fed with the test feed for 7 weeks. FIG. 8 is a diagram showing plasma triglyceride levels of mice in each of the groups I to L. FIG. 9 is a diagram showing the relative weight of periuterine fat relative to the body weight of mice in each of the groups I to L. 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 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 actions such as excellent blood lipid lowering action, visceral fat reducing action, and visceral fat accumulation reducing action. Therefore, abnormal lipid metabolism can be effectively prevented, improved or treated.

  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.

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, accompanied by a decrease in blood flow, and 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 also 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 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.

  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.

  The lipid metabolism improving agent of the present invention can enhance 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.

  The present invention also includes an agent for improving lipid metabolism by the bacterium, which 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, including an α-glucosidase inhibitor. To do. The present invention also includes an anti-obesity effect enhancer by the above-mentioned bacterium, which contains 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.

According to Matsuo et al. (Am J Clin Nutr. 1992. Vol.55 314S-317S), Zucker fatty rats characterized by obesity were given a dietary feed of 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, by using an α-glucosidase inhibitor in combination with a bacterium such as lactic acid bacteria, an effective lipid metabolism improving effect can be obtained 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 less than the usual amount, an excellent lipid metabolism improving effect and anti-obesity effect Is obtained. For this reason, it is possible to effectively enhance the lipid metabolism improving action and the anti-obesity action while reducing the side effects by reducing the dose of the α-glucosidase inhibitor.

  In the lipid metabolism improving agent, lipid metabolism improving action enhancer, anti-obesity agent and anti-obesity action enhancer 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.

At least one bacterium selected from the group consisting of bifidobacteria, lactic acid bacteria, saccharifying bacteria, and butyric acid bacteria is an action that promotes the expression of lipid metabolism and anti-obesity action by an α-glucosidase inhibitor, and 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 bacteria, saccharifying bacteria, and butyric acid bacteria, 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.

  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.

(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 a phenyl group which may be substituted, 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. For example, a phenyl group which may be substituted with lower alkyl, lower alkoxy, halogen, phenyl or the like is included.

  The 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.

  Specific examples of the N-substituted variolamine derivative represented by the above general formula (I) include (1) N-phenethylvariolamine, (2) N- (3-phenylallyl) biolamine, and (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 amine (12) N-geranylvariolamine, (13) N- (1,3-dihydroxy-2-propyl) variolamine, (14) N- (1,3-dihydroxy-1-phenyl-2-) Propyl) variolamine, (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-trihydroxy- 6-methylcyclohexyl] variolamine, (26) N-[(1R, 2S)-(2,4,6 / 3) -2,3,4-trihydroxy-6-methylcyclohexyl] variolamine, ( 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-tetra Dorokishi -5-C-like (hydroxymethyl) cyclohexyl) amino] -4,6-dideoxy -D- glucopyranosyl]-beta-D-glucopyranose and the like.

  Among them, N- (1,3-dihydroxy-2-propyl) variolamine, that is, [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.

  As an α-glucosidase inhibitor in the present invention, the general formula (II) described in JP-A-57-64648 and the like.

(Wherein A is as defined above), a general formula (III) described in JP-A 57-114554, etc.

An N-substituted derivative of valididamine 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, 64, 535-537 (1977), JP 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.

  The α-glucosidase inhibitor in the present invention is represented by the general formula (IV) described in the specification of US Pat. No. 4,639,436.

(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 And R ² may be —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-NHCH 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.

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 ″ are the same or different, and may be substituted, preferably having 1 to 30 carbon atoms (more preferably having 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. Especially, the C1-C10 alkyl group 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.

As 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. Are particularly preferred (generic name: miglitol, chemical name: (-)-(2R, 3R, 4R, 5S) -1- (2-hydroxymethyl) piperidine-3,4,5-triol).

  Further, trestatin [(trestatin), The Journal of Antibiotics, Vol. 36, 1157-1175 (1983) and 37, 182-186 (1984), JP Sho 54-163511], Adiposins [(adiposins), The Journal of Antibiotics, Vol. 35, pp. 2343-1236 (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); JP 123891 A; JP 55-71494 A; JP 55-157595 A], oligostatins ((oligostatins), SF-1130X, JP 53-26398 A; JP 56-43294 A). Gazette, The Journal of Antibiotics (J. Antibiotics), Volume 34, pages 1424 to 1433 (1981)], amino sugar compounds (Japanese Patent Laid-Open No. 54-92909), and the like can be used. In addition, about the alpha-glucosidase inhibitor of the microbial origin containing said compound, the review article of E. Truscheit (E.Truscheit etc. [Angewandte Chemie] volume 93, 738-755 (1981)] Has been reported. These compounds can also be used as an α-glucosidase inhibitor in the present invention.

  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 ACS National meeting Abstracts paper] MEDI 69, August 1981, New York The Journal of Antibiotics (J. Antibiotics), 34, 1429-1433 (1981); and JP-A-57-24397], 1-deoxynojirimycin [(1-deoxynojirimycin) ), Naturwissenschaften, 66, 584-585 (1979)] and its N-substituted derivatives, such as BAYo 1248 [The Journal of Clinical Invest 14 (2-II), 47 (1984); Diabetrosia 27 (2), 288A, 346A, 323A (1984)] and the like are also used in the present invention. It can be used as an inhibitor.

  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.

  Furthermore, as the α-glucosidase inhibitor in the present invention, a substance having an α-glucosidase inhibitory action usually used in foods and drinks is also suitable in addition to the compounds described above. 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.

  Malus extract is an extract component of a plant and acts to inhibit α-glucosidase activity and promote in vitro excretion 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.

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; 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.

  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 longum, 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) Lactobacillus acidophilus, (iii) Lactobacillus gasseri, (iv) Streptococcus (Enterococcus) faecalis, (v) Streptococcus (Enterococcus) faecium, (vi) Bacillus subtilis, (vii) Bacillus mesentericus (i) to (vii) 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) Bacillus mesentericus (i) to (vii) combination of two or more The preferred than Sega. 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 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.

  The said microbial cell can be obtained by culture | cultivating on well-known conditions or the conditions according to it. For example, in the case of bifidobacteria or lactic acid bacteria, usually one or more of the bifidobacteria and lactic acid bacteria is about 4 at about 25-45 ° C. in a liquid medium containing glucose, yeast extract, peptone and the like. The aerobic or anaerobic culture is performed for about 72 hours, and the cells are collected from the culture solution and washed to obtain wet cells. In the case of saccharifying bacteria, aerobic culture is usually carried out at about 25 to 45 ° C. for about 4 to 72 hours in an agar medium 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 is preferably a living bacterium, 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.

  The bacterium used in the present invention may be a dried product (bacterial cell dried product), and the microbial cell dried 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 1-10 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.

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.

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 droplet of single micron means that the particle size of the spray droplet is 1 to 10 μm rounded to the first decimal place.

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.

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.

  A 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.

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 gas amount 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.

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 entrance 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 if 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 the residence time in the drying chamber is shortened to 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.

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.

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.

  The combination of at least one bacterium selected from the group consisting of bifidobacteria, lactic acid bacterium, saccharifying bacterium, and butyric acid bacterium in the present invention and an α-glucosidase inhibitor is not particularly limited. For example, an α-glucosidase inhibitor is generally described above. 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 lipid metabolism improving action and the anti-obesity action of the α-glucosidase inhibitor and / or the bacterium can be remarkably enhanced, and thus excellent lipid metabolism improvement. Action and anti-obesity effect are obtained.

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.

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 containing 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.

  In the present invention, the method of administering an α-glucosidase inhibitor in combination with at least one bacterium selected from the group consisting of bifidobacteria, lactic acid bacteria, saccharifying bacteria, and butyric acid bacteria is 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 of administering both preparations simultaneously or at different times, both α-glucosidase inhibitor 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) 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 simultaneously 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 contains 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 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 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 prepared 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. It is preferable that the number of the bacteria is about 10 ³ to 10 ¹² for about 0.05 to 500 mg, and the number of the bacteria is about 10 ⁵ to 10 ¹¹ for about 0.01 to 300 mg of the α-glucosidase inhibitor. It is particularly preferable to do this.

  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.

  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.

  For example, when manufacturing a tablet, it is good to use a well-known tableting machine. 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.

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 hydrated material, means such as L-drying, freeze-drying and spray-drying can be employed. In order to obtain dry cells (dried cells) of at least one bacterium selected from the group consisting of bifidobacteria, lactic acid bacteria, saccharifying bacteria, and butyric acid bacteria, a suitable stabilizer such as monosodium glutamate, adonitol, etc. Bacteria can be suspended in the added neutral buffer and dried by a method known per se.

  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 times to 4 times a day, usually 1 hour before meal to 2 hours after meal. In particular, when the α-glucosidase inhibitor is a biolamine 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). (Adult / times) It is administered 2 to 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.

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 6 in terms of the number of viable bacteria. 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.

  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 agent, anti-obesity agent, and anti-obesity agent 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 a small amount of use. 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.

  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 and drink 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 a lipid metabolism improving action enhancing agent containing the α-glucosidase inhibitor. This is one of the present inventions. A food / beverage composition for enhancing lipid metabolism improving action by an α-glucosidase inhibitor, which includes a 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 and 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 and drink composition for enhancing obesity-improving action by an α-glucosidase inhibitor, comprising the anti-obesity action enhancer containing the bacterium, 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 determined by appropriately selecting from.

  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.

  When using the agent of this invention as a food-drinks composition, the form is not specifically 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; 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.

  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.

  The food-drinks composition which concerns on this invention may contain the auxiliary component conventionally used in the foodstuff field | area. 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.

  The 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, so it cannot be generally stated, but 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.

  The present invention comprises 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 bacterium, the dose of the α-glucosidase inhibitor can be adjusted so that the inhibitor exerts 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.

  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 before meals 2 to 4 times a day, 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 promoting agent 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.

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 preferable combination of the α-glucosidase inhibitor and the bacterium in the expression promoting agent of lipid metabolism improving action or anti-obesity action is also the same as 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.

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 effect of the bacterium by administering the α-glucosidase inhibitor 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. A method is 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 by the above-mentioned bacteria, wherein the α-glucosidase inhibitor is administered to an animal in combination with at least one kind of 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 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 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 in which 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 an α-glucosidase inhibitor. 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 α-glucosidase inhibitor are the same as the administration methods in the lipid metabolism improving agent described above. is there.

  Hereinafter, the present invention will be described in more detail with reference to examples, but the present invention is not limited thereto. In this example, “%” means “% by mass” unless otherwise specified.

<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 dry cells were 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.

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. 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 addition into 9 mL of the same diluted solution that was 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.

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 6.7-6.9

<Example 2>
(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 voglibose was used as an α-glucosidase inhibitor. As voglibose, pulverized Basin (registered trademark) 0.2 (manufactured by Takeda Pharmaceutical Company Limited) was used.

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 (8 animals / group) of A to D using this as an index, and each test feed was freely ingested.

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 dry BBG9-1 cells (3.4 × 10 ¹¹ / g) obtained by the method of Example 1 at a rate of 10% was mixed and administered.
Group C: Group administered with CE-2 mixed with 0.0003% voglibose and 10% dextrin.
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.

  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.

(result)
FIG. 1 shows changes in body weight when mice in groups A to D were fed each test feed 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, BBG9-1 alone (Group B) and voglibose alone (Group C) did not suppress body weight gain, but BBG9-1 and voglibose combined 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 the neutral fat level in plasma, but BBG9-1 and voglibose were used in combination. Significantly suppressed the increase in triglyceride level (Group D).

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 to which CE-2 mixed with 10% of dextrin was administered as a diet (Group A). White squares are mice fed with CE-2 mixed with 10% of dried BBG9-1 cells (3.4 × 10 ¹¹ / g) obtained by the method of Example 1 (Group B). . White triangles are mice administered with CE-2 mixed with voglibose 0.0003% and dextrin 10% (group C). The black squares are 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, **: p <0.01) from mice (group A) fed with CE-2 mixed with 10% dextrin, respectively. ***, p <0.001), 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.

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 line is a mouse to which CE-2 mixed with 0.0003% voglibose and 10% dextrin was mixed (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) to which CE-2 mixed with 10% of dextrin was administered.

<Example 3>
(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 acarbose was used as an α-glucosidase inhibitor. As acarbose, pulverized glucobay (registered trademark) 100 mg (manufactured by Bayer Yakuhin) was used.

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.

Group E: 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: 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 in a diet group.

  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.

(result)
FIG. 3 shows the change in body weight when mice in groups E to H were fed each test feed 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, neither BBG9-1 alone (Group F) nor acarbose alone (Group G) suppressed the increase in body weight, but the combined use of BBG9-1 and acarbose resulted in an increase in 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), and acarbose alone significantly suppressed (Group G), but the combined use of BBG9-1 and voglibose is total cholesterol. The increase in value was synergistically significantly suppressed (Group H). As is clear from FIG. 5, neither BBG9-1 alone (Group F) nor acarbose alone (Group G) 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 peritoneal 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 significantly suppressed body weight gain, which was shown to be accompanied by a decrease in visceral fat.

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 that were fed with CE-2 mixed with 10% of dextrin (Group E). White 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), 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 administered mice (Group F) 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.

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 slanted line is a mouse fed 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 from mice (Group F) fed with CE-2 mixed with 10% of dry BBG9-1 cells (3.4 × 10 ¹¹ / g) obtained by the above (###: p <0.001) and a significant difference ($: p <0.05) from a mouse (Group G) administered 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. 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 slanted line is a mouse fed 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. 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 slanted line is a mouse fed 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 from mice (Group F) fed with CE-2 mixed with 10% of dry BBG9-1 cells (3.4 × 10 ¹¹ / g) obtained by the above (###: p <0.001) and a significant difference ($: p <0.05) from a mouse (Group G) administered with CE-2 mixed with 0.1% acarbose and 10% dextrin.
In addition, even if bifidobacteria other than BBG9-1, lactic acid bacteria, saccharifying bacteria, or butyric acid bacteria are used in Examples 2-3, the same results as above can be obtained. Moreover, the same results as described above can be obtained using an α-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. 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.

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. 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 addition into 9 mL of the same diluted solution that was 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.

  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 α-glucosidase inhibitor)
3B dried microbial 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.

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.

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: a group to which CE-2 mixed with 0.1% acarbose and 10% dextrin is administered as a diet.
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.

  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.

(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). As described above, 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.

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 represent mice administered with dietary CE-2 mixed with 10% dextrin (group I). White squares are mice 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 J). White triangles are mice administered with 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 10% dextrin, respectively, and 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).

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). Gray is a mouse fed with CE-2 mixed with 10% of 3B dried cells (7.0 × 10 ¹¹ / g) obtained by the method of Example 4 (Group J). The slanted line represents mice administered with dietary 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. In the bar graph, white is a mouse fed with CE-2 mixed with dextrin at a ratio of 10% (group I). Gray is a mouse fed with CE-2 mixed with 10% of 3B dried cells (7.0 × 10 ¹¹ / g) obtained by the method of Example 4 (Group J). The slanted line represents mice administered with dietary 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).

  In Example 5, the same results as above can be obtained even when bifidobacteria, lactic acid bacteria, saccharifying bacteria or butyric acid bacteria other than 3B are used. Moreover, the same result as above can be obtained even when an α-glucosidase inhibitor other than acarbose is used.

  Since the present invention can prevent, improve or treat obesity, dyslipidemia and the like, it is useful for the prevention, improvement or treatment of lifestyle-related diseases, metabolic syndrome and the like.

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 (6)

Lipids from Bifidobacterium bifidum G9-1, which contains acarbose or voglibose and is administered in combination with Bifidobacterium bifidum G9-1 Metabolism-improving action or anti-obesity action-enhancing agent (except for an embodiment wherein the “agent” is a food) .   A lipid metabolism improving action or anti-obesity action enhancing agent comprising acarbose or voglibose and Bifidobacterium bifidum G9-1. Bifidobacterium bifidum G9-1 (Bifidobacterium bifidum G9-1) hints acarbose or in combination with voglibose, characterized in that it is administered acarbose or lipid metabolism improving activity or anti-obesity effect enhancer according voglibose (provided that the " Except for the case where the agent is a food) . Bifidobacterium bifidum G9-1 (Bifidobacterium bifidum G9-1), which is administered in combination with acarbose or voglibose, a lipid metabolism improving action or anti-obesity action expression promoter by acarbose or voglibose (however, , Except for the embodiment in which the “agent” is a food) .   It is a pharmaceutical, The agent as described in any one of Claims 1-4.   The agent for improving lipid metabolism according to claim 2, which is a food or drink composition.