WO2001089525A1 - Combinaison de cerivastatine et d'inhibiteurs de l'enzyme de conversion de l'angiotensine et son utilisation dans des medicaments - Google Patents

Combinaison de cerivastatine et d'inhibiteurs de l'enzyme de conversion de l'angiotensine et son utilisation dans des medicaments Download PDF

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Publication number
WO2001089525A1
WO2001089525A1 PCT/EP2001/005350 EP0105350W WO0189525A1 WO 2001089525 A1 WO2001089525 A1 WO 2001089525A1 EP 0105350 W EP0105350 W EP 0105350W WO 0189525 A1 WO0189525 A1 WO 0189525A1
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WIPO (PCT)
Prior art keywords
combination
component
cerivastatin
medicaments
treatment
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PCT/EP2001/005350
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German (de)
English (en)
Inventor
Gilbert Wagener
Joachim Ippen
Original Assignee
Bayer Aktiengesellschaft
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Application filed by Bayer Aktiengesellschaft filed Critical Bayer Aktiengesellschaft
Priority to AU2001260291A priority Critical patent/AU2001260291A1/en
Publication of WO2001089525A1 publication Critical patent/WO2001089525A1/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
    • A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
    • A61K31/4422—1,4-Dihydropyridines, e.g. nifedipine, nicardipine
    • 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
    • A61K45/06—Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
    • 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

Definitions

  • the invention relates to a combination of at least one ACE inhibitor compound (component A) with the HMG-CoA reductase- ⁇ inhibitor cerivastatin
  • Component B the use of this combination for the prophylaxis and control of diseases, in particular cardiovascular diseases, medicaments containing this combination and their preparation.
  • ACE inhibitors (component A) are well known to those skilled in the art.
  • the abbreviation (component A)
  • ACE angiotensin converting enzyme. They are mainly used to treat high blood pressure and heart failure.
  • ACE inhibitors are: ramipril (see e.g. EP-A 79 022), enalapril or enalaprilat (see e.g. EP-A 12 401) and lisinopril (see e.g. EP- A 12401).
  • HMG-CoA reductase inhibitors are a class of lipid-lowering agents which are also well known to those skilled in the art.
  • statins are known as HMG-CoA reductase inhibitors, such as those e.g. in EP-A-325 130 or US-A-5 177 080.
  • EP-A 461 548 and EP-A 0738 512 (Bristol-Myers Squibb Company) generally disclose the use of HMG-CoA reductase inhibitors alone or in combination with an ACE inhibitor to prevent a second heart attack especially in patients with essentially normal serum cholesterol levels.
  • US 5,298,497 (ER Squibb & Sons, Inc.) describes the use of cholesterol-lowering agents, such as pravastatin, alone or in combination with ACE inhibitors, to reduce the risk of high blood pressure in normotensive patients with insulin resistance.
  • EP-A 0 508 665 (ER Squibb & Sons, Inc.) describes the use of phosphorus-containing ACE inhibitors alone or in combination with cholesterol-lowering agents, such as. B. Pravastatin, for lowering serum cholesterol.
  • EP-A 482 498 (E.R. Squibb & Sons, Inc.) describes the use of cholesterol-lowering agents, such as. B. pravastatin, alone or in combination with ACE inhibitors for the prevention and treatment of diabetes.
  • EP-A 457 514 (E.R. Squibb & Sons, Inc.) relates to the use of ACE inhibitors in combination with a cholesterol-lowering agent, such as pravastatin, for
  • EP-A 459 453 (E.R. Squibb & Sons, Inc.) relates to the use of pravastatin alone or in combination with an ACE inhibitor for the prevention or treatment of the risk of restenosis after angioplasty.
  • the present invention relates to the combination of at least one ACE inhibitor compound as component A with cerivastatin as component B.
  • Ramipril, enalapril or enalaprilat or lisinopril are preferably used as component A; Ramipril is particularly preferred.
  • the invention further relates to pharmaceutical preparations containing these combinations of components A and B and their preparation.
  • the invention further relates to the use of the combinations according to the invention for the prophylaxis and treatment of cardiovascular diseases.
  • ACE inhibitors and cerivastatin can be in stereoisomeric forms that are either like image and mirror image (enantiomers), or that are not like image and
  • the invention relates to both the enantiomers and the diastereomers or their respective mixtures. These mixtures of the enantiomers and diastereomers can be separated into the stereoisomerically uniform constituents in a known manner.
  • the combinations according to the invention have unexpected valuable pharmacological properties, in particular they are suitable for the prophylaxis and treatment of diseases of the cardiovascular system, such as hypertension, which are not associated with increased lipid levels in the plasma. Furthermore, the combinations according to the invention are also suitable for the prophylaxis and treatment of cardiovascular diseases, such as hypertension, with simultaneously increased lipid levels and the prophylaxis or treatment of the complication of diabetes mellitus, insulin-dependent and insulin-independent. These effects are observed regardless of age, which means that the therapeutic use of the combinations according to the invention is both in the elderly, i.e. older than
  • the combinations according to the invention are suitable for the prevention of cardiovascular morbidity and mortality in patients with hyperlipidemia and in patients with an increased cardiovascular risk.
  • HMG-CoA reductase inhibitors the abbreviation "HMG-CoA” stands for "3-hydroxy-3-methylglutaryl-coenzyme A” - and in particular to the appreciation, reference is made to the papers in Drugs ofthe Future 1994, 19 (6), pages 537 - 541 and 1995, 20 (6), page 611 and 1996, 21 (6), page 642.
  • a further overview of HMG-CoA reductase inhibitors is in pharmacy in our time, 28. Jahrg., No. 3, pages 147-152 (1999).
  • statins can usually be used as lactones, esters (for example (C 1 -C 4 ) -alkyl esters) or as carboxylic acids or as salts of the carboxylic acid.
  • esters for example (C 1 -C 4 ) -alkyl esters
  • cerivastatin can therefore also be used in all suitable forms, ie in the form of its salts, hydrates, alcoholates, esters,
  • Physiologically acceptable salts such as metal and ammonium salts are preferred.
  • the following may be mentioned as preferred examples: sodium, potassium, magnesium or calcium salts, and also ammonium salts which are derived from ammonia or organic amines, such as methylamine, ethylamine, propylamine, isopropylamine, di- or triethylamine, diisopropylamine, ethanolamine, di- or triethanolamine, dicyclohexylamine, arginine, lysine or ethylenediamine.
  • Cerivastatin is particularly preferred as a water-soluble, pharmaceutically acceptable carboxylic acid salt, such as. B. as the sodium or potassium salt, in particular as the sodium salt (cerivastatin sodium).
  • HMG-CoA reductase inhibitors are described in EP-A-0 325 130 and in EP-A-0-491 226, both in the name of Bayer AG, the content of which is hereby incorporated by reference. Subject of
  • EP-A-0 325 130 are substituted pyridines;
  • EP-A-0-491 226 describes substituted pvridyldihydroxyheptenoic acid derivatives and their salts, including in particular cerivastatin (claim 6 of EP-A-0 491 226).
  • ACE inhibitors are compounds that inhibit the angiotensin converting enzyme, which converts angiotensin I to angiotensin II. ACE inhibitors lower blood pressure. In principle, ACE inhibitors can be used within the meaning of the invention, which lead to a therapeutic effect on humans. Detailed explanations and lists of ACE inhibitors can be found in the documents mentioned in the introduction EP-A 461 548, EP-A 0738 512,
  • ACE inhibitors are: Alacepril, Benazepril, Captopril, Ceronapril, Cilazapril, Delapril, Enalapril or Enalaprilat, Fosinopril, Imidapril, Lisinopril, Moexipril, Moveltipril, Perindopril, Ramiprililopilil zofenopril.
  • ACE inhibitor also includes the corresponding pharmaceutically acceptable salts, hydrates, solvates, tautomers etc. and derivatives which can be used as prodrugs.
  • ACE He mer are used in the form of an ester, typically a (-C-C 4 ) alkyl ester, as a prodrug, which in the body in the active
  • Metabolites - the corresponding carboxylic acid - is converted.
  • An example is the ester prodrag enalapril, which is also used as an active pharmaceutical ingredient in the form of the active metabolite enalaprilat - a dicarboxylic acid.
  • the combinations according to the invention show a broad and varied spectrum of action.
  • You can e.g. are used for the treatment and / or prophylaxis of cardiovascular diseases such as high blood pressure, arteriosclerosis, stroke, angina pectoris, diseases of the coronary arteries, in particular the arterial coronary arteries, heart failure, primary and secondary myocardial infarction, pathological changes in the vascular wall, circulatory disorders, disorders microcirculation, kidney function disorders; Fat metabolism disorders such as increased concentration of lipoproteins in the serum and possibly a shift in the lipoprotein content, increased serum lipids, hyperlipoproteinemia, hypercholesterolemia, hypertriglyceridemia, increases in both serum cholesterol and serum triglycerides combined with increased VLDL
  • Metabolic disorders such as disorders of lipid metabolism, deficiency of acid lipase, storage diseases, in particular fat storage diseases, phytosteroleae, obesity (obesity), thromboses, pancreatitis, functional disorders of the brain, cerebrovascular insufficiency, cerebral Circulatory disorders, apoplexy, and transient ischemic attacks (TIA).
  • cardiac risk management i.e. for prophylaxis and treatment of diseases that are influenced or caused by more than one risk factor, e.g. Arteriosclerosis, diseases of the coronary arteries of the heart, in particular the arterial coronary arteries, increased serum lipids, hypercholesterolemia, hypertriglyceridemia, increases in both serum cholesterol and serum triglycerides combined with increased VLDL (very low density lipoprotein) and increase in chylomicrons in plasma and syndrome X
  • Typical risk factors are age, gender, cholesterol levels, HDL levels, systolic and diastolic blood pressure, smoking, glucose intolerance, and enlarged heart and heart failure.
  • components A and B according to the invention in particular the special combination of ramipril and cerivastatin, have proven to be surprisingly advantageous in the treatment of hypertension, coronary heart diseases, heart failure, impaired brain performance, apoplexy, circulatory disorders and disorders of the fat metabolism.
  • disorders of the fat metabolism are dyslipidemias, but they also occur in diabetics
  • the combinations according to the invention are particularly suitable for the treatment of hypertension in patients with normal lipid levels. They are also suitable for the treatment of hypertension, which occurs in combination with hyperlipidemia, and for the prevention of secondary diseases in the presence of diabetes mellitus. In addition, the combinations according to the invention are suitable for the prevention of cardiovascular morbidity and mortality in patients with hyperlipidemia and in patients with an increased cardiovascular risk.
  • the combinations according to the invention can be used not only for prevention and treatment of apoplexy (such as classic monotherapy with antihypertensives) but also for the prevention and treatment of heart failure and coronary heart diseases.
  • Components include: platelet aggregation inhibitors such as dipyridamole, sulfinpyrazone, ticlopidine, copidogrel, integrilin, lamibiban, tirofiban and in particular acetylsalicylic acid; Vitamins such as vitamin C, vitamin E and L-arginine. These further components can be added individually or together.
  • platelet aggregation inhibitors such as dipyridamole, sulfinpyrazone, ticlopidine, copidogrel, integrilin, lamibiban, tirofiban and in particular acetylsalicylic acid
  • Vitamins such as vitamin C, vitamin E and L-arginine.
  • “Hyperlipidemia” is to be understood as an elevated plasma level of one or more serum lipids.
  • the LDL level is particularly important. In patients over 45 years of age, values above 130 mg / dl and in patients below are considered as increased levels 45 years considered values over 160 mg / dl.
  • dislipidemia is meant either hypertriglyceridemia or hypercholesterolemia, but especially mixed hyperlipidemia, i.e. a disease with increased cholesterol (LDL and total cholesterol) and increased triglyceride. This can be associated with one
  • HDL high-density lipoprotein
  • the combinations according to the invention are furthermore distinguished by surprisingly good tolerability.
  • the combinations according to the invention are preferably used in human medicine, but are also suitable for veterinary medicine, in particular for the treatment of mammals.
  • the combinations according to the invention can be administered parenterally or, preferably, orally.
  • components A and B can be converted in a known manner into the customary formulations, which can be liquid or solid formulations. Examples are tablets, coated tablets, pills, capsules,
  • the combinations according to the invention are well tolerated and are effective even in low doses, a wide variety of formulation variants can be implemented.
  • the two individual components A and B do not necessarily have to be taken at the same time; rather, taking them at different times can be advantageous in order to achieve optimal effects.
  • the two components are each in separate containers, which are e.g. can be tubes, vials or blister packs.
  • Such separate packaging of the two components in a common primary packaging is also referred to as a kit.
  • Fixed combinations are also suitable as a further formulation variant for the combinations according to the invention.
  • “Fixed combination” is to be understood here to mean those dosage forms in which the two components are present together in a fixed quantity ratio.
  • Such fixed combinations can, for example, be implemented as oral solutions, preferably however, it is a matter of solid oral pharmaceutical preparations, for example capsules or tablets.
  • the combinations according to the invention are dosed up to 3 times a day; preference is given to those combinations which permit one daily application.
  • the combinations according to the invention are usually administered in a daily therapeutic dose of 0.01 to 1000 mg, in particular 0.1 to 100 mg, of active ingredient of component A and 0.01 to 10 mg, in particular 0.05 to 5 mg, of active ingredient of component B. used.
  • the active ingredients of components A and B are particularly suitable for being formulated in a fixed combination in the form of a fixed oral dosage form. It is generally known that the reliability of compliance (compliance) in patients depends crucially on the factors number of dosage forms per time of intake and size and weight of the (fixed oral) dosage form. Therefore, the number of different medications to be taken separately should be as small as possible (advantage of a fixed combination), and the size and weight of a fixed oral dosage form should be as small as possible with full therapeutic potency in order to be taken for the To make patients as comfortable as possible. Leave with it fixed combinations in the form of solid oral pharmaceutical formulations with a minimal size and minimal weight. The fixed combinations according to the invention accordingly offer the highest possible patient compliance and thereby decisively improve the safety and reliability of a therapy.
  • the drug release can be controlled by combining the two components A and B and modifying the composition or functionality. For example, by delaying the release of active ingredient (retardation) of a component, the above-mentioned temporal decoupling of the onset of action can also be achieved in fixed combinations.
  • the solid oral dosage forms listed here are manufactured according to the general standard procedures. Ingredients are those that are pharmaceutically accepted and physiologically harmless, for example: as fillers cellulose derivatives (e.g. microcrystalline cellulose), sugar (e.g. lactose), sugar alcohols
  • binders e.g. polyvinylpyrrolidone, gelatin, starch and cellulose derivatives
  • auxiliaries that are required for the production of pharmaceutical formulations with the desired properties
  • Lubricants magnesium stearate
  • Disintegrants e.g. cross-linked polyvinylpyrrolidone, sodium carboxymethyl cellulose
  • Wetting agents e.g. sodium lauryl sulfate
  • Retardants e.g. cellulose derivatives, polyacrylic acid derivatives
  • Stabilizers e.g. Flavors, e.g. Color pigments.
  • Liquid formulations are also produced by standard methods with pharmaceutically customary auxiliaries and contain the active ingredient or the two active ingredients either dissolved or suspended. Typical application volumes of these pharmaceutical preparations are 1 to 10 ml.
  • auxiliaries in these liquid formulations are: solvents (e.g. water, alcohol, natural and synthetic oils, e.g. medium-chain triglcerides), solubilizers (e.g. glycerol,
  • Glycol derivatives e.g. polysorbate, sodium lauryl sulfate
  • wetting agents e.g. polysorbate, sodium lauryl sulfate
  • Excipients that are required for the production of pharmaceutical formulations with the desired properties, for example viscosity-increasing agents, for example pH value corrections, for example sweeteners and flavors, for example antioxidants, for example stabilizers, for example preservatives.
  • the main components of the capsule formulations are, for example, gelatin or hydroxypropylmethyl cellulose.
  • Component A is a compound having Component A:
  • Ramipril in doses of 0.1 mg to 40 mg, preferably in doses of 2 mg to 10 mg.
  • Enalapril in doses of 1 mg to 80 mg, preferably in doses of 5 mg to 20 mg.
  • Lisinopril in doses of 1 mg to 80 mg, preferably in doses of 2.5 mg to 20 mg.
  • Cerivastatin in doses of 0.05 mg to 3.2 mg, preferably in doses of 0.1 mg to 1.6 mg.

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  • Health & Medical Sciences (AREA)
  • Public Health (AREA)
  • Medicinal Chemistry (AREA)
  • Veterinary Medicine (AREA)
  • Chemical & Material Sciences (AREA)
  • General Health & Medical Sciences (AREA)
  • Animal Behavior & Ethology (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Epidemiology (AREA)
  • Chemical Kinetics & Catalysis (AREA)
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  • Cardiology (AREA)
  • Organic Chemistry (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)
  • Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)

Abstract

L'invention concerne une combinaison comprenant au moins un inhibiteur de l'enzyme de conversion de l'angiotensine (composant A) et de la cérivastatine, inhibiteur de la HMG-CoA-réductase (composant B), l'utilisation de cette combinaison pour la prophylaxie et le traitement de maladies, en particulier de maladies cardio-vasculaires, ainsi que des médicaments contenant cette combinaison et leur production.
PCT/EP2001/005350 2000-05-23 2001-05-10 Combinaison de cerivastatine et d'inhibiteurs de l'enzyme de conversion de l'angiotensine et son utilisation dans des medicaments WO2001089525A1 (fr)

Priority Applications (1)

Application Number Priority Date Filing Date Title
AU2001260291A AU2001260291A1 (en) 2000-05-23 2001-05-10 Combination of cerivastatin with ace inhibitors and the use thereof in medicaments

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
DE10025308.3 2000-05-23
DE10025308A DE10025308A1 (de) 2000-05-23 2000-05-23 Kombination von Cerivastatin mit ACE Inhibitoren und ihre Verwendung in Arzneimitteln

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WO2001089525A1 true WO2001089525A1 (fr) 2001-11-29

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AU (1) AU2001260291A1 (fr)
DE (1) DE10025308A1 (fr)
WO (1) WO2001089525A1 (fr)

Families Citing this family (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US20040137054A1 (en) * 2002-05-03 2004-07-15 Alexandra Hager Stable pharmaceutical formulation for a combination of a statin and an ace-inhibitors
WO2004080488A2 (fr) * 2003-03-10 2004-09-23 Bayer Healthcare Ag Preparations combinees d'acide acetylsalycilique pour la prevention primaire de maladies cardiovasculaires

Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US5298497A (en) * 1990-05-15 1994-03-29 E. R. Squibb & Sons, Inc. Method for preventing onset of hypertension employing a cholesterol lowering drug
WO2000045818A1 (fr) * 1999-02-06 2000-08-10 Astrazeneca Ab Utilisation d'inhibiteurs de la 3-hydroxy-3-methylglutaryle coenzyme a reductase en fabrication d'un medicament destine au traitement de neuropathie diabetique

Patent Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US5298497A (en) * 1990-05-15 1994-03-29 E. R. Squibb & Sons, Inc. Method for preventing onset of hypertension employing a cholesterol lowering drug
WO2000045818A1 (fr) * 1999-02-06 2000-08-10 Astrazeneca Ab Utilisation d'inhibiteurs de la 3-hydroxy-3-methylglutaryle coenzyme a reductase en fabrication d'un medicament destine au traitement de neuropathie diabetique

Non-Patent Citations (1)

* Cited by examiner, † Cited by third party
Title
STEIN E ET AL: "Cerivastatin, a new potent synthetic HMG Co-A reductase inhibitor: Effect of 0.2 mg daily in subjects with primary hypercholesterolemia", JOURNAL OF CARDIOVASCULAR PHARMACOLOGY AND THERAPEUTICS, CHURCHILL LIVINGSTONE, NAPERVILE, IL, US, vol. 2, no. 1, 1997, pages 7 - 16, XP002095846, ISSN: 1074-2484 *

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AU2001260291A1 (en) 2001-12-03
DE10025308A1 (de) 2001-11-29

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