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WO2020218381A1 - Composition favorisant la sécrétion de glp-1 - Google Patents

Composition favorisant la sécrétion de glp-1 Download PDF

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Publication number
WO2020218381A1
WO2020218381A1 PCT/JP2020/017401 JP2020017401W WO2020218381A1 WO 2020218381 A1 WO2020218381 A1 WO 2020218381A1 JP 2020017401 W JP2020017401 W JP 2020017401W WO 2020218381 A1 WO2020218381 A1 WO 2020218381A1
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WO
WIPO (PCT)
Prior art keywords
sample
glp
concentration
reba
secretion
Prior art date
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Ceased
Application number
PCT/JP2020/017401
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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 JP2021516180A priority Critical patent/JPWO2020218381A1/ja
Publication of WO2020218381A1 publication Critical patent/WO2020218381A1/fr
Anticipated expiration legal-status Critical
Ceased legal-status Critical Current

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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
    • A23L2/00—Non-alcoholic beverages; Dry compositions or concentrates therefor; Preparation or treatment thereof
    • A23L2/52—Adding ingredients
    • 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
    • A61K45/00—Medicinal preparations containing active ingredients not provided for in groups A61K31/00 - A61K41/00
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/06—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
    • A61K47/08—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite containing oxygen, e.g. ethers, acetals, ketones, quinones, aldehydes, peroxides
    • A61K47/14—Esters of carboxylic acids, e.g. fatty acid monoglycerides, medium-chain triglycerides, parabens or PEG fatty acid esters
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/06—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
    • A61K47/24—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite containing atoms other than carbon, hydrogen, oxygen, halogen, nitrogen or sulfur, e.g. cyclomethicone or phospholipids
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/06—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
    • A61K47/26—Carbohydrates, e.g. sugar alcohols, amino sugars, nucleic acids, mono-, di- or oligo-saccharides; Derivatives thereof, e.g. polysorbates, sorbitan fatty acid esters or glycyrrhizin
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/30—Macromolecular organic or inorganic compounds, e.g. inorganic polyphosphates
    • A61K47/34—Macromolecular compounds obtained otherwise than by reactions only involving carbon-to-carbon unsaturated bonds, e.g. polyesters, polyamino acids, polysiloxanes, polyphosphazines, copolymers of polyalkylene glycol or poloxamers
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/44—Oils, fats or waxes according to two or more groups of A61K47/02-A61K47/42; Natural or modified natural oils, fats or waxes, e.g. castor oil, polyethoxylated castor oil, montan wax, lignite, shellac, rosin, beeswax or lanolin
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/10—Dispersions; Emulsions
    • 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
    • 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

Definitions

  • the present invention relates to a GLP-1 secretion promoting composition containing emulsified particles containing an oil-in-water emulsifier.
  • 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 11 types of curbitan-type triterpenes contained in bitter gourd as a novel GLP-1 secretagogue component. Further, Patent Document 2 describes that stevioside, rebaugioside A, rebaugioside B, and rebaugioside D have a property of promoting the secretion of GLP-1.
  • the emulsified particle is a composition for promoting GLP-1 secretion, which contains an oil-in-water emulsifier and does not contain a free fatty acid that acts as a ligand for the GT01 protein.
  • the emulsifier contains at least one selected from the group consisting of polyglycerin fatty acid ester, propylene glycol fatty acid ester, enzyme-treated lecithin, sucrose fatty acid ester and organic acid monoglyceride.
  • composition according to any one of the above [1] to [3], wherein the emulsified particles contain a hydrophobic non-GLP-1 secretagogue component [5] The composition according to the above [4], which contains the non-GLP-1 secretagogue component in an amount of 2 to 500 times (mass) of the emulsifier. [6] The composition according to the above [4] or [5], which contains the non-GLP-1 secretagogue component in a proportion of 10 to 50% by mass. [7] The composition according to any one of the above [1] to [6], which contains the emulsifier in a proportion of 0.1 to 5% by mass.
  • a beverage for promoting GLP-1 secretion which contains the composition according to any one of the above [1] to [9].
  • a food for promoting GLP-1 secretion which contains the composition according to any one of the above [1] to [9].
  • a pharmaceutical composition comprising the composition according to any one of the above [1] to [9].
  • An oil-in-water emulsifier is optionally stirred in an aqueous medium together with a non-GLP-1 secretagogue to prepare oil-in-water emulsified particles that do not contain free fatty acids that act as ligands for the GT01 protein.
  • a method for producing a composition for promoting GLP-1 secretion which comprises a step.
  • the GLP-1 secretion promoting effect can be enjoyed without using the GLP-1 secretion promoting component.
  • 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.
  • the present invention relates to a composition for promoting GLP-1 secretion containing emulsified particles.
  • the emulsified particles contained in the composition of the present invention contain an oil-in-water emulsifier and do not contain free fatty acids that act as ligands for the GT01 protein.
  • Examples of free fatty acids that act as ligands for the GT01 protein include long-chain free fatty acids.
  • Long-chain free fatty acids such as saturated free fatty acids of C14 to C18 and unsaturated free fatty acids of C16 to C22 are known to have the property of promoting the secretion of GLP-1 (reference: Akira Hirasawa et al., "Free fatty acids regulate gut increment glucagon-like peptide-1 secretion through GPR120" Nature Medicine volume 11, pages 90-94 (2005)).
  • Examples of saturated free fatty acids of C14 to C18 include palmitic acid and stearic acid.
  • unsaturated free fatty acids C16 to C22 include oleic acid, linoleic acid, and ⁇ -linolenic acid.
  • a free fatty acid that acts as a ligand for the GT01 protein is one of the GLP-1 secretagogue components.
  • the GLP-1 secretagogue component has the property of acting on cells of humans or non-human animals having GLP-1 secretory capacity to increase the amount of GLP-1 secreted (hereinafter, GLP-). 1 It means a substance or composition having a secretagogue ability).
  • the amount of GLP-1 secreted increases.
  • the amount of GLP-1 secreted is confirmed by the same method as in the experimental example. That is, a sample containing the test substance or composition and a non-stimulation negative control sample having the same composition except that the test substance or composition is not contained are prepared, and both samples are secreted under the same conditions as GLP-1. It is given to capable human colon-derived cells (eg, H716) and confirmed to have higher / lower GLP-1 secretion compared to unstimulated negative control samples.
  • the "emulsified particle” means a colloidal particle formed by aggregating molecules or ions derived from an emulsifier.
  • colloidal particles are sometimes called micelles, nanoemulsions, emulsions, etc. depending on their size (see: Toshiyuki Suzuki, J.Soc.Cosmet.Jpn., Vol.44, No.2, 2010), the “emulsified particles” in the present invention include all of these.
  • the emulsified particles formed by using the emulsifier exert the GLP-1 secretion promoting ability, but in addition, it is a non-GLP-1 secretagogue component having no GLP-1 secretion promoting ability.
  • the emulsified particles formed by using a hydrophobic component and this and an oil-in-water emulsifier can exhibit an excellent GLP-1 secretion promoting ability.
  • a certain component is not contained in the emulsified particles means that the hydrophobic group side of the emulsifier gathers around the component to form the emulsified particles, that is, the component is contained in the core of the emulsified particles. It means a state in which the component is not incorporated in the shell existing outside the core of the emulsified particles and which is not in the existing state. In other words, when “a component is not contained in the emulsified particles", the component is in a substantially non-emulsified state.
  • the "core” means the central portion (nucleus) of the emulsified particles.
  • Fats and oils can be mentioned.
  • Fats and oils consist of esters of fatty acids and glycerin.
  • the fatty acid includes a short-chain fatty acid having 2 or 4 carbon atoms, a medium-chain fatty acid having 6 to 12 carbon atoms, and a long-chain fatty acid having 14 to 22 carbon atoms.
  • Fats and oils composed of fatty acids having 6 to 12 carbon atoms, particularly 8 or 10 carbon atoms are preferable.
  • the content (mass) of the non-GLP-1 secretagogue is preferably 2 to 500 times, 2 to 400 times, 2 to 300 times, 2 to 200 times, 5 to 500 times, and 10 to 400 times that of the emulsifier. , 40 to 300 times, 60 to 200 times, 100 to 200 times, 150 to 200 times, 1 to 100 times, 5 to 90 times, 10 to 80 times, 30 to 60 times or 15 to 45 times.
  • the content (mass) of the non-GLP-1 secretagogue component is preferably 1 to 500, 1 to 400, 1 to 300, 1 to 200, 1 to 100, 1 to 80, 1 to 60 of the emulsifier. , 1-40, 1-20, 1-10, 1-7, 1-4, 3-500, 5-500, 7-500, 10-500, 20-500, 30-500, 50-500, 100 ⁇ 500, 3 ⁇ 400, 5 ⁇ 300, 7 ⁇ 200, 10 ⁇ 100, 20 ⁇ 80, 30 ⁇ 60, 3 ⁇ 30, 3 ⁇ 27, 3 ⁇ 24, 3 ⁇ 21, 3 ⁇ 18, 3 ⁇ 15 , 3-12, 3-9 or 6-30 times.
  • the content ratio (mass%) of the non-GLP-1 secretagogue component in the composition of the present invention is preferably 10 to 50, 10 to 40, 10 to 30, 10 to 20, 15 to 50, 20 to 50, It is 25 to 50, 30 to 50, 35 to 50, 40 to 50, 45 to 50, 15 to 40 or 20 to 30% by mass.
  • the content ratio (mass%) of the non-GLP-1 secretagogue component in the composition of the present invention is preferably 0.01 to 10, 0.01 to 8, 0.01 to 7, 0.01 to 6, 0.01 to 5, 0.1 to 10, 0.1 to 8, 0.1 to 7, 0.1 to 6, 0.1 to 5, 0.3 to 10, 0.3 to 8, 0.3 to 7, 0.3 to 6 or 0.3 to 5% by mass.
  • the ratio R of the non-GLP-1 secretagogue component contained in the emulsified particles represented by the following formula is preferably 10 to 50%.
  • R (%) (amount of non-GLP-1 secretagogue component contained in emulsified particles / amount of non-GLP-1 secretagogue component used) ⁇ 100
  • the amount of the non-GLP-1 secretagogue component contained in the emulsified particles is confirmed by fractionating the emulsified particles and the aqueous medium and measuring the non-GLP-1 secretagogue component contained in the fraction on the emulsified particle side. can do.
  • the emulsifier used in the present invention is an oil-in-water emulsifier.
  • the HLB values are 7-18, 9-18, 11-18, 13-18, 15-18, 7-17, 7-15, 7-13, 7-11, 7-9, It is preferably any of 9 to 16 and 11 to 14.
  • the HLB value is calculated by the Griffin method.
  • oil-in-water emulsifiers can be used without limitation.
  • an oil-in-water emulsifier glycerin fatty acid esters such as monoglyceride, organic acid monoglyceride, and polyglycerin fatty acid ester; sorbitan fatty acid ester; sucrose fatty acid ester; under the condition that the HLB value is any of the above values.
  • Propropylene glycol fatty acid ester Stearoyl lactate; Polysorbate; Plant lecithin, egg yolk lecithin, fractionated lecithin, enzyme-treated lecithin and other lecithin; Kiraya extract, Yukkafoam extract; Vegetable sterol; Sphingolipid; Biliary powder; Animal sterol And so on.
  • the oil-in-water emulsifier comprises a polyglycerin fatty acid ester, a propylene glycol fatty acid ester, an enzyme-treated lecithin, a sucrose fatty acid ester and an organic acid monoglyceride, provided that the HLB value is one of the above values. Includes at least one selected from the group.
  • the emulsifier used preferably contains an emulsifier whose hydrophilic group is derived from a sweetening component, provided that the HLB value is any of the above values, particularly from polyglycerin fatty acid esters and sucrose fatty acid esters. It is preferable to contain at least one emulsifier selected from the group.
  • the emulsifier preferably contains a sucrose fatty acid ester or an organic monoglyceride under the condition that the HLB value is any of the above values.
  • the emulsifier contains an emulsifier whose hydrophilic group contains a phosphoric acid group, and particularly preferably lecithins, under the condition that the HLB value is any of the above values.
  • the content ratio (% by mass) of the emulsifier in the composition of the present invention is preferably 0.1 to 5, 0.1 to 4, 0.1 to 3, 0.1 to 2, 0. 1-1, 0.3-5, 0.5-5, 0.7-5, 0.9-5, 1.1-5, 2.1-5, 3.1-5, 4.1- 5, 0.3-4, 0.5-3, 0.7-2, 0.9-1, 0.3-5, 0.5-5.0, 0.7-5.0, 0. 9-5.0, 1-5.0, 1.5-5.0, 2-5.0, 2.5-5.0, 3-5.0, 3.5-5.0, 4- 5.0, 4.5 to 5.0, 0.1 to 4, 0.1 to 3, 0.1 to 2, 0.1 to 1, 0.1 to 0.8, 0.1 to 0. 6, 0.1-0.4, 0.1-0.2, 0.2-4.5, 0.3-4.0, 0.4-3.5, 0.5-3.0, It is 0.6 to 2.5, 0.7 to 2.0, 0.8 to 1.5 or 0.9 to 1.0% by mass.
  • the content ratio (% by mass) of the emulsifier in the composition of the present invention is preferably 0.001 to 1, 0.001 to 0.5, 0.001 to 0.25, 0.001 to 0.2, 0.01 to 1, 0.01 to 0.5 on a mass basis.
  • composition of the present invention may contain components other than the above-mentioned components.
  • Other ingredients include, for example, sweeteners, aqueous bases, proteins, glycoproteins, excipients, binders, disintegrants, coatings, lubricants, colorants, flavoring agents, stabilizers, absorption enhancers. , PH adjusters, preservatives, antioxidants, fragrances, vitamins, trace metal components, etc.
  • steviol glycosides such as rebaudioside A, rebaugioside B, stevia extract, rebaugioside C, stevioside, rebaugioside M, rebaugioside N, rebaugioside O; or mogroside (hereinafter, mogroside may be abbreviated as Mog). There is.).
  • natural sweeteners such as aspartame, neotheme, ariteme
  • synthetic sweeteners such as assesulfam K, saccharin, advantage, ticlo, zulutin
  • Vegetable protein-based sweeteners such as somatin; taumarin; neohesperidin dihydrocalcone
  • sugar alcohols such as erythritol, xylitol, sorbitol, martitol, mannitol; and the like.
  • an aqueous base such as glycerin
  • Aqueous bases are emulsifiers 1-100, 10-90, 20-80, 24.5-73.5, 8-600, 8-500, 8-400, 8-300, 8-200, 8-100. , 8-70, 8-40, 8-10, 12-600, 16-600, 20-600, 40-600, 60-600, 80-600, 100-600, 200-600, 400-600, 12 It is preferably contained in an amount of to 500, 16 to 400, 20 to 300, 40 to 200 or 60 to 100 times (mass).
  • Food additives include, for example, excipients (eg wheat starch, corn starch, cellulose, mannitol, sorbitol, xylitol, pregelatinized starch, magnesium silicate aluminate, calcium silicate, etc.), binders (eg, alpha Chemical starch, hydroxypropylmethylcellulose, polyvinylpyrrolidone, etc.), disintegrants (eg, cellulose, hydroxypropylcellulose, corn starch, etc.), fluidizers (eg, light anhydrous silicic acid, etc.), nutrients (eg, various minerals, various vitamins, etc.) ), Fragrances, sweeteners, flavoring agents, coloring agents, solvents (eg ethanol), salts, pH adjusters, buffers, antioxidants, stabilizers, gelling agents, thickeners, lubricants, capsules Examples include agents, suspending agents, excipients (eg wheat starch, corn starch, cellulose, mannitol, sorbitol,
  • composition of the present invention at least one selected from the group consisting of polyglycerin fatty acid ester, propylene glycol fatty acid ester, enzyme-treated lecithin, sucrose fatty acid ester and organic acid monoglyceride as an oil-in-water emulsifier, emulsified particles.
  • hydrophobic non-GLP-1 secretion-promoting component contained in the above include fats and oils composed of C6 to C12 fatty acids, glycerin as an aqueous base, and an aqueous medium as a dispersion medium, particularly those containing water.
  • composition of the present invention at least one selected from the group consisting of polyglycerin fatty acid ester, propylene glycol fatty acid ester, enzyme-treated lecithin, sucrose fatty acid ester and organic acid monoglyceride as an oil-in-water emulsifier, Non-GLP-1 containing fats and oils composed of C6 to C12 fatty acids as hydrophobic non-GLP-1 secretion promoting components contained in emulsified particles, glycerin as an aqueous base, and an aqueous medium as a dispersion medium, particularly water.
  • the content ratio of the secretion promoting component is 2 to 500 times (mass) of the emulsifier and the content ratio of the aqueous base is 1 to 100 times (mass) of the emulsifier.
  • composition of the present invention at least one selected from the group consisting of polyglycerin fatty acid ester, propylene glycol fatty acid ester, enzyme-treated lecithin, sucrose fatty acid ester and organic acid monoglyceride as an oil-in-water emulsifier, Non-GLP-1 containing fats and oils composed of C6 to C12 fatty acids as hydrophobic non-GLP-1 secretion promoting components contained in emulsified particles, glycerin as an aqueous base, and an aqueous medium as a dispersion medium, particularly water.
  • the content ratio of the secretion promoting component is 1 to 500 times (mass) of the emulsifier and the content ratio of the aqueous base is 1 to 100 times (mass) of the emulsifier.
  • composition of the present invention may be an emulsifier or a composition for promoting GLP-1 secretion containing emulsified particles composed of an emulsifier and fats and oils as an active ingredient.
  • the composition of the present invention may have any shape, and may be, for example, solid (for example, powder), gel or liquid.
  • a composition containing emulsified particles and a composition containing other components are separately prepared, and both compositions are mixed and ingested, taken or administered, or both compositions are ingested, taken or administered separately. You may.
  • the average particle size of the emulsified particles is preferably 0.05 to 0.5, 0.07 to 0.5, 0.05 to 0.4, 0.05 to 0.3, 0.05 before storage (for example, within half a day from production). It is ⁇ 0.2, 0.05 ⁇ 0.1, 0.1 ⁇ 0.4, 0.2 ⁇ 0.3, 0.07 ⁇ 0.15, 0.07 ⁇ 0.12 or 0.07 ⁇ 0.09 ⁇ m.
  • the average particle size of emulsified particles tends not to change much even after long-term storage.
  • Particle size x 100-100) is minus 40% to plus 40%, minus 37% to plus 37%, minus 35% to plus 35%, minus 20% to plus 20%, or minus 12% to plus 12%. ..
  • the average particle size of the emulsified particles can be measured by the laser diffraction scattering method. For example, as shown in Examples described later, a sample is appropriately diluted with ion-exchanged water so that the laser scattering intensity is about 1%, and the diluted sample is a laser diffraction scattering type particle size distribution measuring instrument (Spectris Co., Ltd. Malvern). ⁇ The average particle size of the emulsified particles can be obtained by measuring with the Panasonic Division).
  • composition of the present invention can be applied to the use of promoting GLP-1 secretion.
  • compositions of the present invention are used for suppressing blood glucose elevation, suppressing appetite, suppressing overeating, improving glucose metabolism, preventing or treating diabetes, preventing or treating obesity, reducing body weight, and the like. It can be used for at least one application selected from those for reducing 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).
  • composition of the present invention can be used (ingested, taken or administered) directly on humans or non-human animals capable of secreting GLP-1.
  • compositions of the present invention include those for suppressing increase in blood glucose level, suppressing appetite, suppressing overeating, improving glucose metabolism, preventing or treating diabetes, and obesity.
  • prevention or treatment 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, prevention or treatment of vascular diseases
  • Foods for the 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, instant noodles) , Tofu, confectionery (candy, gum, chocolate, snacks, biscuits, cookies, gummy, etc.), breads, marine or processed livestock foods (kamaboko, ham, sausage, etc.), dairy products (fermented milk, etc.), fats and oils And processed fats and oils (sala
  • 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 dosage forms include, for example, tablets, powders, fine granules, granules, dry syrups, coated tablets, orally disintegrating tablets, chewable tablets, capsules, soft capsules. , Syrups, enteral nutritional supplements, etc.
  • composition of the present invention is produced by a known method according to its use, composition and the like.
  • an oil-in-water emulsifier is optionally stirred in an aqueous medium with a hydrophobic non-GLP-1 secretagogue component and is free of free fatty acids that act as a ligand for the GT01 protein.
  • a hydrophobic non-GLP-1 secretagogue component is free of free fatty acids that act as a ligand for the GT01 protein.
  • the stirring is preferably performed at high speed under more severe conditions than the mixing by using a homomixer or the like so that the hydrophobic non-GLP-1 secretagogue component is present 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.
  • a composition containing emulsified particles in which a non-GLP-1 secretagogue component is present in the core is expected to have excellent storage stability.
  • one aspect of the present invention is the production of a GLP-1 secretagogue composition
  • a GLP-1 secretagogue composition comprising the step of optionally stirring an oil-in-water emulsifier with a hydrophobic non-GLP-1 secretagogue component in an aqueous medium.
  • the present invention relates to a GLP-1 secretagogue composition comprising a method and oil-in-water emulsified particles produced by the method and containing no free fatty acid acting as a ligand for the GT01 protein.
  • the emulsified particles tend to contain a hydrophobic non-GLP-1 secretagogue component.
  • composition of the present invention can also 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 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, etc.
  • foods for specified health use foods with health claims such as foods with nutritional function, supplements (dietary supplements), feeds, etc. are also included.
  • beverages include tea beverages, soft drinks, carbonated beverages (including non-alcoholic beers), nutritional beverages, fruit beverages, lactic acid beverages, juices, drinks, alcoholic beverages, processed milk, prepared soymilk and the like.
  • the food and drink may contain other ingredients as long as it contains the composition of the present invention.
  • other components in this case, the same examples as those shown in the section ⁇ Other components> can be given.
  • the intake amount (dose, dose) of the emulsifier is not particularly limited and can be appropriately selected according to age, body weight, health condition 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 composition of the present invention is not particularly limited, and may be, for example, before meals, during meals, between meals, after meals, before bedtime, and the like.
  • One aspect of the invention is a composition used in the treatment of diseases that can be ameliorated by promoting GLP-1 secretion, containing emulsified particles containing an oil-in-water emulsifier and free of free fatty acids acting as a ligand for the GT01 protein.
  • one aspect of the present invention comprises administering to a subject in need of emulsified particles containing an oil-in-water emulsifier and free of free fatty acids acting as a ligand for the GT01 protein, in the subject GLP-1. It relates to a method of treating a disease that promotes the secretion of GLP-1 or can be ameliorated by promoting the secretion of GLP-1 in a subject.
  • one aspect of the present invention is a medicament for treating a disease of emulsified particles containing an oil-in-water emulsifier and not containing a free fatty acid acting as a ligand for GT01 protein, which can be improved by promoting GLP-1 secretion.
  • a disease of emulsified particles containing an oil-in-water emulsifier and not containing a free fatty acid acting as a ligand for GT01 protein, which can be improved by promoting GLP-1 secretion.
  • each aspect described above may have various features described in the present specification.
  • Diseases include hyperglycemia, bulimia nervosa, hyperacidity, diabetes, obesity, vascular disease, neurodegenerative diseases, non-alcoholic hepatitis, pancreatic disease, asthma and the like.
  • 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

Le développement d'un excellent composant favorisant la sécrétion de GLP-1 a été anticipé. La présente invention concerne une composition qui est destinée à favoriser la sécrétion de GLP-1 et contient des particules émulsifiées, les particules émulsifiées contenant chacune un émulsifiant de type huile dans l'eau, et ne contient pas d'acide gras libre qui agit en tant que ligand pour une protéine GT01.
PCT/JP2020/017401 2019-04-26 2020-04-22 Composition favorisant la sécrétion de glp-1 Ceased WO2020218381A1 (fr)

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JPWO2022201832A1 (fr) * 2021-03-22 2022-09-29

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JP2011046668A (ja) * 2009-08-28 2011-03-10 Nof Corp Ｇｌｐ−１及びインスリンの分泌持続調整剤
JP2015047080A (ja) * 2013-08-30 2015-03-16 株式会社ファンケル 乳化組成物
US20150237901A1 (en) * 2014-02-21 2015-08-27 James and Carol May Family, LLLP Compositions and methods for the solubilization of stevia glycosides
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
WO2019032678A1 (fr) * 2017-08-08 2019-02-14 Engineered Biopharmaceuticals, Inc. Composition d'édulcorant et ses procédés de production

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JPH01176443A (ja) * 1987-12-28 1989-07-12 Nonogawa Shoji:Kk 多価アルコール中油型乳化組成物及び水中油型乳化組成物
JP2011046668A (ja) * 2009-08-28 2011-03-10 Nof Corp Ｇｌｐ−１及びインスリンの分泌持続調整剤
JP2015047080A (ja) * 2013-08-30 2015-03-16 株式会社ファンケル 乳化組成物
US20150237901A1 (en) * 2014-02-21 2015-08-27 James and Carol May Family, LLLP Compositions and methods for the solubilization of stevia glycosides
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
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Cited By (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JPWO2022201832A1 (fr) * 2021-03-22 2022-09-29
WO2022201832A1 (fr) * 2021-03-22 2022-09-29 日清オイリオグループ株式会社 Procédé de criblage de l'agent régulateur de la sécrétion de glp-1, agent régulateur de la sécrétion de glp-1, composition pour prévenir ou atténuer le diabète, l'obésité, l'hyperglycémie postprandiale, les maladies neurodégénératives, l'hypoglycémie, l'adiposité ou la nesidioblastose, procédé pour favoriser la sécrétion de glp-1 dans des cellules exprimant gpr84, procédé pour produire une composition favorisant la sécrétion de glp-1, utilisation d'un agoniste de gpr84 pour produire un agent thérapeutique pour une maladie, agent favorisant la sécrétion de glp-1, et composition pour ingestion orale
JP7289997B2 (ja) 2021-03-22 2023-06-12 日清オイリオグループ株式会社 Ｇｌｐ－１分泌制御剤のスクリーニング方法、ｇｌｐ－１分泌制御剤、糖尿病、肥満、食後高血糖、神経変性疾患、低血糖、脂肪過多、若しくは膵島細胞症の予防又は改善用組成物、ｇｐｒ８４発現細胞におけるｇｌｐ－１分泌の促進方法、ｇｌｐ－１分泌促進用組成物の製造方法、ｇｐｒ８４アゴニストの、疾患の治療薬を製造するための使用、ｇｌｐ－１分泌促進剤、経口摂取用組成物

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