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WO2011068150A1 - Amplificateur de la sécrétion du peptide 1 analogue au glucagon - Google Patents

Amplificateur de la sécrétion du peptide 1 analogue au glucagon Download PDF

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Publication number
WO2011068150A1
WO2011068150A1 PCT/JP2010/071555 JP2010071555W WO2011068150A1 WO 2011068150 A1 WO2011068150 A1 WO 2011068150A1 JP 2010071555 W JP2010071555 W JP 2010071555W WO 2011068150 A1 WO2011068150 A1 WO 2011068150A1
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WO
WIPO (PCT)
Prior art keywords
glp
potato extract
secretion
peptide
glucagon
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Application number
PCT/JP2010/071555
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English (en)
Japanese (ja)
Inventor
仁人 鍔田
博 原
徹 比良
Original Assignee
株式会社東洋新薬
国立大学法人北海道大学
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by 株式会社東洋新薬, 国立大学法人北海道大学 filed Critical 株式会社東洋新薬
Priority to JP2011544281A priority Critical patent/JP5721232B2/ja
Publication of WO2011068150A1 publication Critical patent/WO2011068150A1/fr

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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K36/00—Medicinal preparations of undetermined constitution containing material from algae, lichens, fungi or plants, or derivatives thereof, e.g. traditional herbal medicines
    • A61K36/18—Magnoliophyta (angiosperms)
    • A61K36/185—Magnoliopsida (dicotyledons)
    • A61K36/81—Solanaceae (Potato family), e.g. tobacco, nightshade, tomato, belladonna, capsicum or jimsonweed
    • 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 glucagon-like peptide-1 secretion promoter.
  • GLP-1 Glucagon-like peptide-1
  • GLP-1 a hormone secreted from L cells scattered in the gastrointestinal tract, is a potent stimulator of insulin secretion by stimulating food, stimulation of the satiety center, It has been confirmed to have effects such as peristaltic movement suppression. All of these actions of GLP-1 are considered to be related to the effect of suppressing a rapid increase in blood glucose level due to feeding, and studies have been conducted on the use of GLP-1 for the treatment of diabetes. GLP-1 is also attracting attention for its obesity-inhibiting action.
  • GLP-1 has very low stability in the body, it is necessary to optimize the administration method and route, search for functional analogs with high stability in the body, and the like.
  • Patent Document 1 discloses that acid casein and the like have a GLP-1 secretion promoting action.
  • Patent Document 2 discloses that casein glycomacropeptide (CGMP) has a GLP-1 secretion promoting action.
  • Patent Document 3 discloses a GLP-1 secretion promoter containing ⁇ -casein as an active ingredient.
  • Non-Patent Document 1 discloses that peptide ZeinH obtained by hydrolyzing maize resistant protein Zein with papain has a strong GLP-1 secretion promoting action.
  • Toru Hira “33. Search for food peptides that stimulate the secretion of GLP-1, the gastrointestinal hormone that promotes insulin secretion, and elucidation of the receptor mechanism in the gastrointestinal tract”, Research Report on Sasauehara Memorial Life Science Foundation, 22 (2008)
  • An object of the present invention is to provide a useful glucagon-like peptide-1 secretion promoter.
  • the present invention provides a glucagon-like peptide-1 secretion promoter containing a potato extract.
  • a novel glucagon-like peptide-1 secretion promoter is provided.
  • This glucagon-like peptide-1 secretion promoter can be useful for the prevention and improvement of diabetes and obesity, and can be suitably used for pharmaceuticals and foods and drinks.
  • FIG. 4 is a bar graph showing the amount of GLP-1 secretion in a GLP-1-producing cell line GLUTag derived from a mouse large intestine treated with potato extract and ZeinH. GLP derived from mouse colon by treatment of potato extract, potato extract HP20 non-adsorbed fraction, potato extract HP20 adsorbed-20% ethanol elution fraction, and potato extract HP20 adsorbed-80% ethanol eluted fraction, respectively.
  • FIG. 3 is a graph showing the amount of GLP-1 secreted by one production cell line GLUTag as a bar graph.
  • Potato varieties used as a raw material for the potato extract are not particularly limited, and examples thereof include baron candy, make-in, kitakari, toya, toyoshiro, inca sword, digima, and Tokachi kone.
  • the potato production area is also not particularly limited, but Hokkaido potato is preferred.
  • Raw e.g., unprocessed potatoes within 2 days of collection
  • the potato extract can be prepared as described below.
  • an extraction solvent (acid) is added to a liquid material obtained by pulverizing and squeezing an edible portion (tuber) of potato, the pH is adjusted to be acidic, and then solvent extraction can be performed under heating.
  • acids that can be used as the extraction solvent generally include hydrochloric acid, acetic acid, sulfuric acid, formic acid, citric acid, and ascorbic acid.
  • the amount or concentration of the acid to be added can be appropriately set in such an amount or concentration that the pH is generally 2 to 5, preferably 3 to 4.
  • the solvent extraction is generally carried out at 70 to 90 ° C. for 10 to 60 minutes, preferably at 75 to 85 ° C. for 10 to 20 minutes.
  • the precipitate or insoluble fraction can be removed by an appropriate separation means such as centrifugation or filtration, and the supernatant or soluble fraction can be recovered. Furthermore, the same extraction process can be performed again on the precipitate or insoluble fraction after the extraction, and the supernatant or the soluble fraction can be recovered.
  • a fraction having a molecular weight of 10,000 or more is separated and recovered by membrane treatment, and then caustic soda is added to the cooled extract to adjust the pH. Can be adjusted to neutral or near to obtain a potato extract.
  • membrane treatment for molecular weight fractionation include ultrafiltration membrane treatment and gel filtration membrane treatment, with ultrafiltration membrane treatment being preferred.
  • the potato extract may be further subjected to processing such as drying means and pulverizing means.
  • drying method any known method can be used, and examples thereof include an air drying method, a heat drying method, a spray drying method, and a freeze drying method.
  • the potato extract can be dried, for example, by adding an excipient (eg, dextrin) and spray-drying it.
  • the pulverization method includes means such as pulverization or atomization using a pulverizer or an attritor.
  • the potato extract can be used in a liquid form or a solid form after removal of the solvent.
  • a potato extract manufactured by Toyo Shinyaku Co., Ltd. can be preferably used.
  • Potato extract can directly stimulate and promote GLP-1 secretion.
  • the GLP-1 secretion promoting action can be attributed to the components of the potato extract adsorbed on the adsorbent HP20 and eluted with 80% (v / v) ethanol.
  • a potato extract can be used as a GLP-1 secretion promoter, and a GLP-1 secretion promoter comprising a potato extract is provided.
  • GLP-1 has effects such as strong insulin secretion promotion, stimulation of the satiety center, suppression of peristaltic movement of the digestive tract by stimulation of food.
  • the GLP-1 secretion promoter of the present invention may be useful for the prevention and improvement of diabetes and obesity.
  • the GLP-1 secretion promoter of the present invention may also be useful for the prevention and treatment of any condition that is ameliorated by increased GLP-1 secretion.
  • the GLP-1 secretion promoter of the present invention may be used alone or in various nutritional components, excipients, extenders, binders, thickeners, emulsifiers, coloring agents, flavoring agents, food additives, nutritional supplements, seasonings It can be mixed with a preparation or the like and prepared as a composition for oral administration or ingestion.
  • the amount of the GLP-1 secretion promoter of the present invention depends on the type or dosage form of the product to be formulated, the age, sex, weight or condition of the subject of administration or intake, the method of administration or intake, timing or time, etc. Can be set appropriately.
  • the dose of the GLP-1 secretion promoter of the present invention is, for example, 10 to 2000 mg per adult per day, preferably 100, as an active ingredient when taken as a food or drink such as health food. It can be ⁇ 1000 mg, particularly preferably 300 to 1000 mg.
  • the administration timing of the GLP-1 secretion promoter may be before meal, between meals or after meal, but is preferably within 2 hours before meal, immediately before meal or immediately after meal. It may be administered in several divided doses.
  • compositions for oral administration or ingestion are shaped into capsules such as hard capsules and soft capsules, tablets and pills, or powders, granules, and bowls according to consumer preferences Can be done. It can also be prepared in liquid dosage forms or forms such as solutions, suspensions, or emulsions.
  • the GLP-1 secretion promoter of the present invention can be used as a pharmaceutical, a quasi-drug, a food for specified health use, a nutritional supplement, other food or drink, or can be used in combination with these.
  • a composition for oral administration or ingestion, or a combination product thereof may be eaten as it is depending on the dosage form or shape or preference, or it can be taken by dissolving in water, hot water, milk, soy milk, tea, juice, etc. good.
  • Example 1 GLP-1 secretion promoting action of potato extract
  • GLUTag GLP-1-producing cell line GLUTag (provided by Dr. Daniel J. Drucker, Mount Sinai Hospital, Samuel Lunenfeld Research Institute Banting and Best Diabetes Centre, University of Toronto), 10% in a 48-well plate.
  • the cells were cultured in Dulbecco's modified Eagle's medium containing fetal bovine serum (FBS) in the presence of 37 ° C. and 5% CO 2 until they became subconfluent for 2-3 days.
  • FBS fetal bovine serum
  • the culture medium was removed from the wells, and Hepes buffer (140 mM NaCl, 4.5 mM KCl, 20 mM Hepes, 1.2 mM CaCl 2 , 1.2 mM MgCl 2 , 10 mM D-glucose, 0.1% bovine serum albumin (BSA), pH 7.4)
  • BSA bovine serum albumin
  • the cryopreserved supernatant was appropriately thawed, and the concentration of GLP-1 in the supernatant was quantified using a commercially available ELISA kit (manufactured by Yanaihara Laboratory).
  • the GLP-1 concentration (nM) in the supernatant was defined as the amount of GLP-1 secretion from the GLP-1 producing cell line GLUTag.
  • Potato extract manufactured by Toyo Shinyaku Co., Ltd.
  • papain manufactured by Asahi Breweries Co., Ltd.
  • Lyophilized 2 and 10 mg / ml; used as positive control).
  • FIG. 1 is a bar graph showing the amount of GLP-1 secretion from a mouse large intestine-derived GLP-1 producing cell line GLUTag by potato extract and ZeinH.
  • GLP-1 secretion is expressed in nM
  • “Blank” is a negative control group (no test substance added)
  • “potato extract” is a potato extract treated group (2, 10 mg). / Ze)
  • “ZeinH” represents the result of ZeinH treatment (2, 10 mg / ml).
  • a, b, and c are symbols having different alphabets in Duncan's multigroup significance test, indicating that there is a significant difference between treatment groups (P ⁇ 0.05).
  • the potato extract showed GLP-1 secretion promoting activity in a concentration-dependent manner.
  • Example 2 GLP-1 secretion promoting effect of fraction of potato extract by column chromatography using adsorbent HP20
  • test substances used in this example are as follows: Potato extract (10mg / ml); Potato extract HP20 non-adsorbed fraction (7.44 mg / ml, equivalent to 10 mg / ml of potato extract; Potato extract HP20 adsorption-20% ethanol elution fraction (1.17 mg / ml, equivalent to 10 mg / ml of potato extract); and Potato extract HP20 adsorption-80% ethanol elution fraction (0.45 mg / ml, potato Equivalent to 10 mg / ml of extract).
  • the potato extract HP20 non-adsorbed fraction, the potato extract HP20 adsorbed-20% ethanol elution fraction, and the potato extract HP20 adsorbed-80% ethanol elution fraction were concentrated and then lyophilized. Yields corresponded to 74.4%, 11.7% and 4.5% of the potato extract used for fractionation, respectively.
  • FIG. 2 shows the results of the treatment of potato extract, potato extract HP20 non-adsorbed fraction, potato extract HP20 adsorbed—20% ethanol elution fraction, and potato extract HP20 adsorbed—80% ethanol eluted fraction.
  • FIG. 3 is a graph showing the amount of GLP-1 secreted from a derived GLP-1 producing cell line GLUTag in a bar graph. On the vertical axis, GLP-1 secretion is expressed in nM.
  • “Blank” is the result of the negative control group (no test substance added)
  • “potato extract” is the result of the potato extract treatment group
  • “HP20 non-adsorbed fraction” is the result of the potato extract HP20 non-adsorbed fraction treatment group
  • “HP20 adsorption—20% ethanol elution fraction” is the result of the potato extract HP20 adsorption—20% ethanol elution fraction treatment group
  • “HP20 adsorption—80% ethanol elution fraction” shows the results of the potato extract HP20 adsorption—80% ethanol elution fraction treatment group.
  • “a” and “b” indicate that there is a significant difference between the treatment groups by displaying symbols having different alphabets in Duncan's multigroup significance test (P ⁇ 0.05).
  • the potato extract may be useful for the prevention and improvement of diabetes and obesity based on its GLP-1 secretion promoting action.
  • the GLP-1 secretion promoter containing such a potato extract can be widely used for pharmaceuticals and foods and drinks.
  • the knowledge of the present invention can be useful for improving metabolic syndrome, which is also a social problem.

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  • Health & Medical Sciences (AREA)
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Abstract

La présente invention a pour objet un amplificateur de la sécrétion du peptide 1 analogue au glucagon qui contient de l'extrait de pomme de terre. L'amplificateur de la sécrétion du peptide 1 analogue au glucagon est utile pour la prophylaxie et l'amélioration du diabète et de l'obésité. L'amplificateur de la sécrétion du peptide 1 analogue au glucagon est approprié pour une utilisation dans un produit pharmaceutique, un aliment et une boisson.
PCT/JP2010/071555 2009-12-04 2010-12-02 Amplificateur de la sécrétion du peptide 1 analogue au glucagon WO2011068150A1 (fr)

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JP2011544281A JP5721232B2 (ja) 2009-12-04 2010-12-02 グルカゴン様ペプチド−１分泌促進剤

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JP2009-276994 2009-12-04
JP2009276994 2009-12-04

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Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JP2013063957A (ja) * 2011-09-02 2013-04-11 Kao Corp Ｇｌｐ−１分泌促進剤

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* Cited by examiner, † Cited by third party
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JP6447848B2 (ja) * 2017-11-21 2019-01-09 株式会社東洋新薬 抗糖化用組成物

Citations (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2008120813A1 (fr) * 2007-04-03 2008-10-09 Mitsubishi Tanabe Pharma Corporation Utilisation combinée de composé inhibiteur de dipeptidylpeptidase iv, et d'adoucisseur

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EP1115409A4 (fr) * 1999-07-27 2005-04-13 Kemin Consumer Care L C Composition permettant de prolonger la satiete apres un repas

Patent Citations (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2008120813A1 (fr) * 2007-04-03 2008-10-09 Mitsubishi Tanabe Pharma Corporation Utilisation combinée de composé inhibiteur de dipeptidylpeptidase iv, et d'adoucisseur

Non-Patent Citations (3)

* Cited by examiner, † Cited by third party
Title
ACTA ENDOCRINOLOGICA, vol. 123, no. 4, 1990, pages 464 - 470 *
J. FOOD SCI., vol. 39, 1974, pages 1062 - 1063 *
THE JAPANESE JOURNAL OF NUTRITION, vol. 53, no. 6, 1995, pages 361 - 368 *

Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JP2013063957A (ja) * 2011-09-02 2013-04-11 Kao Corp Ｇｌｐ−１分泌促進剤

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TW201125573A (en) 2011-08-01
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