WO2004014427A1 - Composition medicale abaissant le taux de lipides sanguins - Google Patents

Composition medicale abaissant le taux de lipides sanguins Download PDF

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Publication number
WO2004014427A1
WO2004014427A1 PCT/JP2003/010028 JP0310028W WO2004014427A1 WO 2004014427 A1 WO2004014427 A1 WO 2004014427A1 JP 0310028 W JP0310028 W JP 0310028W WO 2004014427 A1 WO2004014427 A1 WO 2004014427A1
Authority
WO
WIPO (PCT)
Prior art keywords
acid
hmg
bile
reductase inhibitor
coa reductase
Prior art date
Application number
PCT/JP2003/010028
Other languages
English (en)
Japanese (ja)
Inventor
Tatsuhito Kondo
Ikuo Takagi
Masato Nakayama
Yasuhiro Torizumi
Original Assignee
Sankyo Company, Limited
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 Sankyo Company, Limited filed Critical Sankyo Company, Limited
Priority to CA002494916A priority Critical patent/CA2494916A1/fr
Priority to AU2003257814A priority patent/AU2003257814A1/en
Publication of WO2004014427A1 publication Critical patent/WO2004014427A1/fr
Priority to US11/045,407 priority patent/US20050187204A1/en

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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
    • A61K31/21—Esters, e.g. nitroglycerine, selenocyanates
    • A61K31/215—Esters, e.g. nitroglycerine, selenocyanates of carboxylic acids
    • A61K31/22—Esters, e.g. nitroglycerine, selenocyanates of carboxylic acids of acyclic acids, e.g. pravastatin
    • 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
    • A61K31/185—Acids; Anhydrides, halides or salts thereof, e.g. sulfur acids, imidic, hydrazonic or hydroximic acids
    • A61K31/19—Carboxylic acids, e.g. valproic acid
    • A61K31/191—Carboxylic acids, e.g. valproic acid having two or more hydroxy groups, e.g. gluconic acid
    • 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
    • A61K31/335—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin
    • A61K31/35—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin having six-membered rings with one oxygen as the only ring hetero atom
    • A61K31/351—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin having six-membered rings with one oxygen as the only ring hetero atom not condensed with another ring
    • 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
    • A61K31/40—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil
    • 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
    • A61P3/06—Antihyperlipidemics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00—Drugs for disorders of the cardiovascular system
    • A61P9/10—Drugs for disorders of the cardiovascular system for treating ischaemic or atherosclerotic diseases, e.g. antianginal drugs, coronary vasodilators, drugs for myocardial infarction, retinopathy, cerebrovascula insufficiency, renal arteriosclerosis

Definitions

  • the present invention relates to a pharmaceutical composition for lowering blood lipids, comprising a HMG-CoA reductase inhibitor and bile acids.
  • a sutin drug is a drug that specifically and competitively inhibits HMG-CoA reductase in a living body, and is a drug that lowers the blood cholesterol level.
  • bile acid components are known to have a bile stasis ameliorating effect, a cholesterol gallstone dissolving effect, a cholesterol intestinal absorption inhibitory effect, and the like (for example, see Japan Pharmaceutical Collection 2002, Japan Pharmaceutical Information Center, Jiho).
  • statins and bile acid components in combination are almost entirely related to the lytic treatment of cholesterol gallstones.
  • bile properties caused by impaired bile outflow to the duodenum for some reason There are scattered literature on treatment of liver damage, biliary cirrhosis, stasis jaundice, and secondary hypercholesterolemia.
  • statin drug has a significant blood lipid lowering effect when used in combination with a bile acid component, and have completed the present invention.
  • HMG—COA reductase inhibitors are long-lasting, It would be desirable if blood lipid lowering effects could be obtained at lower doses. Furthermore, it would be ideal for a hyperlipidemic patient or animal with cholestasis or cholelithiasis to be able to provide an efficient treatment at one time.
  • the present invention
  • the HMG-CoA reductase inhibitor is selected from the group consisting of pravastatin, lovastatin, simpastatin, flupastatin, rivastatin, atorpastatin, pitapastatin, and rospastatin.
  • pravastatin pravastatin
  • lovastatin simpastatin
  • flupastatin rivastatin
  • atorpastatin atorpastatin
  • pitapastatin rospastatin
  • composition according to (1) wherein the HMG-CoA reductase inhibitor is simpastatin and / or atorpastatin.
  • the bile acids are selected from the group consisting of ursodeoxycholic acid, chenodeoxycholic acid, deoxycholic acid, cholic acid, bile powder, bile extract, bear bile, and beef yellow A composition of two or more,
  • composition according to (1) wherein the bile acids are ursodeoxycholic acid,
  • composition according to (1) for use in prevention or treatment of hyperlipidemia or arteriosclerosis. Further, the present invention provides
  • HMG-CoA reductase inhibitor and bile for lowering blood lipids by simultaneously or separately administering the HMG-CoA reductase inhibitor and bile acids. Combinations with acids, and
  • HMG_CoA reductase inhibitor which is one of the components of the composition according to the present invention, is specific to HMG (3-hydroxy-13-methylidalaryl) -C0A reductase, which is a rate-limiting enzyme in the cholesterol biosynthesis system. It is a drug that inhibits both competitively and competitively and lowers blood cholesterol, so it is originally used as a therapeutic agent for hyperlipidemia.
  • HMG-CoA reductase inhibitors include all natural substances derived from microorganisms, semi-synthetic substances derived therefrom, and all synthetic compounds. For example, Japanese Patent Publication No.
  • HMG-CoA reductase inhibitor which is a component of the composition of the present invention, may be any of the other HMG-CoA reductase inhibitors disclosed in the publications describing the HMG-CoA reductase inhibitor. — Also contains CoA reductase inhibitors.
  • the bile acids include, for example, animal bile such as bear bile obtained from bile such as ursodeoxycholic acid, chenodeoxycholic acid, deoxycholic acid, cholic acid, bile powder, or bile extract. Animal gallstones such as cow yellow can be mentioned, and preferably, ursodeoxycholic acid can be mentioned.
  • each component to be contained may be contained as a pharmacologically acceptable salt.
  • hydrohalides such as hydrofluoride, hydrochloride, hydrobromide, hydroiodide
  • nitrate, perchlorate sulfuric acid Inorganic salts such as salts and phosphates
  • lower organic sulfonates such as methanesulfonate, trifluoromethanesulfonate and ethanesulfonate
  • benzenesulfonate and P-toluenesulfonate Such as aryl sulfonates; amino acid salts such as ortinate and daltamate
  • carboxylate salts such as fumaric acid, succinic acid, citric acid, tartaric acid, oxalic acid and maleic acid.
  • alkali metal salts such as sodium salt, potassium salt, lithium salt, alkaline earth metal salts such as calcium salt and magnesium salt, aluminum salt, iron salt, zinc salt, copper Metal salts such as salts, nickel salts, cobalt salts and the like; inorganic salts such as ammonium salts, octylamine salts, dibenzylamine salts, morpholine salts, dalcosamine salts, phenyldaricin alkyl ester salts, ethylenediamine salts, N— Methyldalcamine salt, guanidine salt, getylamine salt, triethylamine salt, dicyclohexylamine salt, N, N'—dibenzylethylenediamine salt, clomouth pro-force salt, pro-force salt, diethanolamine salt, N— Benzylphenethylamine salt, piperazine salt, tetramethylammonium salt, Squirrel (hydroxy
  • composition for lowering blood lipid of the present invention means lowering blood lipid to a clinically significant level. Examples include lowering of celide, lowering of blood LDL or lowering of total blood cholesterol. Therefore, the composition of the present invention is effective for treating diseases caused by high blood lipid levels (eg, diseases such as hyperlipidemia and arteriosclerosis).
  • the HMG-CoA reductase inhibitor contained in the composition of the present invention for example, plapastin, oral pastatin, simpastatin, flupastatin, ripastatin, atorpastatin, pipabastin or rospastatin is JP-A-57-2240 (USP4346227), JP-A-57-163374 (USP4231 938), JP-A-56-122375 (US-P4444784), JP-T-60-500015
  • JP473 9073 JP-A-1-216974 (USP5006530), JP-A-3-58967 (USP5273995), JP-A-1-279866 (USP5854259 and USP5856336) or JP It can be easily produced according to the method described in 5-178841 (USP 5260440).
  • the pharmaceutical composition of the present invention contains an HMG-C ⁇ A reductase inhibitor and bile acids as essential components, and may optionally contain additives for formulation. o Other components may be contained as long as the combined use of the A reductase inhibitor and bile acids is not adversely affected. Preferably, ⁇ [1 ⁇ 0—.
  • Specific dosage forms of the pharmaceutical composition of the present invention include, for example, tablets, fine granules (including powders), capsules, liquids (including syrups), and the like. It can be produced according to a usual method described in the Japanese Pharmacopoeia or the like, using additives and base materials as appropriate. In each of the above dosage forms, various commonly used additives may be used depending on the dosage form.
  • magnesium metasilicate or magnesium oxide is used as a stabilizer
  • hydroxypropyl cellulose is used as a coating agent
  • magnesium stearate is used, etc.
  • lactose or purified sucrose is used as an excipient
  • metasilicate, magnesium aluminate or magnesium oxide is used as a stabilizer
  • corn starch is used as an adsorbent
  • hydroxypropyl cellulose is used as a binder As can be used.
  • a disintegrating agent such as crospovidone; a surfactant such as polysorbate; an adsorbent such as calcium silicate; a coloring agent such as iron sesquioxide and caramel; Stabilizers; PH regulators; fragrances; and the like can also be added.
  • a disintegrating agent such as crospovidone
  • a surfactant such as polysorbate
  • an adsorbent such as calcium silicate
  • a coloring agent such as iron sesquioxide and caramel
  • Stabilizers PH regulators
  • fragrances and the like
  • the term “combination” refers to a method of administering two or more active ingredients to a human body simultaneously or separately at an interval.
  • each component of the composition can be administered simultaneously or separately at intervals.
  • the “simultaneous” administration described above includes administration at exactly the same time as well as administration at about the same time as pharmacologically permitted.
  • the administration form is not particularly limited as long as it can be administered at substantially the same time, but is preferably a single composition.
  • the above-mentioned “separately administered at different times” is not particularly limited as long as it can be administered separately at different times, but for example, one component is administered, and then After a period of time, other components may be administered.
  • ⁇ administering simultaneously or separately at intervals '' refers to the method of administering all of them at the same time.
  • Subjects to which the pharmaceutical composition of the present invention is administered include mammals, and include, for example, humans, dogs, cats, egrets, puppies, pomas, sheep, and pigs, preferably humans or pigs. Dogs, and more preferably humans.
  • the pharmaceutical composition of the present invention has a blood lipid lowering action, it is useful as a medicament for preventing or treating diseases (eg, hyperlipidemia or arteriosclerosis) caused by a high blood lipid concentration.
  • diseases eg, hyperlipidemia or arteriosclerosis
  • the dose of the HMG-Co A reductase inhibitor varies depending on the type, dosage form, etc. of the HMG-Co A reductase inhibitor, but is usually 1 mg to 20 Omg per day, preferably 5 mg to 16 Omg per day.
  • the dose of bile acids is usually 1 Omg to 500 Omg per day, preferably 10 Omg to 200 Omg per day.
  • the content by weight is, for example, usually 0.005 to 3% in the case of simpastatin, and preferably 0.03 to 2%, Also, in the case of atorpastatin, it is usually 0.01 to 5%, preferably 0.05 to 3%, and in the case of ursodeoxycholic acid, it is usually 0.3. To 90%, preferably 3 to 50%.
  • the content contained in the case where the blood lipid-lowering agent composition of the present invention is a liquid is, for example, the content of simpastatin is usually 0.005 to 5 mg / mL, preferably 0.03 to 5 mg / mL. 3 mg / mL, and the content of atorvastatin is usually 0.01 to 1 Omg / mL, preferably 0.05 to 5 mg / mL, and the content of ursodeoxycholic acid The amount is usually between 1 and 100 mg / mL, preferably between 10 and 50 mg / mL.
  • Simpastatin and atorpastatin calcium used were manufactured by Chemtech Lab Co., Ltd., and ursodeoxycholic acid used was manufactured by Mitsubishi Pharma Corporation.
  • the required amount of the test substance calculated based on the body weight of each test animal was filled into a T0RPAC gelatin capsule (1 Z 2 oz.). After filling, the capsules were placed in cases classified for each animal and kept refrigerated until administration.
  • the capsules filled with the test substance were administered by gavage to the test animals once a day between 9: 0 and 12:30.
  • the test animals were fasted for 2 to 3 hours before administration.
  • the administration period was 11 days.
  • the obtained blood was placed in a test tube, allowed to stand at room temperature for 30 minutes to 1 hour, and then centrifuged (about 1.600 X g, 10 minutes) to use the serum obtained.
  • total cholesterol was measured by an enzymatic method, and LDL was measured by a chemically modified enzyme method.
  • An automatic clinical chemistry analyzer (TBA-120FR, manufactured by Toshiba) was used for the measurement.
  • Ursodeoxycholic acid and simbasitin and atorbasitin calcium The amount of lipids in various blood samples in single and combination doses at each dose was determined using various blood samples 2 weeks and 1 week before administration. The average amount of lipid in the sample was calculated as 100.
  • Tables 1 and 2 show the obtained results. Each value is the average of 5 animals per district. , Fluctuation rate of total blood cholesterol% Test substance (mg / Kg)
  • the pharmaceutical composition containing the HMG-CoA reductase inhibitor and bile acids of the present invention has an effect of lowering blood lipids, diseases caused by high blood lipid levels (eg, hyperlipidemia) It is useful as a medicament for preventing or treating disease or arteriosclerosis.
  • diseases caused by high blood lipid levels eg, hyperlipidemia
  • the present invention will be described in more detail with reference to Examples, Formulation Examples, and Test Examples, but the present invention is not limited thereto.

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  • Health & Medical Sciences (AREA)
  • Veterinary Medicine (AREA)
  • Chemical & Material Sciences (AREA)
  • Medicinal Chemistry (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Animal Behavior & Ethology (AREA)
  • General Health & Medical Sciences (AREA)
  • Public Health (AREA)
  • Epidemiology (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Engineering & Computer Science (AREA)
  • Organic Chemistry (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • General Chemical & Material Sciences (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Urology & Nephrology (AREA)
  • Vascular Medicine (AREA)
  • Cardiology (AREA)
  • Heart & Thoracic Surgery (AREA)
  • Emergency Medicine (AREA)
  • Diabetes (AREA)
  • Hematology (AREA)
  • Obesity (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)

Abstract

L'invention concerne une composition médicale abaissant le taux de lipides sanguins contenant un inhibiteur de d'HMG-CoA réductase et des acides biliaires.
PCT/JP2003/010028 2002-08-08 2003-08-06 Composition medicale abaissant le taux de lipides sanguins WO2004014427A1 (fr)

Priority Applications (3)

Application Number Priority Date Filing Date Title
CA002494916A CA2494916A1 (fr) 2002-08-08 2003-08-06 Composition medicale abaissant le taux de lipides sanguins
AU2003257814A AU2003257814A1 (en) 2002-08-08 2003-08-06 Medicinal composition for lowering blood lipid level
US11/045,407 US20050187204A1 (en) 2002-08-08 2005-01-27 Medicinal composition for lowering blood lipid level

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
JP2002/231618 2002-08-08
JP2002231618 2002-08-08

Related Child Applications (1)

Application Number Title Priority Date Filing Date
US11/045,407 Continuation-In-Part US20050187204A1 (en) 2002-08-08 2005-01-27 Medicinal composition for lowering blood lipid level

Publications (1)

Publication Number Publication Date
WO2004014427A1 true WO2004014427A1 (fr) 2004-02-19

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Family Applications (1)

Application Number Title Priority Date Filing Date
PCT/JP2003/010028 WO2004014427A1 (fr) 2002-08-08 2003-08-06 Composition medicale abaissant le taux de lipides sanguins

Country Status (5)

Country Link
CN (1) CN1688341A (fr)
AU (1) AU2003257814A1 (fr)
CA (1) CA2494916A1 (fr)
TW (1) TW200404533A (fr)
WO (1) WO2004014427A1 (fr)

Cited By (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN109248152A (zh) * 2018-11-02 2019-01-22 河北医科大学第二医院 一种治疗肝胆疾病的药物制剂及其制备方法
CN113563404A (zh) * 2020-04-28 2021-10-29 华东师范大学 胆酸衍生物的制备方法

Families Citing this family (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
AU2018301924B2 (en) * 2017-07-17 2021-07-29 Eli Lilly And Company Pharmaceutical compositions

Non-Patent Citations (4)

* Cited by examiner, † Cited by third party
Title
SHUICHIRO OKAMOTO ET AL.: "Effects of pravastatin and ursodeoxycholic acid on cholesterol and bile acid metabolism in patients with cholesterol gallstones", JOURNAL OF GASTROENTEROLOGY, vol. 29, 1994, pages 47 - 55, XP002973863 *
STEIN DANIEL T. ET AL.: "Effect of statin therapy on remnant lipoprotein cholesterol levels in patients with combined hyperlipidemia", ARTERIOSCLER., THROMB. VASC. BIOL., vol. 21, 2001, pages 2026 - 2031, XP002973865 *
TADASUKE YAMAMOTO ET AL.: "Ko cholesterol kessho ni taisuru urso-san to pravastatin heiyo ryoho no kento- tokuni Lp(a) koka sayo ni tsuite-", DOMYAKUKOKA, vol. 20, 1992, pages 857, XP002973862 *
TAZUMA S. ET AL.: "A combination therapy with simvastatin and ursodeoxycholic acid is more effective for cholesterol gallstone dissolation than in ursodeoxycholic acid monotherapy", J. CLIN. GASTROENTEROL., vol. 26, no. 4, 1998, pages 287 - 291, XP002973864 *

Cited By (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN109248152A (zh) * 2018-11-02 2019-01-22 河北医科大学第二医院 一种治疗肝胆疾病的药物制剂及其制备方法
CN109248152B (zh) * 2018-11-02 2021-01-12 河北医科大学第二医院 一种治疗肝胆疾病的药物制剂及其制备方法
CN113563404A (zh) * 2020-04-28 2021-10-29 华东师范大学 胆酸衍生物的制备方法
CN113563404B (zh) * 2020-04-28 2024-03-12 华东师范大学 胆酸衍生物的制备方法

Also Published As

Publication number Publication date
AU2003257814A1 (en) 2004-02-25
TW200404533A (en) 2004-04-01
CA2494916A1 (fr) 2004-02-19
CN1688341A (zh) 2005-10-26

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