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WO2020218382A1 - Sécrétagogue de glp-1 - Google Patents

Sécrétagogue de glp-1 Download PDF

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Publication number
WO2020218382A1
WO2020218382A1 PCT/JP2020/017402 JP2020017402W WO2020218382A1 WO 2020218382 A1 WO2020218382 A1 WO 2020218382A1 JP 2020017402 W JP2020017402 W JP 2020017402W WO 2020218382 A1 WO2020218382 A1 WO 2020218382A1
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WO
WIPO (PCT)
Prior art keywords
sample
concentration
glp
reba
solution
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Ceased
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PCT/JP2020/017402
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English (en)
Japanese (ja)
Inventor
聡一郎 浦井
浩二 長尾
芳明 横尾
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Suntory Holdings Ltd
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Suntory Holdings Ltd
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Priority to JP2021516181A priority Critical patent/JPWO2020218382A1/ja
Publication of WO2020218382A1 publication Critical patent/WO2020218382A1/fr
Anticipated expiration legal-status Critical
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    • A—HUMAN NECESSITIES
    • A23—FOODS OR FOODSTUFFS; TREATMENT THEREOF, NOT COVERED BY OTHER CLASSES
    • A23L—FOODS, FOODSTUFFS OR NON-ALCOHOLIC BEVERAGES, NOT OTHERWISE PROVIDED FOR; PREPARATION OR TREATMENT THEREOF
    • A23L33/00—Modifying nutritive qualities of foods; Dietetic products; Preparation or treatment thereof
    • A23L33/10—Modifying nutritive qualities of foods; Dietetic products; Preparation or treatment thereof using additives
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/70—Carbohydrates; Sugars; Derivatives thereof
    • A61K31/7028—Compounds having saccharide radicals attached to non-saccharide compounds by glycosidic linkages
    • A61K31/7034—Compounds having saccharide radicals attached to non-saccharide compounds by glycosidic linkages attached to a carbocyclic compound, e.g. phloridzin
    • A61K31/704—Compounds having saccharide radicals attached to non-saccharide compounds by glycosidic linkages attached to a carbocyclic compound, e.g. phloridzin attached to a condensed carbocyclic ring system, e.g. sennosides, thiocolchicosides, escin, daunorubicin
    • 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
    • A61P3/00—Drugs for disorders of the metabolism
    • A61P3/08—Drugs for disorders of the metabolism for glucose homeostasis
    • A61P3/10—Drugs for disorders of the metabolism for glucose homeostasis for hyperglycaemia, e.g. antidiabetics
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07H—SUGARS; DERIVATIVES THEREOF; NUCLEOSIDES; NUCLEOTIDES; NUCLEIC ACIDS
    • C07H15/00—Compounds containing hydrocarbon or substituted hydrocarbon radicals directly attached to hetero atoms of saccharide radicals
    • C07H15/20—Carbocyclic rings
    • C07H15/24—Condensed ring systems having three or more rings
    • C07H15/256—Polyterpene radicals

Definitions

  • the present invention relates to a GLP-1 secretagogue and the like. More specifically, the present invention relates to a GLP-1 secretagogue containing a steviol glycoside having a structure to which rhamnose is bound.
  • GLP-1 [Glucagon-like peptide-1] is a hormone secreted from the gastrointestinal mucosal epithelium and the like. Known actions of GLP-1 include stimulation of insulin synthesis and secretion, inhibition of glucagon secretion, inhibition of food intake, and reduction of hyperglycemia. By activating the secretion of GLP-1, these effects can be expected to be improved.
  • Patent Document 1 describes a GLP-1 secretion-promoting composition containing at least one component (A) selected from 11 types of curbitan-type triterpenes contained in bitter gourd. Further, Patent Document 2 describes that stevioside, rebaugioside A, rebaugioside B, and rebaugioside D have a property of promoting the secretion of GLP-1.
  • a GLP-1 secretagogue characterized by containing 0.4 to 4,440 ppm of a steviol glycoside having a structure to which rhamnose is bound.
  • a pharmaceutical composition comprising the GLP-1 secretagogue according to any one of the above [1] to [4].
  • the GLP-1 secretagogue of the present invention can be used in applications where promotion of GLP-1 secretion is desired.
  • 6 is a graph showing the relationship between the concentration of the mixed solution of the RebA-containing sample and the emulsified particle-containing sample and the amount of GLP-1 secreted obtained in Experimental Example 11. It is a graph which shows the relationship between the concentration of the glycerin-containing sample obtained in Experimental Example 12 and the amount of GLP-1 secretion. It is a graph which shows the relationship between the concentration of the MCT oil-containing sample obtained in Experimental Example 13 and the amount of GLP-1 secretion. It is a graph which shows the cytotoxicity (indicator of dead cell) of various samples obtained in Experimental Examples 15-20.
  • a is the result 2 hours after administration, and b is the result 24 hours after administration.
  • a is the result 2 hours after administration, and b is the result 24 hours after administration.
  • It is a figure which shows the influence of the storage temperature on the flavor characteristic in Experimental Example 33.
  • a steviol glycoside having a rhamnose-bound structure such as RebC acts on cells of humans or non-human animals having GLP-1 secretory ability by itself to secrete GLP-1. It was found that it has the effect of increasing GLP-1, that is, it has the ability to promote GLP-1 secretion.
  • GLP-1 secretagogue GLP-1 secretagogue composition
  • Rhamnose is a hexose having the following structure and represented by the chemical formula C 6 H 12 O 5 .
  • Rhamnose is sometimes called 6-deoxymannose, mannomethyrose.
  • the rhamnose-based steviol glycoside contains at least one selected from the group consisting of rebaugioside C, rebaugioside K, zulucoside A, zulucoside C, zulucoside D and zulucoside F. More preferably, the rhamnose-based steviol glycoside comprises rebaugioside C.
  • Zulcoside A The structures of Zulcoside A, Zulcoside C, Zulcoside D and Zulcoside F are as follows.
  • the content ratio of the rhamnose-based steviol glycoside in the GLP-1 secretion promoter of the present invention is 0.4 to 4,440 ppm.
  • .4-40 0.4-30, 0.4-20, 0.4-10, 0.4-5, 0.4-1, 1-4,440, 5-4,440, 10-4 , 440, 50-4,440, 100-4,440, 300-4,440, 500-4,440, 700-4,440, 900-4,440, 1,000-4,440, 2,000 To 4,440, 3,000 to 4,440, 1 to 3,440, 5 to 2,440, 10 to 1,440, 50 to 940 or 100 to 440 ppm.
  • the content ratio of the rhamnose-based steviol glycoside in the GLP-1 secretagogue of the present invention is 5, 10, 15, 20, 25, 30, 35, 40, 45, 50, 55, 60. , 65, 70, 75, 80, 85, 90, 95, 96, 97, 98 or 99% by mass or more, and a suitable upper limit value is 100% by mass or less.
  • the content ratio of the rhamnose-based steviol glycoside in the GLP-1 secretagogue of the present invention is 95 to 10,000 or 950 to 10,000 ppm on a mass basis.
  • a rhamnose-based steviol glycoside may be combined with another glycoside sweetener.
  • glycoside sweeteners include, for example, steviol, rebaudioside A, rebaugioside B, rebaugioside D, rebaudioside F, rebaugioside M, rebaudioside N, rebaugioside O, rebaugioside E, rubusoside and other ramnorth-free steviol glycosides; Mogrosides such as mogroside IV, 11-oxo-MogV, siamenocid I, and mogroside V (hereinafter, mogroside may be abbreviated as Mog); glycyrrhizic acid glycosides; and the like.
  • glycoside sweeteners preferably contain those having GLP-1 secretagogue, and include steviol glycosides or mogrosides without ramnorose, provided that they have GLP-1 secretagogue. More preferably, it further preferably contains at least one selected from the group consisting of RebA, RebB, stevioside or mogroside V, and particularly preferably contains RebA.
  • P is preferably in the following numerical range. 1-100,000, 5-100,000, 10-100,000, 30-100,000, 50-100,000, 70-100,000, 90-100,000, 100-100,000, 200-100,000, 300-100,000, 400-100,000, 500-100,000, 600- 100,000, 700-100,000, 800-100,000, 900-100,000, 1-9,000, 5-9,000, 10-9,000, 30-9,000, 50-9,000, 70-9,000, 90-9,000, 100-9,000, 200-9,000, 300-9,000, 400-9,000, 500-9,000, 600-9,000, 700-9,000, 800-9,000, 900-9,000, 1-8,000, 5-8,000, 10-8,000, 30-8,000, 50-8,000, 70- 8,000, 90-8,000, 100-8,000, 200-8,000, 300-8,000, 400-8,000, 500-8,000, 600-8,000, 700-8,000, 800-8,000, 900-8,000, 1-7,000, 5-8,000, 10-8,000, 30-8,000, 50-8,000, 70- 8,000, 90-8,000, 100-8,000, 200-8,000,
  • P is preferably in the following numerical range.
  • P is preferably in the following numerical range. 100-10,000, 200-10,000, 300-10,000, 400-10,000, 500-10,000, 600-10,000, 700-10,000, 800-10,000, 900-10,000, 1,000-10,000, 2,000-10,000, 3,000-10,000, 4,000- 10,000, 5,000-10,000, 6,000-10,000, 7,000-10,000, 8,000-10,000, 9,000-10,000, 100-9,000, 200-9,000, 300-9,000, 400-9,000, 500-9,000, 600-9,000, 700-9,000, 800-9,000, 900-9,000, 1,000-9,000, 2,000-9,000, 3,000-9,000, 4,000-9,000, 5,000-9,000, 6,000-9,000, 7,000-9,000, 8,000-9,000, 100-8,000, 200-8,000, 300- 8,000, 400-8,000, 500-8,000, 600-8,000, 700-8,000, 800-8,000, 900-8,000, 1,000-8,000, 2,000-8,000, 3,000-8,000, 4,000-8,000, 5,000-8,000, 6,000-8,000, 7,000-8,000, 100-7,000, 200-7,000, 300-7,000, 400-7,000, 500
  • the GLP-1 secretagogue of the present invention may contain components other than the above-mentioned rhamnose-based steviol glycoside and other glycoside sweeteners appropriately contained, as long as the effects of the present invention are not impaired. ..
  • Other ingredients include rhamnose-based steviol glycosides and other sweeteners other than glycoside sweeteners, emulsifiers, proteins, glycoproteins, excipients, binders, disintegrants, coatings, lubricants. , Colorants, flavoring agents, stabilizers, absorption promoters, pH adjusters, preservatives, antioxidants, fragrances, vitamins, trace metal components and the like.
  • sweeteners may be natural sweeteners, sugar alcohols, artificial sweeteners and the like.
  • glucose fructose; maltose; sucrose; lactose; rare sugars; peptide-based sweeteners such as aspartame, neotheme, and ariteme; sucrose derivatives such as sucralose; synthetic sweeteners such as assesulfam K, saccharin, advantheme, ticlo, and zultin.
  • Vegetable protein-based sweeteners such as monerin, curculin, brazein, and somatin; taumarin; neohesperidin dihydrocalcone; sugar alcohols such as erythritol, xylitol, sorbitol, martitol, and mannitol; high fructose syrup; High fructose corn syrup; oligo sugar; honey; sugar cane juice (brown sugar honey); sugar (sucrose, warm sugar, brown sugar, Japanese bonsai, etc.); maple syrup; moraces (sugar honey); water candy and the like.
  • the GLP-1 secretion-promoting agent of the present invention may have any shape, and may be, for example, solid (for example, powder), gel or liquid.
  • the GLP-1 secretagogue of the present invention can be used for the purpose of actions / functions caused by or related to the GLP-1 secretagogue action.
  • the GLP-1 secretagogue of the present invention is used for suppressing blood glucose elevation, suppressing appetite, suppressing overeating, improving glucose metabolism, preventing or treating diabetes, preventing or treating obesity, and body weight. It can be used for at least one application selected from reduction and reduction of body fat percentage. Preferably, it can be used for at least one application selected from for improving glucose metabolism, for suppressing appetite, and for preventing or ameliorating diabetes or obesity.
  • vascular diseases such as atherosclerosis, neurodegenerative diseases, non-alcoholic hepatitis, ulcers, and asthma (see: Young-Sun Lee et al., "Anti-Inflammatory”. Effects of GLP-1-Based Therapies beyond Glucose Control ", Mediators of Inflammation Volume 2016, Article ID 3094642, 11 pages).
  • the GLP-1 secretagogue of the present invention can be used (ingested, taken or administered) directly on humans or non-human animals having GLP-1 secretagogue ability.
  • the GLP-1 secretion-promoting agent of the present invention includes for suppressing an increase in blood glucose level, for suppressing appetite, for suppressing overeating, for improving glucose metabolism, and for preventing or treating diabetes.
  • the GLP-1 secretion-promoting agent of the present invention includes for suppressing an increase in blood glucose level, for suppressing appetite, for suppressing overeating, for improving glucose metabolism, and for preventing or treating diabetes.
  • for prevention or treatment of obesity for weight reduction, for reducing body fat ratio, for promoting gastric content excretion, for suppressing gastric acid secretion, for suppressing hepatic glucose release, for myocardial protection, for improving learning memory
  • vascular disease Foods for the prevention or treatment of, prevention or treatment of neurodegenerative diseases, prevention or treatment of non-alcoholic hepatitis, prevention or treatment of kanpan, or prevention or treatment of asthma, such as noodles (soba, udon, Chinese noodles) Noodles, instant noodles, etc.), tofu, confectionery (candy, gum, chocolate,
  • the foods for the above-mentioned uses include foods for specified health use, foods with health claims such as foods with nutritional claims, supplements (dietary supplements), and feeds.
  • foods with health claims such as foods with nutritional claims, supplements (dietary supplements), and feeds.
  • for suppressing the rise in blood glucose level for suppressing appetite, for suppressing overeating, for improving glucose metabolism, for preventing or treating diabetes, for preventing or treating obesity, for weight reduction, for reducing body fat ratio, and excreting stomach contents.
  • hepatic glucose release For promotion, suppression of gastric acid secretion, suppression of hepatic glucose release, myocardial protection, improvement of learning memory, prevention or treatment of vascular diseases, prevention or treatment of neurodegenerative diseases, prevention or treatment of non-alcoholic hepatitis Beverages for the prevention or treatment of kanpan, or for the prevention or treatment of asthma, such as tea drinks, soft drinks, carbonated drinks (including non-alcoholic beer), nutritional drinks, fruit drinks, lactic acid drinks, juices, drinks, Alcoholic beverages, processed milk, prepared soy milk; etc.
  • the GLP-1 secretion-promoting agent of the present invention can be used in a state of being contained in a beverage, food, pharmaceutical composition or the like by an oral, nasal, intestinal or other route or by a tube route. ..
  • the type of the food or drink is not particularly limited.
  • Foods include, for example, noodles (soba, udon, Chinese noodles, instant noodles, etc.), tofu, confectionery (candy, gum, chocolate, snacks, biscuits, cookies, gummy, etc.), breads, marine or processed livestock foods (soba, margarine or processed livestock foods).
  • Kamaboko, ham, sausage, etc. dairy products (fermented milk, etc.), fats and oils and processed fats and oils (salad oil, tempura oil, margarine, mayonnaise, shortening, whipped cream, dressing, fat spread, etc.), seasonings (sauce, sauce, etc.) ), Cooked or semi-cooked foods (champles, etc.), retort foods (curry, stew, bowls, porridge, miscellaneous dishes, etc.), cold confectionery (ice cream, sherbet, shaved ice, etc.), powdered foods (powdered beverages, powdered soup, etc.) , Enteral liquid food and the like.
  • foods with health claims such as foods with nutritional function, supplements (dietary supplements), feeds, etc. are also included.
  • Beverages include, for example, tea beverages, soft drinks, carbonated beverages (including non-alcoholic beers), nutritional beverages, fruit beverages, lactic acid beverages, juices, drinks, alcoholic beverages, processed milk, prepared soy milk and the like.
  • the food and drink may contain other components such as a food additive (food additive) as long as the GLP-1 secretagogue of the present invention is contained.
  • the food additive is not particularly limited, but for example, excipients (for example, wheat starch, corn starch, cellulose, lactose, sucrose, mannitol, sorbitol, xylitol, pregelatinized starch, casein, magnesium silicate aluminate, etc.
  • Calcium silicate, etc. excipients (eg, pregelatinized starch, hydroxypropylmethylcellulose, polyvinylpyrrolidone, etc.), disintegrants (eg, cellulose, hydroxypropylcellulose, corn starch, etc.), fluidizers (eg, light anhydrous silicic acid)
  • Oils eg, soybean oil, sesame oil, olive oil, flaxseed oil, sesame oil, rapeseed oil, coconut oil, corn oil and other vegetable oils or animal / fish-derived oils
  • nutrients eg, various minerals, various vitamins, etc.
  • Amino acids include fragrances, sweeteners other than ramnorse starch glycosyl, flavoring agents, coloring agents, solvents (eg ethanol), salts, pH adjusters, buffers, antioxidants, stabilizers, gelling agents, Examples include thickeners, starches, encapsulants, suspending agents, coating agents, preservatives, emulsifiers and the like.
  • the food additive may be contained alone or in combination of two or more.
  • the GLP-1 secretagogue of the present invention is contained in foods and drinks, it is preferable to use an emulsifier.
  • rhamnose-based steviol glycosides and other glycoside sweeteners used as needed are incorporated into the emulsified particles formed by the emulsifier, or rhamnose-based steviol glycosides are incorporated into the core of the emulsified particles.
  • it is not always necessary that a specific glycoside is always incorporated or continuously contained in a specific emulsified particle. Glycosides are incorporated or included in the majority of the emulsified particles throughout the system, while the glycosides are incorporated into, contained, and migrated to regions outside the emulsified particles. Is preferable.
  • an emulsifier can be expected to have a further effect of promoting GLP-1 secretion or an effect of reducing the bitterness of rhamnose-based steviol glycosides.
  • emulsifier a known emulsifier can be used.
  • Known emulsifiers include glycerin fatty acid esters such as monoglyceride, organic acid monoglyceride, and polyglycerin fatty acid ester; sorbitan fatty acid ester; sucrose fatty acid ester; propylene glycol fatty acid ester; stearoyl lactate; polysolvate; plant lecithin, egg yolk lecithin, fractionated lecithin. , Lecithins such as enzyme-treated lecithin; Kiraya extract, Yukkafoam extract; vegetable sterol; sphingolipid; bile powder; animal sterol and the like.
  • the emulsifier preferably contains an oil-in-water emulsifier, more preferably contains an oil-in-water emulsifier having an HLB value of 7 to 18, and more preferably has an HLB value of 7 to 18. Underneath, it comprises sucrose fatty acid esters, lecithins, glycerin fatty acid esters or polyglycerins, more preferably lecithins under the condition that the HLB value is 7-18, and particularly preferably the HLB value. Includes enzyme-treated lecithin, provided that is 7-18.
  • emulsifier When using an emulsifier, it is preferable to combine a component that can be present in the core of emulsified particles such as fat and oil composed of fatty acids having 6 to 12 carbon atoms and an aqueous base such as glycerin.
  • a component that can be present in the core of emulsified particles such as fat and oil composed of fatty acids having 6 to 12 carbon atoms and an aqueous base such as glycerin.
  • the proportion (ppm) of rhamnose-based steviol glycosides in foods and drinks is preferably based on mass, for example, 2-550, 25-550, 30-550, 35-550, 40-550, 45-550, 50-550, 55-550, 20-540, 25-540, 30-540, 35-540, 40-540, 45-540, 50-540, 55-540, 20-530, 25-530, 30- 530, 35-530, 40-530, 45-530, 50-530, 55-530, 20-520, 25-520, 30-520, 35-520, 40-520, 45-520, 50-520, 55-520, 20-510, 25-510, 30-510, 35-510, 40-510, 45-510, 50-510, 55-510, 20-505, 25-505, 30-505, 35- 505, 40-505, 45-505, 50-505, 55-505, 20-500, 25-500, 30-500, 35-500, 40-500, 45-500, 50-500, 55-500, 20-495, 25-495, 30
  • the intake amount (dose, dose) of the rhamnose-based steviol glycoside is not particularly limited, and can be appropriately selected according to the target age, body weight, health condition, and the like.
  • the dosage forms include, for example, tablets, powders, fine granules, granules, dry syrups, coated tablets, orally disintegrating tablets, chewable tablets, and capsules. Agents, soft capsules, syrups, enteral nutritional supplements and the like.
  • the present invention can be used or applied to either therapeutic (medical) or non-therapeutic applications. Specifically, regardless of whether or not it is classified into pharmaceuticals, quasi-drugs, cosmetics, etc., the function of promoting the secretion of GLP-1 or the function caused by the promotion of the secretion of GLP-1 is explicitly or It can be used or applied as any composition or food or drink that is implicitly appealing.
  • the product using the present invention may be labeled with a function of promoting the secretion of GLP-1 or a function caused by promoting the secretion of GLP-1.
  • Such a display is not particularly limited, but is limited to a GLP-1 secretion promoting function and a function caused by GLP-1 secretion promoting, for example, a blood glucose level elevation suppressing function, an appetite suppressing function, an overeating suppressing function, and sugar metabolism.
  • diabetes prevention or treatment function diabetes prevention or treatment function, obesity prevention or treatment function, weight reduction function, body fat ratio reduction function, stomach content excretion promotion function, gastric acid secretion suppression function, hepatic glucose release suppression function, myocardial protection Function, learning memory enhancement function, prevention or treatment function of vascular disease, prevention or treatment function of neurodegenerative disease, prevention or treatment function of non-alcoholic hepatitis, prevention or treatment function of pancreatic disease, prevention or treatment function of asthma, Alternatively, a display that can be equated with these can be mentioned.
  • the timing of use of the GLP-1 secretagogue of the present invention is not particularly limited, and may be, for example, before meals, during meals, between meals, after meals, and before bedtime.
  • One aspect of the invention relates to rhamnose-based steviol glycosides used at 0.4-4,440 ppm for the treatment of diseases that can be ameliorated by promoting GLP-1 secretion.
  • one aspect of the present invention promotes the secretion of GLP-1 in a subject, which comprises administering a rhamnose-based steviol glycoside at a concentration of 0.4-4,440 ppm to a subject in need thereof. Or a method of treating a disease that can be ameliorated by promoting GLP-1 secretion in a subject.
  • one aspect of the present invention relates to the use of 0.4-4,440 ppm of rhamnose-based steviol glycosides in the manufacture of a medicament for treating a disease that can be ameliorated by promoting GLP-1 secretion.
  • Diseases include hyperglycemia, bulimia nervosa, hyperacidity, diabetes, obesity, vascular disease, neurodegenerative diseases, non-alcoholic hepatitis, pancreatic disease, asthma and the like.
  • the GLP-1 secretagogue of the present invention is produced by a known method according to its use, composition and the like.
  • the GLP-1 secretion promoter of the present invention contains an emulsifier, a step of mixing an oil-in-water emulsifier, a ramnorth-based steviol glycoside, and an aqueous medium to prepare a mixture, and the result.
  • the mixture is produced by adding a component that can be contained in the core of the emulsified particles such as fats and oils to the mixture and stirring the mixture, at least a part of the ramnorse-based steviol glycoside is incorporated into the emulsified particles, resulting in the result.
  • the GLP-1 secretion promoting effect can be further improved.
  • the stirring speed is preferably 5,000 to 10,000, 5,000 to 8,000, or 8,000 to 10,000 rpm.
  • the GLP-1 secretagogue of the present invention contains an emulsifier
  • a step of mixing an oil-in-water emulsifier and an aqueous medium to prepare a mixture, and the resulting mixture can also be produced through a step of adding a ramnorth-based steviol glycoside and a component that can be contained in the core of emulsified particles such as oil and fat and stirring.
  • a homomixer or the like stir at high speed under conditions more intense than mixing so that fats and oils are included in the core of the emulsified particles.
  • the stirring speed is preferably 5,000 to 10,000, 5,000 to 8,000 or 8,000 to 10,000 rpm.
  • the term "subject” means any living organism capable of secreting GLP-1, preferably an animal, more preferably a mammal, and even more preferably a human.
  • the subject may be healthy (for example, not having a specific or arbitrary disease) or may be suffering from any disease, but treatment of a disease that can be improved by promoting GLP-1 secretion, etc. When intended, it typically means a subject who has or is at risk of developing the disease.
  • treatment shall include all types of medically acceptable prophylactic and / or therapeutic interventions aimed at the cure, temporary remission or prevention of disease.
  • treatment includes medically acceptable interventions for a variety of purposes, including delaying or stopping the progression of a disease, regressing or eliminating lesions, preventing the onset or recurrence of the disease, and the like. Therefore, the compositions of the present invention can be used for the treatment and / or prevention of diseases.
  • Experimental Example 14 is a missing number.
  • ⁇ Experimental example 1> It was examined whether RebA, RebB, RebM, RebN, RebD, RebC, MogV and stevioside have a GLP-1 secretagogue effect. Specifically, the amount of GLP-1 secreted was measured by the following procedure, and the one having a higher amount of secretion than the control no sample was determined to have a GLP-1 secretion promoting effect.
  • Each test substance (B, C, D, E, F, G, I, J) was dissolved with PBS (Thermo Fisher Scientific) (Cat. No. 14190250) to obtain a stock solution.
  • the concentration of the stock solution is shown below.
  • GLP-1 was quantified.
  • Fig. 1 According to FIG. 1, it was RebA, RebB, RebC, MogV, and stevioside that secreted significantly more GLP-1 than no sample.
  • Example 5 490 g of glycerin, 100 g of RebA, and 10 g of polyglycerin fatty acid ester were mixed and dissolved at a temperature of 70 ° C. to prepare an aqueous mixed solution. 300 g of MCT oil was added as fat and oil to this aqueous mixed solution, and emulsified with a homomixer (manufactured by Tokushu Kika Kogyo Co., Ltd.) at a rotation speed of 8000 rpm. After the stirring was completed, the mixture was cooled to 40 ° C. and 100 g of water was added to obtain a RebA processing solution.
  • a homomixer manufactured by Tokushu Kika Kogyo Co., Ltd.
  • Example FC (mM) The final concentration in the medium is shown in the "Sample FC (mM)" column of Table 1. After a predetermined time (2 hours) had elapsed from the addition, a 96-well plate was collected. The collected 96-well plate was centrifuged at 300 g ⁇ 5 minutes, and the supernatant was collected.
  • FIGS. 2 to 5 show the amount of GLP-1 secreted from a 1% DMSO-containing solution as a non-irritating control (negative control) and the water system of PMA (manufactured by Fujifilm Wako Pure Chemical Industries, Ltd., model number: 162-23591) as a positive control. The amount of GLP-1 secreted from the solution was also listed.
  • Table 1 is shown below.
  • the positive control in Table 1 is also referred to as the positive control.
  • Negative controls are also called negative controls.
  • Example 7 Evaluation of flavor characteristics> The flavor characteristics of the emulsified composition of Liver were evaluated by the following procedure. RebA was dissolved in pure water to prepare 100 ppm and 300 ppm aqueous solutions, which were used as controls. Next, the RebA processing solution prepared in Experimental Example 5 was added to pure water to prepare 100 ppm and 300 ppm aqueous solutions in the same manner. Seven well-trained sensory panelists evaluated the flavor of the aqueous solution containing the RebA processing solution in 0.5-point increments with a control of 3 points, and the average value is shown in the figure. The flavor was evaluated based on sweetness intensity, sweetness aftertaste, and bitterness intensity. The results are shown in FIG.
  • Example 9 490 g of glycerin, 100 g of RebA, and 10 g of polyglycerin fatty acid ester were mixed and dissolved at a temperature of 70 ° C. to prepare an aqueous mixed solution. 300 g of MCT oil was added as fat and oil to this aqueous mixed solution, and emulsified with a homomixer (manufactured by Tokushu Kika Kogyo Co., Ltd.) at a rotation speed of 8000 rpm. After the stirring was completed, the mixture was cooled to 40 ° C. and 100 g of water was added to obtain a RebA processing solution.
  • a homomixer manufactured by Tokushu Kika Kogyo Co., Ltd.
  • Example 10 A solution C was obtained in the same manner as in the preparation of the RebA processing solution of Experimental Example 9, except that 490 g of glycerin, 10 g of polyglycerin fatty acid ester, 300 g of MCT oil and 200 g of water were used without using 100 g of RebA. To 483.5 ⁇ L of the obtained C solution, 10 ⁇ L of DMSO (manufactured by Fujifilm Wako Pure Chemical Industries, Ltd., model number: 037-24053) and 506.5 ⁇ L of PBS were added and stirred by vortexing to obtain a stock solution having a concentration equivalent to RebA of 50 mM. It was.
  • DMSO manufactured by Fujifilm Wako Pure Chemical Industries, Ltd., model number: 037-24053
  • the obtained stock solution was diluted with PBS containing 1% DMSO to obtain Sample C-1 mM to Sample C-25 mM.
  • Table 2 shows the concentration equivalent to RebA.
  • the RebA equivalent concentration means that the concentration of glycerin, polyglycerin fatty acid ester and MCT oil in Sample C is the same as the concentration of glycerin, polyglycerin fatty acid ester and MCT oil in Sample B processing in Experimental Example 9. It means the concentration of RebA during the processing of the sample B.
  • Sample C-2 mM, Sample C-5 mM, Sample C-10 mM, Sample C-20 mM, Sample C-30 mM, Sample C-40 mM, and Sample C-50 mM were obtained.
  • the concentration behind the hyphen indicates the concentration equivalent to RebA.
  • Sample B and sample C (for example, sample B-2 mM and sample C-2 mM) having the same concentration were mixed in equal amounts to obtain sample B + C-1 mM to sample B + C-25 mM.
  • Table 2 shows the concentration of RebA.
  • Example 12 To 118.5 ⁇ L of glycerin, 10 ⁇ L of DMSO (manufactured by Fujifilm Wako Pure Chemical Industries, Ltd., model number: 037-24053) and 871.5 ⁇ L of PBS were added and stirred by vortexing to obtain a stock solution having a concentration equivalent to RebA of 25 mM. The obtained stock solution was diluted with PBS containing 1% DMSO as needed to obtain Sample D-1 mM to Sample D-25 mM. Table 2 shows the concentration equivalent to RebA.
  • the RebA equivalent concentration means the concentration of RebA during the processing of the sample B when the glycerin concentration in the sample D and the glycerin concentration during the processing of the sample B of the experimental example 9 are the same.
  • Example 13 To 72.5 ⁇ L of MCT oil, 10 ⁇ L of DMSO (manufactured by Fujifilm Wako Pure Chemical Industries, Ltd., model number: 037-24053) and 917.5 ⁇ L of PBS were added and stirred by vortexing to obtain a stock solution having a concentration equivalent to RebA of 25 mM. .. The obtained stock solution was diluted with PBS containing 1% DMSO as needed to obtain Sample E-1 mM to Sample E-25 mM. Table 2 shows the concentration equivalent to RebA.
  • the RebA equivalent concentration means the concentration of RebA during the processing of the sample B when the concentration of the MCT oil in the sample E and the concentration of the MCT oil during the processing of the sample B in Experimental Example 9 are the same.
  • GLP-1 in the collected supernatant was quantified using a Human GLP-1 (7-36 amide) Immunoassay kit manufactured by PerkinElmer.
  • the standard range of the calibration curve is 30 to 100,000 pg / mL, and some values larger than 100,000 pg / mL cause an error. Therefore, a value considered to be 100,000 pg / mL or more is set to 100, Calculated as 000 pg / mL.
  • Outliers (p ⁇ 0.01) were excluded by the Smirnov-Grabs test. The results are shown in FIG. In FIG.
  • the amount of GLP-1 secretion was also measured on another plate. Specifically, using the same culture supernatant as in FIG. 8, the amount of GLP-1 was measured using samples B to D on one assay plate and sample E on another assay plate. The results of measuring the culture supernatant after 2 hours on the same assay plate are shown in FIGS. 9 to 14. The concentration of each sample used is shown in FIGS. 9-14. The concentrations of C, D, and E shown in FIGS. 11, 13, and 14 are the concentrations equivalent to RebA.
  • the range of the calibration curve was 30 to 100,000 pg / mL, but this time there was no error value with a value larger than 100,000 pg / mL, so values larger than 100,000 pg / mL are calculated as theoretical values. did.
  • Table 2 is shown below.
  • the positive control in Table 2 is also referred to as the positive control.
  • Negative controls are also called negative controls.
  • Example 15 After adding 9.4 ⁇ L of DMSO (manufactured by Fujifilm Wako Pure Chemical Industries, Ltd., model number: 034-24053) to 36.3 mg of RebA, 929.0 ⁇ L of PBS was added and stirred by vortex, and a stock solution having a RebA concentration of 40 mM was added. Got The obtained stock solution and PBS were diluted with PBS containing 1% DMSO to obtain Sample B-0.31 mM to Sample B-20 mM. Table 3 shows the concentration of RebA.
  • DMSO manufactured by Fujifilm Wako Pure Chemical Industries, Ltd., model number: 034-24053
  • Example 16 490 g of glycerin, 100 g of RebA, and 10 g of polyglycerin fatty acid ester were mixed and dissolved at a temperature of 70 ° C. to prepare an aqueous mixed solution. 300 g of MCT oil was added as fat and oil to this aqueous mixed solution, and emulsified with a homomixer (manufactured by Tokushu Kika Kogyo Co., Ltd.) at a rotation speed of 8000 rpm. After the stirring was completed, the mixture was cooled to 40 ° C. and 100 g of water was added to obtain a RebA processing solution.
  • a homomixer manufactured by Tokushu Kika Kogyo Co., Ltd.
  • a solution C was obtained in the same manner as in the preparation of the RebA processing solution of Experimental Example 16 except that 490 g of glycerin, 10 g of polyglycerin fatty acid ester, 300 g of MCT oil and 200 g of water were used without using 100 g of RebA.
  • 10 ⁇ L of DMSO manufactured by Fujifilm Wako Pure Chemical Industries, Ltd., model number: 037-24053
  • 603.2 ⁇ L of PBS were added and stirred by vortexing to obtain a stock solution having a concentration equivalent to RebA of 40 mM. ..
  • the stock solution was diluted with PBS containing 1% DMSO to obtain Sample C-0.31 mM to Sample C-20 mM.
  • Table 3 shows the concentration equivalent to RebA.
  • the RebA equivalent concentration is the concentration of RebA during the processing of Sample B when the concentration of the polyglycerin fatty acid ester in the sample C and the concentration of the polyglycerin fatty acid ester during the processing of the sample B in Experimental Example 16 are the same. means.
  • Sample B and sample C (for example, sample B-0.62 mM and sample C-0.62 mM) having the same concentration were mixed in equal amounts to obtain sample B + C-0.31 mM to sample B + C-20 mM.
  • Table 3 shows the concentration of RebA.
  • Example 19 To 94.8 ⁇ L of glycerin, 10 ⁇ L of DMSO (manufactured by Fujifilm Wako Pure Chemical Industries, Ltd., model number: 037-24053) and 895.2 ⁇ L of PBS were added and stirred by vortexing to obtain a stock solution having a concentration equivalent to RebA of 20 mM. The obtained stock solution was diluted with PBS containing 1% DMSO as needed to obtain Sample D-0.31 mM to Sample D-20 mM. Table 3 shows the concentration equivalent to RebA.
  • the RebA equivalent concentration means the concentration of RebA during the processing of the sample B when the concentration of the glycerin in the sample D and the concentration of the glycerin during the processing of the sample B of the experimental example 16 are the same.
  • the RebA equivalent concentration means the concentration of RebA during the processing of the sample B when the concentration of the MCT oil in the sample E and the concentration of the MCT oil during the processing of the sample B of the experimental example 16 are the same.
  • H716 cells were seeded on 96-well plates at 2 ⁇ 10 5 cells / 90 ⁇ L / well (for evaluation of dead cells) and on 48-well plates at 4 ⁇ 10 5 cells / 180 ⁇ L / well (for morphological observation).
  • the FBS in the medium when seeded on the plate was 0.5%.
  • samples of each concentration were added at 10 ⁇ L / well (96 well plate) or 20 ⁇ L / well (48 well plate). The final concentration in the medium is shown in the "Sample FC" column of Table 3. Two hours after sample addition, the highest concentration of each sample (# 1, # 6, # 10, # 14, # 18, # 22, # 26, # 30 shown in Table 3) was evaluated.
  • Dead cell rate (%) number of dead cells / total number of cells x 100
  • the dead cell rate at the time of adding each sample is 0% when not added 24 hours after cell seeding, and 100% when 70% ethanol is added and allowed to stand on ice for 30 minutes or more. Corrected.
  • the results are shown in FIG. FIG. 15a shows the result after 2 hours, and FIG. 15b shows the result after 24 hours.
  • the dead cell rate was the highest when sample B + C (RebA concentration 2 mM) was added, but the dead cell rate was equivalent to the lowest concentration of PMA. there were. Except for sample B + C, the dead cell rate was equal to or lower than that of the negative control (-) (also referred to as negative control). Therefore, it is unlikely that cell death was induced in sample B + C, and cell death was not induced in other samples.
  • - negative control
  • Table 3 is shown below.
  • the positive control in Table 3 is also referred to as the positive control.
  • Negative controls are also called negative controls.
  • Example 22 The C-1 solution was prepared in the same manner as in Experimental Example 16 except that 100 g of RebA was replaced with 100 g of water and 10 g of sucrose fatty acid ester was used instead of 10 g of polyglycerin fatty acid ester as an emulsifier.
  • 100 g of RebA was replaced with 100 g of water
  • 10 g of sucrose fatty acid ester was used instead of 10 g of polyglycerin fatty acid ester as an emulsifier.
  • the obtained stock solution was diluted with PBS containing 1% DMSO to obtain Sample C-1-1 mM to Sample C-1-20 mM.
  • Table 4 shows the concentration equivalent to RebA.
  • the RebA equivalent concentration is the concentration of RebA in the sample B + C-1 when the concentration of the glycerin and the emulsifier in the sample C-1 is the same as the concentration of the glycerin and the emulsifier in the sample B + C-1 of Experimental Example 25. Means concentration.
  • Table 4 shows the concentration equivalent to RebA.
  • the RebA equivalent concentration is the concentration of RebA in Sample B + C-2 when the concentration of glycerin and emulsifier in Sample C-2 is the same as the concentration of glycerin and emulsifier in Sample B + C-2 of Experimental Example 26. Means concentration.
  • Table 4 shows the concentration equivalent to RebA.
  • the RebA equivalent concentration is the concentration of RebA in Sample B + C-3 when the concentration of glycerin and emulsifier in Sample C-3 is the same as the concentration of glycerin and emulsifier in Sample B + C-3 of Experimental Example 27. Means concentration.
  • sample C-1-2 mM, sample C-1-5 mM, sample C-1-10 mM, sample C-1-20 mM, sample C-1-30 mM, and sample C-1-40 mM were obtained.
  • the concentration behind the hyphen indicates the concentration equivalent to RebA.
  • Sample B and sample C (for example, sample B-1-2 mM and sample C-1-2 mM) having the same concentration were mixed in equal amounts to obtain sample B + C-1-1 mM to sample B + C-1-20 mM.
  • Table 4 shows the concentration of RebA.
  • Example 28 Add 339 ⁇ L of DMSO (manufactured by Fujifilm Wako Pure Chemical Industries, Ltd., model number: 037-24053) to 13.1 mg of sucrose fatty acid ester, vortex, and further dilute with DMSO 20 times to stock a RebA equivalent concentration of 2,000 mM. Obtained liquid. PBS was added to the obtained stock solution to obtain a 20 mM solution. The obtained 20 mM solution was diluted with PBS containing 1% DMSO as needed to obtain Sample G-1-1 mM to Sample G-1-20 mM. Table 4 shows the concentration equivalent to RebA.
  • DMSO manufactured by Fujifilm Wako Pure Chemical Industries, Ltd., model number: 037-24053
  • the RebA equivalent concentration is the concentration of the sucrose fatty acid ester in the sample G-1 and the concentration of the sucrose fatty acid ester in the sample B + C-1 of Experimental Example 25 when the concentration is the same in the sample B + C-1. It means the concentration of RebA.
  • Example 29 Add 540 ⁇ L of PBS to 20.9 mg of enzymatically decomposed lecithin, vortex it, and dilute it 20-fold with DMSO (manufactured by Fujifilm Wako Pure Chemical Industries, Ltd., model number: 037-24053) to stock a RebA equivalent concentration of 2,000 mM. Obtained liquid. PBS and DMSO were mixed with the stock solution to prepare a 20 mM solution (1% DMSO). The obtained 20 mM solution was diluted with PBS containing 1% DMSO as needed to obtain Sample G-2-1 mM to Sample G-2-20 mM. Table 4 shows the concentration equivalent to RebA.
  • the RebA equivalent concentration is the concentration of RebA in the sample B + C-2 when the concentration of the enzymatically decomposed lecithin in the sample G-2 is the same as the concentration of the enzymatically decomposed lecithin in the sample B + C-2 of Experimental Example 26. Means concentration.
  • Example 30 The organic acid monoglyceride was dissolved at 60 ° C., 905 ⁇ L of DMSO was added to 35.0 mg for vortexing, and the mixture was further diluted 20-fold with DMSO to obtain a stock solution having a concentration equivalent to RebA of 2,000 mM. PBS was added to the stock solution to obtain a 20 mM solution. The obtained 20 mM solution was diluted with PBS containing 1% DMSO as needed to obtain Sample G-3-1 mM to Sample G-3-20 mM. Table 4 shows the concentration equivalent to RebA.
  • the RebA equivalent concentration is the concentration of RebA in Sample B + C-3 when the concentration of organic acid monoglyceride in Sample G-3 is the same as the concentration of organic acid monoglyceride in Sample B + C-3 of Experimental Example 27. Means concentration.
  • the RebA equivalent concentration means the concentration of RebA in the sample B + C when the concentration of the polyglycerin fatty acid ester in the sample G-4 and the concentration of the emulsifier in the sample B + C of Experimental Examples 25 to 27 are the same. To do.
  • ⁇ GLP-1 secretion amount> The samples obtained in Experimental Examples 21 to 31 were given to cells, and the amount of GLP-1 secreted was measured 2 hours and 24 hours later.
  • the specific procedure is as follows. H716 cells were cultured in RPMI1640 (Thermo Fisher Scientific, model number: 61870-136) (10% FBS (Gibco, model number: SH102770), 1 mM Sodium Pyruvate) in an incubator at 37 ° C. and 5% CO 2 . .. H716 cells were seeded on 96-well plates in 2 ⁇ 10 5 cells / 90 ⁇ L / well. The FBS in the medium when seeded on the plate was 0.5%.
  • FIG. 16 the amount of GLP-1 secreted in a 1% DMSO-containing solution as a non-irritating control and the amount of GLP-1 secreted in an aqueous solution of PMA (manufactured by Fujifilm Wako Pure Chemical Industries, Ltd., 162-23591) as a positive control are also shown. I put it.
  • Table 4 is shown below.
  • the positive control in Table 4 is also referred to as the positive control.
  • Negative controls are also called negative controls.
  • Example 32 The distribution ratios of stevioside, RebA, RebD, and RebM were measured.
  • the structural formulas of stevioside, RebA, RebD, and RebM are shown below. Specifically, the following operations were performed. About 100 mL of pure water and about 100 mL of toluene were placed in a separatory funnel, and then 30 mg of each steviol glycoside was added. The liquid was sealed so as not to leak, and the separating funnel was allowed to stand after stirring with a shaker for about 30 minutes. When the liquid layer was separated into two layers, the distribution ratio was measured by LCMS after sampling from each layer. The measurement results and photographs during the test are shown in FIG. A photograph of the RebA-containing liquid after the test is shown in FIG.
  • Example 33 ⁇ Experimental Example 33> 1.
  • Sample preparation Samples SA-70A, SA-70B, SA-200A, SA-200B, SA-206A, SA-206B, SA-207A, and SA-207B were prepared by the following procedure.
  • the sample ending in A is a sample prepared by dissolving RebA in an aqueous system.
  • the sample ending in B is a sample prepared by dispersing RebA in an oil system.
  • 300 g of MCT was added as fat and oil to this aqueous mixed solution, and emulsified with a homomixer (manufactured by Tokushu Kika Kogyo Co., Ltd.) at a rotation speed of 8000 rpm. After the stirring was completed, the mixture was cooled to 40 ° C. and 100 g of water was added to obtain an emulsified composition SA-70A.
  • a homomixer manufactured by Tokushu Kika Kogyo Co., Ltd.
  • a homomixer manufactured by Tokushu Kika Kogyo Co., Ltd.
  • a homomixer manufactured by Tokushu Kika Kogyo Co., Ltd.
  • a homomixer manufactured by Tokushu Kika Kogyo Co., Ltd.
  • a homomixer manufactured by Tokushu Kika Kogyo Co., Ltd.
  • a homomixer manufactured by Tokushu Kika Kogyo Co., Ltd.
  • a homomixer manufactured by Tokushu Kika Kogyo Co., Ltd.
  • Flavor characteristics were evaluated using the sample prepared in. Specifically, the evaluation was performed according to the following procedure. RebA was dissolved in pure water to prepare an aqueous solution having a RebA concentration of 467 ppm, which was used as a control. Next, 1. Pure water was added to each sample prepared in (1) to prepare an aqueous solution having a RebA concentration of 467 ppm. Seven well-trained sensory panelists evaluated the flavor of each aqueous solution in 0.5-point increments with a control of 3 points, calculated the average value, and then ranked them. The flavor was evaluated based on sweetness intensity, sweetness aftertaste, and bitterness intensity. Those with the same score were given the same ranking. The ranking is shown in the column of each evaluation item in the table below. The sum of the rankings is shown in the total column of the table below.
  • Emulsification stability, flavor characteristics, and vibration stability after storage were evaluated using the sample prepared in. Specifically, the evaluation was performed according to the following procedure. 3,483 ml of pure water was added to 16990.3 mg of sample SA-70A to obtain an evaluation liquid 70A.
  • An evaluation liquid 206A was obtained in the same manner except that sample SA-206A was used instead of sample SA-70A.
  • the composition of each evaluation liquid is as follows. The obtained evaluation liquid 70A and evaluation liquid 206A were allowed to stand in a refrigerator having an internal temperature of 5 ° C. for 4 weeks. Further, another evaluation liquid 70A and an evaluation liquid 206A were allowed to stand in a constant temperature storage at 55 ° C. for 4 weeks.
  • the pH of the evaluation liquid 70A and the evaluation liquid 206A was adjusted to 2.5 using citric acid anhydride, and the mixture was allowed to stand in a refrigerator having an internal temperature of 5 ° C. for 4 weeks.
  • the pH of another evaluation solution 70A and evaluation solution 206A was adjusted to 2.5 using citric acid anhydride, and the mixture was allowed to stand in a constant temperature storage at 55 ° C. for 4 weeks.
  • the evaluation solution 70A with no pH adjustment and a standing temperature of 5 ° C. was used as a control.
  • the flavor of the evaluation solution 70A without pH adjustment and at a standing temperature of 55 ° C. was evaluated in 0.5 point increments.
  • the panelists were four well-trained sensual panelists. The average value of the evaluation of each panelist was calculated.
  • the evaluation liquid 206A without pH adjustment at a standing temperature of 5 ° C. was used as a control, and the flavor of the evaluation liquid 206A without pH adjustment at a standing temperature of 55 ° C.
  • the evaluation liquid 70A having a pH of 2.5 and a standing temperature of 5 ° C. was used as a control, and the flavor of the evaluation liquid 70A having a pH of 2.5 and a standing temperature of 55 ° C. was evaluated in 0.5 point increments.
  • the evaluation liquid 206A having a pH of 2.5 and a standing temperature of 5 ° C. was used as a control, and the flavor of the evaluation liquid 206A having a pH of 2.5 and a standing temperature of 55 ° C. was evaluated in 0.5 point increments.
  • degree of decrease in sweetness intensity The degree of decrease in sweetness intensity due to emulsification was evaluated using the samples SA-70A and SA-206A prepared in. Specifically, the evaluation was performed according to the following procedure. RebA was dissolved in pure water to prepare an aqueous solution of 467 ppm, which was used as a control. Next, 1. Each sample adjusted in 1 was added to pure water to prepare an aqueous solution having a RebA concentration of 467 ppm. Four well-trained sensory panelists were asked to choose which of the sucrose aqueous solutions Brix 2, 5, 8, 11, 14 each aqueous solution was close to. The average value of the evaluation results of each panelist was calculated. The results are shown in FIG.
  • Evaluation liquid 70A and evaluation liquid 206A were obtained in the same manner as in “4. Evaluation of various characteristics after storage” of Experimental Example 33.
  • the obtained evaluation liquid 70A and evaluation liquid 206A were diluted with PBS containing DMSO to prepare a diluted liquid having a RebA concentration shown in the column of addition concentration in the table below.
  • another evaluation liquid 70A and an evaluation liquid 206A were allowed to stand in a constant temperature storage at 55 ° C. for 4 weeks.
  • the evaluation solution 70A and the evaluation solution 206A after standing were diluted with PBS containing DMSO to prepare a diluted solution having a RebA concentration shown in the column of addition concentration in the table below.
  • a 1% DMSO-containing solution was prepared as a non-irritating control (negative control). Further, as a positive control, PMA (manufactured by Fujifilm Wako Pure Chemical Industries, Ltd., model number: 162-23591) was adjusted by diluting with 1% DMSO so as to have the concentration shown in the addition concentration column in the table below.
  • the diluent No. 1-27 was added to the medium, and the cells were cultured in the obtained medium.
  • the specific procedure is as follows. H716 cells were cultured in RPMI1640 (Thermo Fisher Scientific, model number: 61870-136) (10% FBS (Gibco, model number: SH102770), 1 mM Sodium Pyruvate) in an incubator at 37 ° C. and 5% CO 2 . .. H716 cells were seeded on 96-well plates at 2 ⁇ 10 5 cells / 90 ⁇ L / well. The FBS in the medium when seeded on the plate was 0.5%. After 24 hours from cell seeding, the diluent No.
  • the cell viability was confirmed 2 hours and 24 hours after the addition of the diluent. There was no problem with either sample.
  • the 96-well plate was centrifuged at 300 ⁇ g for 5 minutes, and the culture supernatant was collected.
  • GLP-1 in the collected culture supernatant was quantified using a Human GLP-1 (7-36 amide) Immunoassay kit (manufactured by PerkinElmer, model number: AL359C). For quantitative values, values that exceeded the range of the calibration curve and resulted in an error were excluded.
  • a Box plot was created using statistical analysis software R, and cases where a value smaller than the first quartile or larger than the third quartile was 1.5 quartiles or more were excluded as outliers. The results are shown in FIG.

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Abstract

L'invention porte sur le développement d'un nouveau sécrétagogue de GLP-1 qui favorise la sécrétion de GLP-1. La présente invention concerne un sécrétagogue de GLP-1 caractérisé en ce qu'il comprend 0,4 à 4 440 ppm d'un glycoside de stéviol présentant une structure à laquelle du rhamnose est fixé.
PCT/JP2020/017402 2019-04-26 2020-04-22 Sécrétagogue de glp-1 Ceased WO2020218382A1 (fr)

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Citations (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JP2003521528A (ja) * 2000-02-01 2003-07-15 ステヴィア，エイプス 食事補強剤、又は非インシュリン依存性糖尿病、高血圧及び／又は代謝症候群の治療のための薬剤の調製に使用する物質
WO2017018404A1 (fr) * 2015-07-27 2017-02-02 サントリーホールディングス株式会社 Composition contenant un dipeptide cyclique et un édulcorant
WO2017159725A1 (fr) * 2016-03-16 2017-09-21 サントリーホールディングス株式会社 Composition pour favoriser la sécrétion de glp-1, et son procédé de fabrication
WO2018124143A1 (fr) * 2016-12-27 2018-07-05 サントリーホールディングス株式会社 Nouveau glycoside de stéviol, son procédé de production et composition d'édulcorant le contenant
WO2018181515A1 (fr) * 2017-03-31 2018-10-04 サントリーホールディングス株式会社 Nouveau glycoside de stéviol et son procédé de production, et composition d'édulcorant contenant celui-ci

Patent Citations (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JP2003521528A (ja) * 2000-02-01 2003-07-15 ステヴィア，エイプス 食事補強剤、又は非インシュリン依存性糖尿病、高血圧及び／又は代謝症候群の治療のための薬剤の調製に使用する物質
WO2017018404A1 (fr) * 2015-07-27 2017-02-02 サントリーホールディングス株式会社 Composition contenant un dipeptide cyclique et un édulcorant
WO2017159725A1 (fr) * 2016-03-16 2017-09-21 サントリーホールディングス株式会社 Composition pour favoriser la sécrétion de glp-1, et son procédé de fabrication
WO2018124143A1 (fr) * 2016-12-27 2018-07-05 サントリーホールディングス株式会社 Nouveau glycoside de stéviol, son procédé de production et composition d'édulcorant le contenant
WO2018181515A1 (fr) * 2017-03-31 2018-10-04 サントリーホールディングス株式会社 Nouveau glycoside de stéviol et son procédé de production, et composition d'édulcorant contenant celui-ci

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