WO2007088705A1 - Remede contre le diabete - Google Patents

Remede contre le diabete Download PDF

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Publication number
WO2007088705A1
WO2007088705A1 PCT/JP2007/000041 JP2007000041W WO2007088705A1 WO 2007088705 A1 WO2007088705 A1 WO 2007088705A1 JP 2007000041 W JP2007000041 W JP 2007000041W WO 2007088705 A1 WO2007088705 A1 WO 2007088705A1
Authority
WO
WIPO (PCT)
Prior art keywords
diabetes
pitapastatin
enalapril
salt
insulin resistance
Prior art date
Application number
PCT/JP2007/000041
Other languages
English (en)
Japanese (ja)
Inventor
Taro Aoki
Katsutoshi Miyosawa
Original Assignee
Kowa Co., Ltd.
Nissan Chemical Industries, Ltd.
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 Kowa Co., Ltd., Nissan Chemical Industries, Ltd. filed Critical Kowa Co., Ltd.
Priority to JP2007556799A priority Critical patent/JP5101306B2/ja
Priority to KR1020087011885A priority patent/KR101436644B1/ko
Publication of WO2007088705A1 publication Critical patent/WO2007088705A1/fr

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Classifications

    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/47—Quinolines; Isoquinolines
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K38/00—Medicinal preparations containing peptides
    • 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
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P5/00—Drugs for disorders of the endocrine system
    • A61P5/48—Drugs for disorders of the endocrine system of the pancreatic hormones
    • A61P5/50—Drugs for disorders of the endocrine system of the pancreatic hormones for increasing or potentiating the activity of insulin

Definitions

  • the present invention relates to a therapeutic agent for diabetes that exhibits an excellent improving action on insulin resistance.
  • Thiazolidine-based drugs are listed as representative drugs that improve insulin resistance. Rosiglitazone is a thiazolidine drug represented by pioglitazone, which is known to bind to and activate the nuclear receptor PPAR r (see Non-Patent Document 1) and to differentiate fat cells. .
  • thiazolidine drugs have side effects such as hepatotoxicity, edema, and weight gain, and are administered as an adjunct to sulfonylureas in the treatment of diabetes.
  • Patent Document 3 European Patent No. 304063
  • Patent Document 4 International Publication No. 2004Z096276
  • Non-Patent Document 1 J B i o l C h em 270, 1 2953- 1 2956, 1 995
  • Non-Patent Document 2 L ancet, (2002), 359: 2072
  • Non-Patent Document 4 T he r a p e u t i c Re r e a r c h (0289—80 20) Vol. 24, No. 7, P a g e 1 329 _ 1 337 (July 2003) Disclosure of the Invention
  • An object of the present invention is to provide a drug which has few side effects and exhibits an excellent improving action on insulin resistance.
  • pravastatin for example, is combined with enalabril maleate, which is an ACE inhibitor. It showed only an effect of improving glucose tolerance abnormalities in the same way as when succinate was used alone.
  • enalabril maleate which is an ACE inhibitor.
  • pitapastatin was used in combination with enalapril maleate, its glucose tolerance ameliorating effect was greatly enhanced, and it was found useful not only for improving lipid metabolism abnormalities but also for improving insulin resistance.
  • the present invention has been completed.
  • the therapeutic agent of the present invention has an excellent glucose tolerance ameliorating action (insulin resistance improving action), and is useful for the treatment of diabetes, especially type I diabetes.
  • insulin resistance improving action insulin resistance improving action
  • combined treatment of abnormal lipid metabolism and insulin resistance is possible for hyperlipidemic patients with hyperglycemia due to insulin resistance.
  • FIG. 1 is a graph showing AUC (area under the glucose concentration curve) of blood glucose concentration by the combined administration of pitapastatin calcium (indicated as pitapastatin) and enalapril maleate.
  • Enalapril used in the present invention is an ACE inhibitor and can be easily obtained as a commercial product.
  • the salt of enalapril is pharmaceutically acceptable.
  • Inorganic salts such as hydrochloride, sulfate, nitrate, hydrobromide, phosphate, etc .; acetate, trifluoroacetate, fumarate, maleate, Examples include lactate, tartrate, citrate, succinate, malonate, methanesulfonate, and organic acid salts such as p-toluenesulfonate. Of these, maleates are preferred.
  • the present invention administers pitapastatins and enalapril or a salt thereof in combination, and as shown in the Examples below, in an evaluation system using KKA y mice, pitapastatins or enalapril or Compared to when each salt was administered alone, the combined administration of both drugs showed a marked improvement in impaired glucose tolerance.
  • K K Ay mice are a type I diabetes model, and the effect of improving the insulin resistance of a drug, that is, the effect of improving glucose tolerance, can be evaluated by whether the glucose tolerance in K K Ay mice is improved. Therefore, the drug of the present invention is useful for the treatment of diseases in which abnormal glucose tolerance occurs, particularly type I diabetes.
  • the administration form of pitapastatins and enalapril or a salt thereof in the therapeutic agent of the present invention can be appropriately selected according to the patient's condition and the like.
  • powders, granules, dry syrups, tablets, capsules, injections Any of these agents may be used, and these dosage forms can be produced by blending a pharmaceutically acceptable carrier with pitapastatins and enalapril or a salt thereof, and using conventional production methods known to those skilled in the art.
  • binders Water, ethanol, propanol, simple syrup, gelatin solution, hydroxypropylcellulose, methylcellulose, ethylcellulose, shellac, calcium phosphate, polyvinylpyrrolidone, etc., as disintegrant, agar powder, sodium bicarbonate, sodium lauryl sulfate, stearin Acid monodalides, etc., refined talc, stearate, borax, polyethylene glycol, etc. as lubricants, ⁇ -carotene, yellow trioxide, caramel, etc. as colorants, white sugar, orange as flavoring agents Examples include skins.
  • liquid preparations for oral use
  • liquid preparations, syrups, elixirs, etc. can be produced by conventional methods with the addition of corrigents, buffers, stabilizers, preservatives and the like.
  • Such additives may be those commonly used in the field, such as sucrose as a flavoring agent, sodium citrate as a buffering agent, tragacanth as a stabilizer, and the like.
  • the preservative include paraoxy benzoate.
  • PH preparations, stabilizers, tonicity agents are added, and subcutaneous, intramuscular and intravenous injections can be produced by conventional methods.
  • additives may be those commonly used in the field, such as sodium phosphate as a pH regulator, and sodium pyrosulfite as a stabilizer.
  • isotonic agent include sodium chloride.
  • the mode of use of the drug of the present invention is not particularly limited, and both drugs may be administered simultaneously, or may be administered separately at intervals. That is, pitapastatin and enalapril or a salt thereof may be used as a set (kit) in which both drugs are formulated into a single preparation or both drugs are formulated separately. When both drugs are formulated separately, both drugs do not have to be in the same dosage form. The number of application of each component may be different.
  • the compounding ratio of pitapastatins and enalapril or a salt thereof is in the range of 1: 0.05 to 1:50, and more preferably 1: 0.0. It is preferably in the range of 1 to 1:10.
  • pitapastatin calcium hereinafter referred to as pitapastatin
  • enalapril maleate on glucose tolerance
  • mice 4 groups (6 mice in each group), namely, control group, pitapastatin alone (10 mgZk g) group, enalapril maleate alone (1 mgZk g) group, pitapastatin (1 OmgZk g) And enalapril maleate (1 mgZkg) was randomly divided into groups.
  • 1 OmLZk g was orally administered once a day for 21 days, and 0.5 mass 0 / o aqueous solution (1 OmLZkg) of sodium carboxymethylcellulose was orally administered to the control group.
  • the oral darcos load test was performed after fasting for 18 hours from the last dose.
  • the blood darcos concentration was measured with a Medisafe Reader (GR-101: Terumo Corporation). After the measurement, a glucose aqueous solution (2 gZ1 OmLZkg) was orally administered, and blood glucose concentration was measured by the same method after 15, 30, 60, 120 minutes. Furthermore, in each group, the area under the time curve (AUC) of blood glucose concentration was calculated.
  • a multi-group comparison between the control group and the drug-administered group was carried out using the analysis of variance of Bart l ett and the multiple comparison test of Du nn ett, and a risk rate of less than 5% was judged to be significant.
  • AUC area under the glucose concentration curve
  • the blood glucose concentration A UC represents the amount of blood glucose exposure, and a decrease in this value is an indicator of the glucose tolerance improvement action.
  • Pravastatin was prepared to have a concentration of 5 mg Zm L, and the other procedures were performed in the same manner as in the examples.
  • mice 24 KK Ay mice were divided into the following 4 groups (6 animals each): control group, pravastatin alone (50 mgZk g) group, enalapril maleate alone (1 mgZk g) group, and pravastatin (50 mgZk g) and malee Randomly divided into the enalapril (I mgZk g) combination group. Same as example The test was conducted.
  • AUC area under the glucose concentration curve
  • AUC of blood glucose concentration showed a decreasing tendency in the pitavastatin alone group, pravastatin alone group, and enalapril maleate alone group compared to the control group.
  • the AUC remained in a decreasing trend and no combination effect was observed.
  • the AUC decrease, that is, the glucose tolerance improvement action was significantly enhanced (p 0.05) compared to each single group, and the effect was synergistic.
  • the combined administration of pitapastatin and enalapril maleate of the present invention has a marked glucose tolerance ameliorating action as compared with other combined administration of HMG_CoA reductase inhibitor and enalapril maleate. .

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  • Health & Medical Sciences (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Veterinary Medicine (AREA)
  • Public Health (AREA)
  • General Health & Medical Sciences (AREA)
  • Animal Behavior & Ethology (AREA)
  • Chemical & Material Sciences (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Medicinal Chemistry (AREA)
  • Diabetes (AREA)
  • Engineering & Computer Science (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Organic Chemistry (AREA)
  • General Chemical & Material Sciences (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • Epidemiology (AREA)
  • Endocrinology (AREA)
  • Obesity (AREA)
  • Hematology (AREA)
  • Emergency Medicine (AREA)
  • Immunology (AREA)
  • Proteomics, Peptides & Aminoacids (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)

Abstract

La présente invention concerne un remède contre le diabète qui présente un effet excellent de réduction de la résistance à l'insuline. Ledit remède contre le diabète est caractérisé par la présence de pitavastatine ou de l'un de ses dérivés et d'énalapril ou de l'un de ses sels.
PCT/JP2007/000041 2006-01-31 2007-01-30 Remede contre le diabete WO2007088705A1 (fr)

Priority Applications (2)

Application Number Priority Date Filing Date Title
JP2007556799A JP5101306B2 (ja) 2006-01-31 2007-01-30 糖尿病治療剤
KR1020087011885A KR101436644B1 (ko) 2006-01-31 2007-01-30 당뇨병 치료제

Applications Claiming Priority (4)

Application Number Priority Date Filing Date Title
JP2006021817 2006-01-31
JP2006-021817 2006-01-31
JP2006-171250 2006-06-21
JP2006171250 2006-06-21

Publications (1)

Publication Number Publication Date
WO2007088705A1 true WO2007088705A1 (fr) 2007-08-09

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ID=38327287

Family Applications (1)

Application Number Title Priority Date Filing Date
PCT/JP2007/000041 WO2007088705A1 (fr) 2006-01-31 2007-01-30 Remede contre le diabete

Country Status (3)

Country Link
JP (1) JP5101306B2 (fr)
KR (1) KR101436644B1 (fr)
WO (1) WO2007088705A1 (fr)

Cited By (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2009044547A1 (fr) 2007-10-03 2009-04-09 Kowa Company, Ltd. Inhibiteur de la mort des cellules nerveuses
JP2012510511A (ja) * 2008-12-01 2012-05-10 インヴアスク セラピューテイックス インコーポレイテッド レニン−アンジオテンシン−アルドステロン系阻害剤及びリポ酸化合物を含有する組成物、並びに、レニン−アンジオテンシン−アルドステロン系に関連した疾患の治療のためのそれらの使用
CN109520989A (zh) * 2017-09-18 2019-03-26 三星电子株式会社 估计葡萄糖暴露以及产生葡萄糖暴露估计模型的装置和方法

Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JP2003530342A (ja) * 2000-04-12 2003-10-14 ノバルティス アクチエンゲゼルシャフト ＡＴ１レセプターアンタゴニスト又はＡＣＥインヒビター又はＨＭＧ−Ｃｏ−Ａレダクターゼインヒビターからなる群から選ばれた少なくとも２つの化合物の組合せ
JP2004519424A (ja) * 2000-08-22 2004-07-02 ノバルティス アクチエンゲゼルシャフト 組み合わせ
WO2004080488A2 (fr) * 2003-03-10 2004-09-23 Bayer Healthcare Ag Preparations combinees d'acide acetylsalycilique pour la prevention primaire de maladies cardiovasculaires
JP2005538977A (ja) * 2002-07-02 2005-12-22 ファイザー・プロダクツ・インク 抗高血圧剤との組み合わせのｃｅｔｐ阻害剤及びその使用

Patent Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JP2003530342A (ja) * 2000-04-12 2003-10-14 ノバルティス アクチエンゲゼルシャフト ＡＴ１レセプターアンタゴニスト又はＡＣＥインヒビター又はＨＭＧ−Ｃｏ−Ａレダクターゼインヒビターからなる群から選ばれた少なくとも２つの化合物の組合せ
JP2004519424A (ja) * 2000-08-22 2004-07-02 ノバルティス アクチエンゲゼルシャフト 組み合わせ
JP2005538977A (ja) * 2002-07-02 2005-12-22 ファイザー・プロダクツ・インク 抗高血圧剤との組み合わせのｃｅｔｐ阻害剤及びその使用
WO2004080488A2 (fr) * 2003-03-10 2004-09-23 Bayer Healthcare Ag Preparations combinees d'acide acetylsalycilique pour la prevention primaire de maladies cardiovasculaires

Cited By (8)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2009044547A1 (fr) 2007-10-03 2009-04-09 Kowa Company, Ltd. Inhibiteur de la mort des cellules nerveuses
US7973053B2 (en) 2007-10-03 2011-07-05 Kowa Company, Ltd. Nerve cell death inhibitor
JP5399909B2 (ja) * 2007-10-03 2014-01-29 興和株式会社 神経細胞死抑制剤
JP2012510511A (ja) * 2008-12-01 2012-05-10 インヴアスク セラピューテイックス インコーポレイテッド レニン−アンジオテンシン−アルドステロン系阻害剤及びリポ酸化合物を含有する組成物、並びに、レニン−アンジオテンシン−アルドステロン系に関連した疾患の治療のためのそれらの使用
CN109520989A (zh) * 2017-09-18 2019-03-26 三星电子株式会社 估计葡萄糖暴露以及产生葡萄糖暴露估计模型的装置和方法
JP2019053061A (ja) * 2017-09-18 2019-04-04 三星電子株式会社Ｓａｍｓｕｎｇ Ｅｌｅｃｔｒｏｎｉｃｓ Ｃｏ．，Ｌｔｄ． グルコース露出量推定装置、方法及びプログラム、グルコース露出量推定モデル生成装置、並びに糖指数測定装置
JP7165542B2 (ja) 2017-09-18 2022-11-04 三星電子株式会社 グルコース露出量推定装置、方法及びプログラム、グルコース露出量推定モデル生成装置、並びに糖指数測定装置
US11642050B2 (en) 2017-09-18 2023-05-09 Samsung Electronics Co., Ltd. Apparatus and method for estimating glucose exposure and generating glucose exposure estimation model

Also Published As

Publication number Publication date
JP5101306B2 (ja) 2012-12-19
KR20080091082A (ko) 2008-10-09
KR101436644B1 (ko) 2014-09-01
JPWO2007088705A1 (ja) 2009-06-25

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