WO2021153718A1 - 線維芽細胞増殖因子２１誘導剤、及びアルコール嗜好性又は単純糖質嗜好性を抑制するための組成物 - Google Patents

線維芽細胞増殖因子２１誘導剤、及びアルコール嗜好性又は単純糖質嗜好性を抑制するための組成物 Download PDF

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WO2021153718A1
WO2021153718A1 PCT/JP2021/003182 JP2021003182W WO2021153718A1 WO 2021153718 A1 WO2021153718 A1 WO 2021153718A1 JP 2021003182 W JP2021003182 W JP 2021003182W WO 2021153718 A1 WO2021153718 A1 WO 2021153718A1
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Prior art keywords
fgf21
sugar
preference
tagatose
sorbitol
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English (en)
French (fr)
Japanese (ja)
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佐々木　努
翔 松居
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Kyoto University NUC
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Kyoto University NUC
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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/045—Hydroxy compounds, e.g. alcohols; Salts thereof, e.g. alcoholates
    • A61K31/047—Hydroxy compounds, e.g. alcohols; Salts thereof, e.g. alcoholates having two or more hydroxy groups, e.g. sorbitol
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/70—Carbohydrates; Sugars; Derivatives thereof
    • A61K31/7004—Monosaccharides having only carbon, hydrogen and oxygen atoms
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/30—Drugs for disorders of the nervous system for treating abuse or dependence
    • A61P25/32—Alcohol-abuse
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P3/00—Drugs for disorders of the metabolism
    • A61P3/04—Anorexiants; Antiobesity agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K14/00—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof
    • C07K14/435—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from animals; from humans
    • C07K14/475—Growth factors; Growth regulators
    • C07K14/50—Fibroblast growth factor [FGF]

Definitions

  • the present invention relates to a fibroblast growth factor 21 (hereinafter referred to as "FGF21") inducer. More specifically, the present invention comprises at least one sugar selected from the group consisting of D-sorbitol, D-psicose, and D-tagatose, and sugar residues of the at least one sugar.
  • FGF21 fibroblast growth factor 21
  • the present invention relates to an FGF21 inducer containing either one or both of oligosaccharides.
  • the present invention also relates to a composition containing the FGF21 inducer for suppressing alcohol preference or simple sugar preference in mammals.
  • FGF21 is a hormone that regulates energy homeostasis and is induced to be expressed in the liver in response to various metabolic stresses including starvation and high carbohydrate diets. FGF21 acts via a complex of the cell membrane FGF receptor and the single transmembrane protein ⁇ -Klotho. FGF21 is known to regulate alcohol preference and sweetness preference (Non-Patent Document 1). The present inventors have found that the suppression of palatability for simple sugars is caused by the activation of oxytocin (Oxt) nerves in the brain by the formation of a complex of secreted FGF21 and ⁇ -Klotho (non-). Patent Document 2).
  • OFT oxytocin
  • Alcoholic beverages are popular as a part of life and culture.
  • alcohol is addictive and chronic exposure to alcohol can cause organ damage (eg, liver disease or stroke).
  • organ damage eg, liver disease or stroke.
  • Disulfiram, cyanamide solution, acamprosate, and nalmefene are commercially available as pharmaceuticals for suppressing the amount of alcohol.
  • Glucose is used as almost the only energy source in the brain and central nervous system, and plays an important role in life activities. However, excessively ingested sugar accumulates as fat in adipose tissue and causes obesity. It is reported that there are about 20 million obese patients and their reserve forces in Japan.
  • Mazindol and gastrointestinal lipase inhibitors are commercially available as pharmaceuticals for treating obesity.
  • One object of the present disclosure is to provide a novel composition capable of suppressing one or both of alcohol preference and simple sugar preference.
  • the present inventors focused on FGF21 as a target capable of suppressing one or both of alcohol preference and simple sugar preference. We examined various sugars that can be taken orally and found that certain rare sugars or sugar alcohols increase the amount of FGF21 secreted.
  • An exemplary embodiment of the present disclosure provides an FGF21 inducer, a composition for suppressing alcohol preference, and a composition for suppressing simple sugar preference. More specifically, the exemplary embodiments of the present disclosure provide the following embodiments.
  • [Item 1] At least one sugar selected from the group consisting of D-sorbitol, D-psicose and D-tagatose, and / or selected from the group consisting of D-sorbitol, D-psicose and D-tagatose.
  • Item 5 The FGF21 inducer according to Item 1, wherein at least two sugars selected from the group consisting of D-sorbitol, D-psicose and D-tagatose are contained as sugars and / or sugar residues. ..
  • a composition for suppressing alcohol preference in mammals which comprises the FGF21 inducer according to any one of Items 1 to 5.
  • [Item 7] A composition for suppressing simple sugar preference in mammals, which comprises the FGF21 inducer according to any one of Items 1 to 5.
  • [Item 8] The composition according to Item 6 or Item 7, which is a supplement.
  • [Item 9] The pharmaceutical composition according to Item 6, wherein the pharmaceutical composition for treating alcohol dependence is used.
  • [Item 10] The pharmaceutical composition according to Item 7, for treating obesity.
  • FIG. 1 (a) is a box-and-whisker plot showing the preference for 4% ethanol aqueous solution for ⁇ -Klotho Flox mice (white) and Oxt neuron-specific Klb knockout mice (gray), respectively.
  • FIG. 1B is a boxplot showing the preference for an 8% aqueous ethanol solution.
  • FIG. 1 (c) is a box-and-whisker plot showing the preference for a 16% aqueous ethanol solution.
  • FIG. 2A is a bar graph showing the preference for a 16% aqueous ethanol solution for mice fed a normal diet (NC: white) and mice fed a high sucrose diet (HSD: gray). Is.
  • NC normal diet
  • HSD high sucrose diet
  • FIG. 2B is a bar graph showing the preference for an 8% aqueous ethanol solution.
  • FIG. 2C is a bar graph showing the preference for a 4% ethanol aqueous solution.
  • 2 (d) to (f) show the mice fed the normal diet (white) and the mice fed the high sucrose diet (gray) shown in FIGS. 2 (a) to 2 (c). It is a bar graph which shows the plasma FGF21 concentration for each.
  • FIG. 2 (g) is a scatter plot showing the result of preference for the 16% ethanol aqueous solution shown in FIGS. 2 (a) and 2 (d) and the result of the plasma FGF21 concentration.
  • FIG. 2 (h) is a scatter plot showing the results of FIGS. 2 (b) and 2 (e), respectively.
  • FIG. 2 (i) is a scatter plot showing the results of FIGS. 2 (c) and 2 (f), respectively.
  • FIG. 3 (a) is a box-and-whisker plot showing the preference for a 100 mM sucrose aqueous solution for ⁇ -Klotho Flox mice (white) and Oxt neuron-specific Klb knockout mice (gray), respectively.
  • FIG. 3B is a boxplot showing the preference for a 0.2% saccharin aqueous solution.
  • FIG. 3C is a boxplot showing the preference for a 2% dextrin aqueous solution.
  • FIG. 11 (a) is a box-and-whisker plot showing the FGF21 concentration in mouse plasma administered with D-Sorbitol, D-Psicose, or D-Tagatose.
  • FIG. 11B is a bar graph showing the area under the FGF21 concentration-time curve (AUC) in mouse plasma. It is a bar graph which shows that the preference for a 50 mM sucrose aqueous solution is suppressed. It is a bar graph which shows that the preference for an 8% ethanol aqueous solution is suppressed.
  • sugar means a carbohydrate containing sugar or sugar alcohol.
  • the sugar according to the present disclosure means at least one compound selected from the group consisting of D-sorbitol, D-psicose and D-tagatose.
  • the sugar may be, for example, at least two compounds selected from the group consisting of D-sorbitol, D-psicose and D-tagatose.
  • the sugar may be D-sorbitol, D-psicose, or D-tagatose alone.
  • the sugar is a combination of D-sorbitol and D-psicose, a combination of D-psicose and D-tagatos, a combination of D-sorbitol and D-tagatos, or a combination of D-sorbitol, D-psicose and D.
  • -It may be a combination of tagatoses.
  • sugar or “simple sugar” means a monosaccharide or a disaccharide.
  • Simple sugars include, but are not limited to, glucose, fructose, sucrose, lactose and maltose.
  • polysaccharide means a sugar compound in which a plurality of sugars are bound to each other and has 20 or more sugars.
  • a polysaccharide consisting of only one type of monosaccharide is called a homoglycan, and a polysaccharide consisting of only one type of monosaccharide is also called a heteroglycan.
  • Polysaccharides include, but are not limited to, amylose, amylopectin, dextrin, starch, and glycogen.
  • synthetic sweetener means a compound that does not exist in nature and is produced by chemical synthesis and that makes the mammal feel sweet when taken orally. do. Synthetic sweeteners include, but are not limited to, aspartame, sucralose, neotame, advantame, saccharin, and acesulfame potassium.
  • oligosaccharide means a sugar compound in which a plurality of sugar residues are bound and is 3 sugars or more and less than 20 sugars.
  • the oligosaccharide according to the present disclosure is preferably 3 sugars or more and 10 sugars or less.
  • Oligosaccharides have, for example, a molecular weight of 300 to 3,000.
  • the oligosaccharide may consist of one type of sugar residue or two types of sugar residue.
  • Oligosaccharides are synthesized from at least one sugar selected from the group consisting of D-sorbitol, D-psicose and D-tagatose according to an organic chemical synthesis method or an enzymatic chemical synthesis method, but not limited to. Can be done.
  • Oligosaccharides can be synthesized, for example, by a method using a glycosyltransferase (glucosyltransferase) and / or a method using a reverse reaction of a glycosyltransferase (glycosidase).
  • D-sorbitol or “D-sorbitol” means a sugar alcohol represented by the formula 1.
  • Equation 1 Since D-sorbitol has a low calorie of about 75% as compared with sucrose, it is used as a sweetener for low-calorie foods.
  • D-sorbitol can be produced according to known methods and is also commercially available. Such known production methods include, but are not limited to, a method of reducing D-glucose with the enzyme aldose reductase. D-sorbitol can be commercially obtained, for example, from Tokyo Chemical Industry Co., Ltd.
  • D-psicose or “D-Psicose” means hexacarbonate sugar represented by the formula 2.
  • D-psicose also called allulose, uses only 0.3% of the calories of sucrose as energy.
  • D-psicose can be produced according to known methods and is commercially available. Such known production methods include, but are not limited to, a method of producing from fructose using the enzyme D-tagatos 3-epimerase, or a method of extracting from a plant of the genus Itea.
  • D-psicose can be obtained commercially, for example, from Tokyo Chemical Industry Co., Ltd.
  • D-tagatose or “D-Tagatose” means hexacarbonate sugar represented by the formula 3. (Equation 3) D-tagatose has 92% sweetness of sucrose, but only 38% of calories are used as energy. D-tagatose can be produced according to known methods and can also be commercially available. Known production methods include, but are not limited to, a method of hydrolyzing lactose to isomerize galactose separated from glucose by allowing calcium hydroxide to act in an alkaline environment. A solid D-tagatose can also be obtained by purifying and crystallizing the tagatose mixture obtained by the above method. D-tagatose is commercially available, for example, from Tokyo Chemical Industry Co., Ltd.
  • enantiomer means a stereoisomer having a mirror image relationship with an image that cannot be superimposed.
  • the stereoisomer of sugar is based on the three-dimensional configuration of d-glyceraldehyde, and the three-isomer corresponding to this configuration is the D-form, and the enantiomer thereof is the L-form.
  • D-sorbitol, D-psicose, and D-tagatose are all D-forms corresponding to the configuration of d-glyceraldehyde. From a mixture of different enantiomers, the desired enantiomer can be separated to increase its purity according to known methods. Such known methods include, but are not limited to, chiral HPLC.
  • FGF21 is a hormonal protein encoded by the Fgf21 gene in mammals and secreted from the liver.
  • FGF21 belongs to the endocrine FGF class of fibroblast growth factor (FGF) and acts via a cell membrane FGF receptor that forms a complex with the transmembrane protein ⁇ -Klotho.
  • FGF21 and ⁇ -Klotho can activate oxytocin (Oxt) nerves in the brain and suppress alcohol preference and simple sugar preference.
  • An increase in the amount of FGF21 in blood can suppress alcohol preference and simple sugar preference.
  • the amount of FGF21 in blood is the concentration of FGF21 in mammalian blood (whole blood, plasma or serum) (for example, ng / ml, nM) and the weight of FGF21 contained in a predetermined amount of blood (for example, ng, mg). It's okay.
  • the amount of FGF21 in blood can be measured according to a known method. Known methods include, but are not limited to, ELISA that utilizes an anti-FGF21 antibody.
  • the term "inducing agent” means a substance containing a substance that induces the expression of a desired product in the body of a mammal.
  • the compound may be composed of a single component or may be a composition containing two or more kinds of components.
  • the formulation may be in solid or liquid form, without limitation.
  • Inducers include, for example, substances that produce the desired product that is secreted into the blood within the cells of a mammal. In this example, the inducer can result in a desired increase in the amount of product in the blood of a mammal.
  • the "FGF21 inducer” means a substance containing a substance that induces the expression of FGF21 in the body of a mammal.
  • FGF21 inducers include, but are not limited to, substances that induce the expression of FGF21 secreted into blood in mammalian hepatocytes.
  • the FGF21 inducer according to the present invention is an oligosaccharide containing at least one sugar selected from the group consisting of D-sorbitol, D-psicose and D-tagatose, and sugar residues of the at least one sugar. Either or both of the above is contained as a substance that induces the expression of FGF21 in the body of a mammal.
  • the FGF21 inducer is a sugar of D-sorbitol, D-psicose or D-tagatose, and / or a sugar residue of D-sorbitol, D-psicose or D-tagatose.
  • FGF21 inducers containing only D-psicose, oligosaccharides containing D-psicose sugar residues, or both as components that induce FGF21 can increase the blood FGF21 concentration relatively quickly.
  • An FGF21 inducer containing only one of D-sorbitol and D-tagatose as a sugar and / or a sugar residue can maintain a high blood FGF21 concentration for a relatively long period of time.
  • the FGF21 inducer comprises at least two sugars selected from the group consisting of D-sorbitol, D-psicose and D-tagatose as sugars and / or sugar residues.
  • the FGF21 inducer is selected from the group consisting of at least two sugars selected from the group consisting of D-sorbitol, D-psicose and D-tagatose, and / or the group consisting of D-sorbitol, D-psicose and D-tagatose.
  • the at least two sugars or sugar residues are a combination of D-sorbitol and D-psicose, a combination of D-sorbitol and D-tagatos, a combination of D-psicose and D-tagatos, and D-sorbitol, D-. It may be a combination of psicose and D-tagatos.
  • the at least two sugars and / or the oligosaccharides can exert a synergistic or additive effect on the induction of FGF21.
  • the FGF21 inducer containing at least two kinds of sugars and / or the oligosaccharides can exert a high FGF21 inducing action while reducing the intake thereof.
  • FGF21 inducers containing D-tagatose and D-sorbitol or D-psicose as sugars and / or sugar residues can exert a high FGF21-inducing effect while reducing their intake.
  • FGF21 inducers containing D-tagatose and D-psicose as sugars and / or sugar residues increase the blood FGF21 concentration relatively quickly and are high for a relatively long time while reducing their intake.
  • the FGF21 concentration can be maintained.
  • FGF21 inducers containing D-psicose and D-tagatose or D-sorbitol as sugars and / or sugar residues increase FGF21 in blood relatively quickly and maintain high FGF21 concentrations for a relatively long period of time. obtain.
  • FGF21 inducers containing D-sorbitol and D-tagatose as sugars and / or sugar residues can maintain FGF21 at high concentrations for a relatively long period of time.
  • FGF21 inducers containing D-sorbitol, D-psicose and D-tagatose as sugars and / or sugar residues increase FGF21 in blood relatively quickly and maintain high FGF21 concentrations for a relatively long period of time. obtain.
  • the form of the FGF21 inducer is not limited, but may be an orally ingestible form, for example, a tablet, a capsule, a granule, a powder, a powder, a syrup, or a liquid.
  • the additives allowed for oral ingestion are, but are not limited to, excipients, disintegrants, binders, wetting agents, stabilizers, buffers, lubricants, preservatives, seasonings, flavoring agents, etc. It may be a fragrance, an acidulant, a colorant, or a combination thereof.
  • the FGF21 inducer can be produced, but not limited to, according to a known method according to the form thereof.
  • the FGF21 inducer is a powder, for example, an oligosaccharide containing the sugar residue of the at least one sugar in powder form and / or the sugar residue of the at least one sugar, and, if necessary, orally ingested. It can be produced by blending with an additive in an acceptable powder form.
  • the FGF21 inducer is a liquid agent, it can be produced, for example, by blending an oligosaccharide containing the sugar residue of the at least one sugar and / or the at least one sugar with the aqueous liquid preparation.
  • Formulation of FGF21 inducer containing at least one sugar selected from the group consisting of D-sorbitol, D-psicose and D-tagatose, and / or an oligosaccharide containing a sugar residue of the at least one sugar.
  • the amount is appropriately set according to the form of the agent.
  • the daily intake of the at least one sugar and / or the oligosaccharide containing the sugar residue of the at least one sugar contained in the FGF21 inducer is not limited, but is not limited.
  • the significance test can be performed by Tukey's test, but not limited to.
  • the mammal is, for example, a mouse.
  • the amount that can significantly increase the amount of FGF21 in blood in a mouse is, for example, 1 to 10 g / kg body weight, 3 to 7 g / kg body weight or 5 g / kg body weight.
  • the amount that significantly increases the amount of FGF21 in blood in mammals other than mice can be appropriately set by those skilled in the art in light of the disclosure contents of the present specification.
  • the sugar intake according to the present disclosure for mammals other than mice can be set according to, for example, the human equivalent dose (HED) based on body surface area.
  • HED human equivalent dose
  • the amount that significantly increases the amount of FGF21 in blood in humans is, for example, 100 mg to 1 g / kg body weight, 200 to 700 mg / kg body weight, 300 to 500 mg / kg body weight or 300 to 400 mg / kg body weight.
  • the number of times the FGF21 inducer is ingested per day may be, for example, one daily intake or a plurality of ingestion times.
  • the FGF21 inducer to be ingested once a day includes, for example, only the sugar of either D-sorbitol or D-tagatose as the component for inducing FGF21, and only the oligosaccharide containing the sugar residue of the sugar. Or both of them as sugars or sugar residues, or at least two sugars selected from the group consisting of D-sorbitol, D-psicose and D-tagatose, sugars of the at least two sugars. Contains oligosaccharides containing residues, or both.
  • the FGF21 inducer may be ingested as it is as a supplement, or may be ingested in addition to foods and drinks, without limitation.
  • composition may be in a solid form or a liquid form, without limitation.
  • the composition is, for example, a compound containing a substance that can suppress alcohol preference in mammals.
  • the composition can result in, for example, an increase in products in the blood of mammals that can play an inhibitory effect on alcohol preference.
  • the term "supplement” means a non-pharmaceutical composition that is orally ingested for the purpose of preventing the onset of predetermined symptoms in a mammal and maintaining the physical condition or health of the mammal.
  • the supplement is a functional food.
  • treatment means prevention of the onset of a predetermined symptom or condition, or treatment of a predetermined symptom or condition.
  • treatment means amelioration, alleviation, or complete cure of a predetermined medical condition or condition.
  • a composition for suppressing one or both of alcohol preference and simple sugar preference in mammals is selected from the group consisting of D-sorbitol, D-psicose and D-tagatose. At least one sugar and / or an oligosaccharide containing a sugar residue of the at least one sugar can suppress one or both of alcohol preference and simple sugar preference in mammals. Contains as a substance.
  • the composition contains, but is not limited to, the FGF21 inducer described herein.
  • the composition is a composition for suppressing alcohol preference in mammals.
  • the composition is a composition for suppressing simple sugar preference in mammals.
  • the composition is a composition for suppressing alcohol preference and simple sugar preference in mammals.
  • the form described for the FGF21 inducer is appropriately applied.
  • the composition for suppressing the preference for simple sugar is a composition for suppressing the preference for glucose, fructose, sucrose, lactose, and maltose.
  • the composition for suppressing the preference for simple sugars is a composition for suppressing the preference for glucose, fructose, and sucrose.
  • the composition for suppressing the preference for simple sugars suppresses the preference for simple sugars, but substantially alters the preference for one or both of synthetic sweeteners and polysaccharides. It is a composition that does not allow.
  • the composition for suppressing simple sugar preference is at least one sugar (eg, one or two) selected from the group consisting of D-sorbitol and D-tagatose, and / Or contains an oligosaccharide containing a sugar residue of at least one of the above sugars.
  • the synthetic sweetener is, but is not limited to, at least one compound selected from the group consisting of aspartame, sucralose, neotame, advantame, saccharin, and acesulfame potassium.
  • the synthetic sweetener is, for example, saccharin.
  • the polysaccharide is, but is not limited to, at least one compound selected from the group consisting of amylose, amylopectin, dextrin, starch, and glycogen.
  • the polysaccharide is, for example, dextrin.
  • the composition for suppressing simple sugar preference is a composition that suppresses the preference for simple sugar but does not substantially change the preference for saccharin and dextrin.
  • the composition for suppressing alcohol preference is for suppressing preference for an aqueous composition (eg, alcoholic beverage) containing a substance (eg, ethanol) in which a hydrocarbon atom is replaced with a hydroxyl group. It is a composition of.
  • the composition for suppressing alcohol preference is at least one sugar (eg, one or two) selected from the group consisting of D-psicose and D-tagatose, and / or It contains an oligosaccharide containing a sugar residue of at least one of the above sugars.
  • the daily intake of oligosaccharides containing the sugar residue of the above is not limited, but either or both of the alcohol preference and the simple sugar preference of the mammal before ingesting the composition. This is an amount that significantly reduces either or both of the alcohol preference and the simple sugar preference of the mammal ingesting the composition for one week.
  • the significance test can be performed by Tukey's test, but not limited to.
  • the mammal is, for example, a mouse.
  • the amount that can significantly increase the amount of FGF21 in blood in a mouse is, for example, 1 to 10 g / kg body weight, 3 to 7 g / kg body weight or 5 g / kg body weight.
  • the amount that significantly increases the amount of FGF21 in blood in mammals other than mice can be appropriately set by those skilled in the art in light of the disclosure contents of the present specification.
  • the amount that significantly increases the amount of FGF21 in blood in humans is, for example, 100 mg to 1 g / kg body weight, 200 to 700 mg / kg body weight, 300 to 500 mg / kg body weight or 300 to 400 mg / kg body weight.
  • the term "pharmaceutical” or “pharmaceutical composition” means a substance containing a substance for treating a predetermined symptom or sign in a mammal.
  • the formulation may be in solid or liquid form, without limitation.
  • a pharmaceutical or pharmaceutical composition is, for example, a compound containing a substance for treating alcohol dependence in a mammal.
  • the pharmaceutical or pharmaceutical composition may provide a prophylactic, therapeutic, or alleviating effect on alcohol dependence.
  • pharmaceutical for treating obesity or “pharmaceutical for treating alcohol dependence” is at least one selected from the group consisting of D-sorbitol, D-psicose and D-tagatose.
  • a sugar and / or an oligosaccharide containing a sugar residue of at least one of the above sugars is blended as a substance for treating obesity or alcoholism.
  • the medicament comprises, but is not limited to, the FGF21 inducer described herein.
  • the medicament is a pharmaceutical composition for the treatment of obesity.
  • Pharmaceutical compositions for the treatment of obesity are administered, for example, for the purpose of reducing the intake of simple sugars.
  • the medicament is a pharmaceutical composition for the treatment of alcohol dependence.
  • compositions for the treatment of alcohol dependence are administered, for example, for the purpose of reducing the intake of alcoholic beverages (alcoholic beverages).
  • the pharmaceutical composition for the treatment of alcohol dependence is at least one sugar selected from the group consisting of D-psicose and D-tagatose, and / or a sugar of the at least one sugar. Contains oligosaccharides containing residues.
  • the form of the pharmaceutical is not limited, but may be an orally ingestible form, for example, a tablet, a capsule, a granule, a powder, a powder, a syrup, or a liquid.
  • an additive known in the pharmaceutical field and an additive described for the FGF21 inducer can be appropriately used.
  • the drug can be produced, but not limited to, according to a known method according to its form.
  • the number of times of ingestion of the composition or the medicine disclosed in the present specification per day may be, for example, one daily intake or a plurality of ingestion times.
  • the compositions or pharmaceuticals disclosed herein, which are ingested once daily include, for example, only the sugar of either D-sorbitol or D-tagatose as a component for inducing FGF21, and the sugar residue of the sugar.
  • the FGF21 inducer or medicament described herein is at least one sugar selected from the group consisting of D-sorbitol, D-psicose and D-tagatose, with the total amount being 100% by weight. It contains 1 to 99% by mass, 5 to 80% by mass, and 10 to 50% by mass of oligosaccharides containing sugar residues of quality and / or at least one of the above sugars. In one embodiment, the FGF21 inducers or pharmaceuticals described herein contain 1-99% by weight of D-sorbitol, D-psicose, or D-tagatose, with a total amount of 100% by weight, 5-80% by weight. %, 10 to 50% by mass.
  • alcohol means a group of physiological, behavioral, and / or cognitive phenomena in which drinking is of great value to the subject and takes precedence over other behaviors.
  • Physiological conditions in alcoholism include a group of alcohol withdrawal symptoms, including seizures and hallucinations, due to discontinuation of alcohol consumption or decreased alcohol consumption.
  • Cognitive phenomena in alcoholism include a strong desire to drink, a feeling of threat (craving), loss of control over drinking or drinking, and diminished or lost interest in non-drinking entertainment.
  • Alcohol addiction may be associated with the acquisition of alcohol tolerance. Alcohol tolerance means that you have to drink more than before to get the same degree of sickness.
  • “obesity” means a condition requiring weight loss with a health disorder caused by or related to obesity (hereinafter, also referred to as “obesity-related disease”).
  • Obesity-related diseases include glucose intolerance (eg, impaired glucose tolerance, impaired glucose tolerance), dyslipidemia, hypertension, hyperuricemia or gout, coronary artery disease (eg, myocardial infarction, or angina), cerebral infarction (eg, cerebral infarction).
  • Cerebral thrombosis or transient cerebral ischemic attack impaired glucose tolerance or impaired glucose tolerance (eg, pregnancy hypertension syndrome, pregnancy diabetes, or hearing loss), sleep aspiration syndrome or obesity hypoventilation syndrome, orthopedic disease (For example, glucose tolerance, spondylosis deformans), and obesity-related kidney disease.
  • the FGF21 inducer is orally ingested by, for example, a mammal.
  • the medicine is administered to a mammal.
  • Mammals may be, but are not limited to, humans, primates (monkeys, chimpanzees), livestock animals (cows, horses, pigs, sheep), pets (dogs, cats). Mammals are preferably humans.
  • the drug is preferably administered orally to humans.
  • the composition for suppressing alcohol preference is orally ingested by alcoholics, addiction reserves or high-risk drinkers.
  • the composition for suppressing simple sugar preference is orally ingested by an obese patient or an obese reserve army person.
  • the medicament for treating alcoholism is orally administered to an alcoholic patient. In one embodiment, the medicament for treating obesity is orally administered to an obese patient.
  • At least one sugar selected from the group consisting of D-sorbitol, D-psicose and D-tagatose for producing a medicament for treating alcoholism or obesity in mammals.
  • the use of qualities and / or oligosaccharides containing the sugar residues of at least one of the above-mentioned sugars is provided.
  • the features described herein for FGF21 inducers, compositions or pharmaceuticals also apply to this embodiment.
  • a method of treating alcoholism or obesity comprising orally administering to a mammal in need thereof a medicine for treating alcoholism or obesity, wherein the medicine.
  • a medicine for treating alcoholism or obesity wherein the medicine.
  • the use of oligosaccharides containing quality sugar residues in said mammals is provided.
  • the amount of FGF21 in the blood is increased as compared with the amount of FGF21 in the blood before the use of the sugar and / or the oligosaccharide.
  • the features described herein for FGF21 inducers, compositions or pharmaceuticals are also included in this embodiment.
  • a method of inducing FGF21 in a mammal at least one sugar selected from the group consisting of D-sorbitol, D-psicose and D-tagatose, and / or at least one of the above.
  • a method comprises administering to a mammal an oligosaccharide containing a sugar residue of the sugar of.
  • the amount of FGF21 in the blood is increased as compared with the amount of FGF21 in the blood before administration of the sugar and / or the oligosaccharide.
  • the features described herein for FGF21 inducers, compositions or pharmaceuticals are also included in this embodiment.
  • Example 1 9-week-old male ⁇ -Klotho Flox mice were used as the control group.
  • Test solution A 4% ethanol aqueous solution, an 8% ethanol aqueous solution, and a 16% ethanol aqueous solution were used as test solutions.
  • (2 bottle selection test) ⁇ First period (adaptation to experimental conditions): Present two water bottles for measuring the amount of trace water containing sterilized water for 24 hours and four days, and drink water from the two water bottles for measuring the amount of water consumed. I made them learn.
  • -Second period Measurement of preference for the baseline test solution: Two water bottles for measuring the amount of micro-drinking water containing sterilized water and the water bottle for measuring the amount of micro-drinking water containing the test solution for 24 hours, 4 Presented for days. To eliminate the effect of palatability on the location, the two water bottles for measuring trace water intake were repositioned every 24 hours.
  • FIGS. 1 (a) to 1 (c) show that the preference for alcohol was increased in oxytocin (Oxt) nerve-specific ⁇ -Klotho knockout mice (gray) as compared with ⁇ -Klotho Flox mice (white). show.
  • Example 2 A 9-week-old male C57BL / 6JJcl mouse (Nippon Marie Co., Ltd.) was used. (Breeding conditions) Mice were individually bred under basically the same conditions as in Example 1 except that the solid diet (CE-2) was changed to the powder diet (CE-2). During the test period below, the diet was replaced with new diet as appropriate. In the fourth period below, powdered diet (CE-2) and high sucrose powdered diet (high sucrose diet; Oriental Bio Service Co., Ltd.) were given to the corresponding groups, respectively. (Test solution) An aqueous ethanol solution having the same concentration as in Example 1 was used. (Measurement of ingested solution amount and calculation of palatability) The same method as in Example 1 was used.
  • Second period (adaptation to experimental conditions): Present two water bottles for measuring the amount of trace water containing sterilized water for 24 hours and four days, and drink water from the two water bottles for measuring the amount of water consumed. I made them learn.
  • -Second period (measurement of preference for the baseline test solution): Two bottles, a water bottle for measuring the amount of micro-drinking water containing sterilized water and a water bottle for measuring the amount of water drunk containing the test solution, for 24 hours. Presented for 4 days. To eliminate the effect of palatability on the location, the two water bottles for measuring trace water intake were repositioned every 24 hours.
  • -Third period (cool-off period for eliminating the influence of alcohol in the second period): Two water bottles for measuring the amount of trace water consumed containing sterilized water were presented for 24 hours and 7 days.
  • mice ingesting powdered food were used as the control group.
  • Two groups of mice ingesting a high sucrose diet (HSD) powder diet (high sucrose diet; Oriental Bio Service Co., Ltd.) were used as experimental groups.
  • the food was fed by a multi-feeder for mice and replaced with a new powder food every 24 hours.
  • -Fifth period blood collection: After the fourth period, one water bottle containing sterile water was presented for 24 hours, and then blood was collected from the heart under anesthesia. Blood was treated with heparin (final concentration: 10 ⁇ g / ml; Wako Pure Chemical Industries, Ltd.) and then centrifuged at 4 ° C., 2000 rpm for 20 minutes, and plasma was collected. Plasma FGF21 concentration was measured using Fibroblast Growth Factor 21 Mouse / Rat ELISA (BioVendor) according to the attached instructions.
  • FIGS. 2 (d) to 2 (f) show FGF21 in plasma in the experimental group (gray) ingesting a high sucrose diet as compared with the control group (white) ingesting a normal diet (CE-2). Indicates that the concentration has increased significantly.
  • FIGS. 2 (g) to 2 (i) show that there is a negative correlation between alcohol preference and plasma FGF21 concentration.
  • Test solution 0.2% saccharin (Fujifilm Wako Pure Chemical Industries, Ltd.), 100 mM sucrose (Fujifilm Wako Pure Chemical Industries, Ltd.), and 2% dextrin (Fujifilm Wako Pure Chemical Industries, Ltd.) adjusted to the specified concentration using sterile water. Co., Ltd.) was used as a test solution.
  • (2 bottle selection test) ⁇ First period (adaptation to experimental conditions): Present two water bottles for measuring the amount of trace water containing sterilized water for 24 hours and four days, and drink water from the two water bottles for measuring the amount of water consumed. I made them learn.
  • -Second period (measurement of preference for test solution): Two water bottles for measuring micro-drinking amount containing sterilized water and a water bottle for measuring micro-drinking amount containing test solution were presented for 24 hours and 3 days. .. To eliminate the effect of palatability on the location, the two water bottles for measuring trace water intake were repositioned every 24 hours.
  • FIG. 3 shows that the preference for the simple saccharide sucrose was significantly increased in the oxytocin (Oxt) nerve-specific ⁇ -Klotho knockout mouse (gray) as compared with the ⁇ -Klotho Flox mouse (white). Show that you did.
  • 3 (b) and 3 (c) are synthetic sweeteners in oxytocin (Oxt) nerve-specific ⁇ -Klotho knockout mice (gray), respectively, as compared to ⁇ -Klotho Flox mice (white).
  • Example 4 (Preparation of primary cultured hepatocytes) Using 9-week-old male C57BL / 6JJcl mice (Nippon Claire Co., Ltd.), primary cultured hepatocytes were prepared according to the following procedure. Under anesthesia, a silicone tube was inserted into the portal vein of the mouse and the subabdominal aorta was amputated. At the same time as the aorta was cut, the EGTA solution (37 ° C.) was poured through the silicon tube inserted into the portal vein, and then the collagenase solution (37 ° C.) was poured. The liver was then dissected and transferred to a petri dish. Hepatocytes were released from the dissected liver by pipetting.
  • the culture medium was Williams' medium E (Sigma-Aldrich), fetal bovine serum (10%; ThermoFisher), ITS-G supplement (x100) (1 ⁇ M; Fujifilm Wako Pure Chemical Industries, Ltd.), dexamethasone (1 ⁇ M; Fujifilm sum). The one prepared by adding Kojunyaku Co., Ltd. was used.
  • the prepared primary cultured hepatocytes were placed in a culture medium supplemented with a test solution of each sugar 1 to 6 shown in the table below so as to have a concentration of 25 mM or a culture medium supplemented with the same volume of Vehicle (distilled water). Incubated for hours.
  • FIG. 5 shows that Vehicle and 25 mM D-mannitol are classified into group a, which are significantly different from the amount of FGF21 secreted by 25 mM D-Glucose or 5 mM D-Tagatose classified into group b.
  • FIG. 5 shows that the amount of FGF21 secreted by the addition of D-Tagatose increases significantly depending on the dose.
  • Example 6 (Experiment of addition of sugar or sugar alcohol to primary cultured hepatocytes and measurement of FGF21 secretion)
  • the primary hepatocytes prepared in the same manner as in Example 4 were subjected to a culture solution or a vehicle (distilled water) having the same volume to which a test solution of each sugar or sugar alcohol 1 to 48 shown in the following table was added so as to be 25 mM.
  • the cells were cultured in the added culture solution for 24 hours.
  • the culture supernatant was collected and stored at ⁇ 30 ° C. until the amount of FGF21 in the culture supernatant was measured.
  • Test results The results of the amount of FGF21 in the culture supernatant to which each test solution was added are summarized in FIG.
  • FIG. 6 the average value of the positive control is shown by a dash line.
  • FIG. 6 shows that when D-Fructose, D-Sorbitol, D-Xylitol, D-Arabitol, D-Psicose, and D-Tagatose were added to the culture medium, the expression level of FGF21 by the positive control was exceeded.
  • D-Xylitol is known to increase Fgf21 gene expression (Uebanso T et al. PLos One. 2011; 6 (8): e22976.).
  • D-Sorbitol D-Psicose
  • D-Tagatose D-Tagatose
  • the concentration in the culture solution was set to a series of concentrations of 5 mM, 10 mM, 15 mM, and 25 mM, and the cells were cultured in the same manner as above.
  • D-Tagatose As in Example 5, the expression level of FGF21 also increased in a dose-dependent manner of D-Tagatose, except that the expression level of FGF21 was highest at 15 mM. At the same concentration of 25 mM, D-Sorbitol and D-Tagatose had a higher ability to stimulate FGF21 secretion than D-Glucose.
  • Example 7 In the same manner as in Example 4 except that the test solutions of sugars or sugar alcohols 1 to 4 shown in the following table were added so as to be 25 mM in place of the sugar (Table 1) used in Example 4. , The amount of FGF21 mRNA was measured. The amount of FGF21 mRNA was measured 4 hours, 8 hours, 12 hours and 24 hours after the addition of sugar or sugar alcohol.
  • Example 8 In the same manner as in Example 4 except that the test solutions of sugars or sugar alcohols 1 to 5 shown in the following table were added so as to be 25 mM instead of the sugar (Table 1) used in Example 4. , The amount of FGF21 mRNA was measured. The amount of FGF21 mRNA was measured 4 hours, 8 hours, 12 hours and 24 hours after the addition of sugar or sugar alcohol.
  • FIG. 9 shows that the expression level of the Fgf21 gene was significantly increased 4 to 12 hours after the addition of D-Psicose.
  • FIG. 9 shows that the expression level peaked 4 or 8 hours after the addition of D-Psicose and decreased to the same level as Vehicle at 24 hours.
  • FIG. 10 shows that the expression level of the Fgf21 gene was significant (the expression level of the Fgf21 gene was significant when all the combinations of sugars used in Example 9 and the sugars of D-Fructose, D-Tagatose, D-Sorbitol and D-Xylitol alone were used. It shows that it increased to P ⁇ 0.01).
  • the expression level of the Fgf21 gene was highest when the combination of D-Tagatose and D-Sorbitol was used.
  • the amount of increase from the total expression level of the Fgf21 gene when each sugar was used was the largest when the combination of D-Tagatose and D-Psicose was used.
  • the combination of D-Tagatose and D-Sorbitol and the combination of D-Tagatose and D-Psicose are more than the total Fgf21 gene expression level of each of the two sugars constituting each combination, Fgf21 in the combination.
  • the gene expression level was higher (Fig. 10).
  • the Fgf21 gene expression level when the combination of D-Xylitol and D-Tagatose, the combination of D-Xylitol and D-Sorbitol, or the combination of D-Xylitol and D-Psicose is used constitutes each combination. It was less than or almost equivalent to the total expression level of Fgf21 gene in each of the two sugars (Fig. 10). These results indicate that the combination does not have a synergistic effect on Fgf21 gene expression.
  • Example 10 (mouse) A 9-week-old male C57BL / 6JJcl mouse (Claire Japan) was used. (Breeding conditions) The same breeding conditions as in Example 1 were used.
  • mice were orally administered 5 g / kg body weight of distilled water or various sugars D-Glucose, D-Tagatose, D-Psicose or D-Sorbitol. After 4 hours, 6 hours, 8 hours, 12 hours and 24 hours of oral administration, 80 ⁇ L of blood was collected from the tail vein of mice using a hematocrit capillary tube (heparin treatment; AS ONE). The collected blood was centrifuged at 2,000 g ⁇ 20 minutes at 4 ° C., plasma was collected and stored at ⁇ 30 ° C. until analysis. (Measurement of FGF21 amount in plasma) The amount of FGF21 in the collected plasma was measured using Fibroblast Growth Factor 21 Mouse / Rat ELISA as in Example 2.
  • FIG. 11b shows that D-Psicose, D-Tagatose and D-Sorbitol all significantly increased the amount of FGF21 in plasma, and that the AUC values for each sugar were almost the same.
  • Example 11 (mouse) A 9-week-old male C57BL / 6JJcl mouse (Claire Japan) was used. (Breeding conditions) The same breeding conditions as in Example 1 were used. (Test solution) A 50 mM sucrose aqueous solution was used as the test solution.
  • Second period (adaptation to experimental conditions): Present two water bottles for measuring the amount of trace water containing sterilized water for 24 hours and four days, and drink water from the two water bottles for measuring the amount of water consumed. I made them learn.
  • -Second period (baseline measurement): A water bottle for measuring a small amount of drinking water containing sterilized water and a water supply for measuring a small amount of drinking water containing a 50 mM sucrose aqueous solution to mice to which 5 g / kg of body weight of distilled water was orally administered. Two bottles of water were presented for 24 hours and 2 days. To eliminate the effect of palatability on the location, the two water bottles for measuring trace water intake were repositioned every 24 hours.
  • -Third period administration experiment: The same test as in the second period was performed on mice to which 5 g / kg body weight vehicle (distilled water) or various sugars D-Tagatose, D-Psicose or D-Sorbitol were orally administered. went. (Measurement of ingested solution amount) The amount of the solution ingested by the mouse was measured using a water bottle for measuring the amount of trace water intake for mice and rats (Drink-O-Measurer, manufactured by Shin Factory).
  • FIG. 12 shows that the amount of 50 mM sucrose aqueous solution consumed was significantly reduced in the group of mice to which D-sorbitol or D-Tagatose was administered (*: p ⁇ 0.05).
  • Example 12 (mouse) A 9-week-old C57BL / 6JJcl male mouse (Claire Japan) was used. (Breeding conditions) The same breeding conditions as in Example 1 were used. (Test solution) 8% ethanol was used as the test solution. The ethanol concentration was adjusted using sterile water.
  • Second period (adaptation to experimental conditions): Present two water bottles for measuring the amount of trace water containing sterilized water for 24 hours and two days, and drink water from the two water bottles for measuring the amount of water consumed. I made them learn.
  • -Second period (measurement of preference for the baseline test solution): Two water bottles for measuring the amount of micro-drinking water containing sterilized water and the water bottle for measuring the amount of micro-drinking water containing the test solution for 24 hours, 6 Presented for ⁇ 7 days. To eliminate the effect of palatability on the location, the two water bottles for measuring trace water intake were repositioned every 24 hours.
  • the amount of the solution ingested by the mouse was measured using a water bottle for measuring the amount of trace water intake for mice and rats (Drink-O-Measurer, manufactured by Shin Factory).
  • -Third period (measurement of change in palatability due to sugar administration): For mice whose palatability for alcohol was 66% or more in the second period, a water bottle for measuring a small amount of drinking water containing sterilized water was used. Two water bottles for measuring a small amount of drinking water containing the test solution were presented for 24 hours and 2 days.
  • 5 g / kg body weight vehicle (distilled water) or various sugars D-Tagatose, D-Sorbitol or D-Psicose were orally administered (once / day; 14:00) to improve palatability. It was measured.

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