WO2011068149A1 - Amplificateur de la sécrétion de la cholécystokinine - Google Patents

Amplificateur de la sécrétion de la cholécystokinine Download PDF

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Publication number
WO2011068149A1
WO2011068149A1 PCT/JP2010/071554 JP2010071554W WO2011068149A1 WO 2011068149 A1 WO2011068149 A1 WO 2011068149A1 JP 2010071554 W JP2010071554 W JP 2010071554W WO 2011068149 A1 WO2011068149 A1 WO 2011068149A1
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Prior art keywords
potato extract
cck
potato
secretion
extract
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PCT/JP2010/071554
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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
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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 JP2011544280A priority Critical patent/JP5674047B2/ja
Publication of WO2011068149A1 publication Critical patent/WO2011068149A1/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
    • A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00

Definitions

  • the present invention relates to a cholecystokinin secretion promoter.
  • CCK Cholecystokinin
  • Patent Literature 1 includes a) a protein selected from the group consisting of casein, whey and soybean, b) a glycomacropeptide or casein macropeptide, c) a long chain fatty acid (C 12 to C 18 ), and d) A composition comprising soluble fiber or insoluble fiber or a mixture thereof;
  • Patent Document 2 includes a pepsin degradation product of soybean ⁇ -conglycinin;
  • Patent Document 3 includes whey protein and whey protein hydrolyzate; , Whey protein hydrolysates; and US Pat. No. 6,057,095 describe the use of peptides derived from whey protein hydrolysates.
  • Patent Document 6 discloses oral administration of a trypsin inhibitor that enhances satiety by stimulating CCK release. Trypsin inhibitors are presumed to act by suppressing negative feedback signals for CCK secretion. In this way, the trypsin inhibitor maintains the concentration of CCK, thereby sustaining a feeling of fullness.
  • Patent Document 7 shows that potato proteinase inhibitor II (PI2) increases the CCK concentration in plasma.
  • Patent Document 8 describes that an extract or an extract obtained by hot water extraction of yeast promotes CCK secretion.
  • An object of the present invention is to provide a factor useful for promoting the secretion of cholecystokinin, which is an important regulator of satiety.
  • the present invention provides a cholecystokinin secretion promoter containing a potato extract.
  • a novel cholecystokinin secretion promoter is provided.
  • This cholecystokinin secretion promoter can be useful as a means for giving a feeling of satiety and suppressing appetite, and can be suitably used for pharmaceuticals and foods and drinks.
  • FIG. 3 is a bar graph showing the amount of CCK secreted from a mouse small intestine-derived CCK-producing cell line STC-1 by treatment with a potato extract, soybean trypsin inhibitor, and soybean ⁇ -conglycinin peptone. Production of CCK derived from the small intestine of the mouse by each 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.
  • FIG. 3 is a graph showing the amount of CCK secretion of cell line STC-1 in 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 the secretion of CCK.
  • CCK secretion promoting action in animals (including humans) in vivo, suppression of CCK secretion inhibition by inhibiting the action of trypsin which is a CCK secretion inhibitor is known, but potato extract produces CCK. Stimulating and promoting effects of CCK production and secretion itself from the cells that can be expected.
  • the CCK 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 CCK secretion promoter, and a CCK secretion promoter comprising a potato extract is provided.
  • the CCK secretion promoter of the present invention can give a feeling of satiety to target animals (including humans) and suppress appetite by administration or ingestion thereof.
  • the CCK secretion promoter of the present invention may also be useful for the prevention and treatment of any condition that is ameliorated by increased CCK secretion.
  • the CCK secretion promoter of the present invention may be used alone or in various nutritional components, excipients, extenders, binders, thickeners, emulsifiers, coloring agents, fragrances, food additives, nutritional supplements, seasonings, etc. And can be prepared as a composition for oral administration or ingestion.
  • the amount of the CCK secretion promoter of the present invention is appropriately determined according to the type or dosage form of the product to be formulated, the age, sex, weight or condition of the subject of administration or ingestion, the method of administration or ingestion, timing or time, etc. Can be set.
  • the dose of the CCK secretion promoter of the present invention is, for example, as an active ingredient when ingested as a food or drink such as health food, usually 10 to 2000 mg, preferably 100 to 1000 mg per adult per day as an active ingredient. Particularly preferably, it may be 300 to 1000 mg.
  • the administration time of the CCK 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 CCK 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.
  • 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 Appetite suppression effect of potato extract
  • Potato extract and soybean trypsin inhibitor SBTI: Sigma Type II-S, manufactured by Sigma were examined for effects on appetite suppression in rats. SBTI has been reported to increase the release of CCK and consequently reduce food intake (Patent Document 6).
  • FIG. 1 is a bar graph showing the amount of food consumed by rats at 1, 2, 3 and 6 hours after feeding with potato extract treatment and soybean trypsin inhibitor treatment.
  • the vertical axis represents food intake in g, and the horizontal axis represents elapsed time (hours) after feeding.
  • the results of negative control (administration of water alone), SBTI treatment, and potato extract treatment are shown in order from the left.
  • a and b in the figure indicate that there is a significant difference between treatment groups in the same elapsed time section by displaying symbols having different alphabets in Duncan's multigroup significance test (P ⁇ 0.05). .
  • SBTI administration caused a significant decrease in food intake compared to 1 to 6 hours later, compared to a negative control in which only water was administered.
  • Administration of potato extract also caused a decrease in food intake, and a significant decrease in food intake was observed after 1 hour and 3 hours.
  • the protein content was about 20% (measured by the Kjeldahl method) for potato extract, whereas SBTI was a reagent-grade pure product.
  • Example 2 CCK secretion promoting effect of potato extract
  • STC-1 mouse small intestine-derived CCK-producing cell line STC-1 (provided by Dr. D. Hanahan, University of California, San Francisco, Calif.) was dulbecco containing 10% fetal bovine serum (FBS) in a 48-well plate.
  • FBS fetal bovine serum
  • the cells were cultured for 2 to 3 days in a modified Eagle medium in the presence of 5% CO 2 at 37 ° C. until they became subconfluent.
  • 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 CCK concentration in the supernatant was quantified using a commercially available ELISA kit (Phoenix Pharmaceuticals Inc).
  • the CCK concentration (pM) in the supernatant was taken as the amount of CCK secretion from the CCK producing cell line STC-1.
  • Potato extract (1, 5, 10 and 20 mg / ml); SBTI (Sigma Type II-S, Sigma; 1, 5, 10 and 20 mg / ml); and soybean ⁇ -conglycinin peptone (BconP: pepsin hydrolyzate of soybean ⁇ -conglycinin: ⁇ -conglycinin (Fuji Oil Co., Ltd.) (Made by SIGMA) was added to the substrate at 0.5% by mass, reacted at 37 ° C. for 10 minutes, and boiled to lose pepsin. After activating, the centrifuged supernatant was neutralized and desalted); 5 mg / ml; used as a positive control).
  • FIG. 2 is a bar graph showing the amount of CCK secreted from the mouse small intestine-derived CCK-producing cell line STC-1 by treatment with potato extract, soybean trypsin inhibitor, and soybean ⁇ -conglycinin peptone.
  • CN is the result of the negative control group (no test substance added)
  • BconP is the result of the soybean ⁇ -conglycinin peptone treatment group of 5 mg / ml
  • SBTI indicates the result of the soybean trypsin inhibitor treatment group (1, 5, 10, and 20 mg / ml)
  • potato extract indicates the result of the potato extract treatment group (1, 5, 10, and 20 mg / ml).
  • a, b, and c 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).
  • SBTI did not show CCK secretion promoting activity
  • potato extract showed CCK secretion promoting activity in a concentration-dependent manner.
  • the potato extract showed a CCK secretion promoting activity comparable to that of the positive control BconP at a concentration of 5 mg / ml.
  • SBTI a trypsin inhibitor that has been reported to increase CCK release, did not show CCK secretion promoting activity, whereas potato extract was found to have strong CCK secretion promoting activity. It was done.
  • the trypsin inhibitory activity of each of the potato extract and SBTI was examined using the synthetic substrate benzoylarginine-p-nitroanilide (BAPNA). At 50% inhibition, SBTI had trypsin inhibitory activity more than 10 times (20-30 times) that of potato extract. Even SBTI 50 mg had higher trypsin inhibitory activity than potato extract 100 mg.
  • BAPNA synthetic substrate benzoylarginine-p-nitroanilide
  • Example 3 CCK 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 (5 mg / ml); Potato extract HP20 non-adsorbed fraction (3.72 mg / ml, equivalent to 5 mg / ml of potato extract; Potato extract HP20 adsorption-20% ethanol elution fraction (0.59 mg / ml, equivalent to 5 mg / ml of potato extract); and Potato extract HP20 adsorption-80% ethanol elution fraction (0.23 mg / ml, potato Equivalent to 5 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. 3 shows mouse small intestine 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 elution fraction.
  • FIG. 6 is a graph showing the amount of CCK secretion of the derived CCK-producing cell line STC-1 in a bar graph. On the vertical axis, the amount of CCK secretion is expressed in pM.
  • “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, b, and c 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).
  • Example 4 Adsorption of potato extract HP20-concentration dependence on CCK secretion promoting action of 80% ethanol elution fraction
  • test substances used in this example are as follows: Potato extract (5mg / ml) Potato extract HP20 adsorption-80% ethanol elution fraction 0.225 mg / ml (prepared in the same manner as in Example 3. equivalent to 5 mg / ml of potato extract) 0.113 mg / ml (The above 0.225 mg / ml preparation was diluted 2-fold with Hepes buffer)
  • FIG. 4 shows the potato extract (5 mg / ml), as well as the CCK producing cell line STC derived from the mouse small intestine by the respective treatment of 0.225 mg / ml or 0.113 mg / ml potato extract HP20 adsorbed-80% ethanol elution fraction.
  • FIG. 3 is a bar graph showing the amount of CCK secretion of ⁇ 1. On the vertical axis, CCK secretion is expressed in pM, and on the horizontal axis, “Blank” is the negative control group (no test substance added), and “potato extract 5 mg / ml” is the potato extract (5 mg / ml).
  • “0.113 mg / ml” of “HP20 adsorption—80% ethanol elution fraction” is 0.113 mg / ml of potato extract HP20 adsorption—80% ethanol elution fraction treatment group result, and “0.225 mg / ml "shows the result of the potato extract HP20 adsorption-80% ethanol elution fraction treatment group with 0.225 mg / ml.
  • a, b, and c 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).
  • Potato extract HP20 adsorption-80% ethanol elution fraction promoted CCK secretion in a concentration-dependent manner.
  • the potato extract HP20 adsorption-80% ethanol elution fraction showed CCK secretion promoting activity comparable to that of the potato extract (5 mg / ml) treatment group even at a low concentration of 0.113 mg / ml.
  • the potato extract can be useful as a means of suppressing appetite by giving a feeling of satiety to target animals (including humans) administered or ingested based on its cholecystokinin secretion promoting action.
  • the cholecystokinin 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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Abstract

La présente invention a pour objet un amplificateur de la sécrétion de la cholécystokinine qui contient de l'extrait de pomme de terre. L'amplificateur de la sécrétion de la cholécystokinine est utile en tant que moyen pour fournir une sensation de satiété et supprimer l'appétit. L'amplificateur de la sécrétion de la cholécystokinine est approprié pour une utilisation dans un produit pharmaceutique, un aliment et une boisson.
PCT/JP2010/071554 2009-12-04 2010-12-02 Amplificateur de la sécrétion de la cholécystokinine WO2011068149A1 (fr)

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JP2011544280A JP5674047B2 (ja) 2009-12-04 2010-12-02 コレシストキニン分泌促進剤

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Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JP2015211663A (ja) * 2014-05-07 2015-11-26 株式会社東洋新薬 ポリペプチド

Citations (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JP2008533013A (ja) * 2005-03-08 2008-08-21 ケミン・フーズ・エル・シー 空腹時の血漿コレシストキニン濃度を高めるのに活性を示すポテトプロテナーゼ阻害剤ｉｉ

Patent Citations (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JP2008533013A (ja) * 2005-03-08 2008-08-21 ケミン・フーズ・エル・シー 空腹時の血漿コレシストキニン濃度を高めるのに活性を示すポテトプロテナーゼ阻害剤ｉｉ

Non-Patent Citations (3)

* Cited by examiner, † Cited by third party
Title
JOURNAL OF JAPAN SOCIETY FOR THE STUDY OF OBESITY, vol. 15, September 2009 (2009-09-01), pages 236 *
JOURNAL OF JAPAN SOCIETY FOR THE STUDY OF OBESITY, vol. 15, September 2009 (2009-09-01), pages 237 *
PHYSIOLOGY & BEHAVIOR, vol. 48, 1990, pages 241 - 246 *

Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JP2015211663A (ja) * 2014-05-07 2015-11-26 株式会社東洋新薬 ポリペプチド

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