EP1140082A1 - Combination of cerivastatin and fibrates - Google Patents

Combination of cerivastatin and fibrates

Info

Publication number
EP1140082A1
EP1140082A1 EP99964522A EP99964522A EP1140082A1 EP 1140082 A1 EP1140082 A1 EP 1140082A1 EP 99964522 A EP99964522 A EP 99964522A EP 99964522 A EP99964522 A EP 99964522A EP 1140082 A1 EP1140082 A1 EP 1140082A1
Authority
EP
European Patent Office
Prior art keywords
cerivastatin
combination
fenofibrate
fibrate
fibrates
Prior art date
Legal status (The legal status 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 status listed.)
Withdrawn
Application number
EP99964522A
Other languages
German (de)
French (fr)
Inventor
Joachim Ippen
Ulrike Schopen
Reiner Ziegler
Fritz Schückler
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Bayer AG
Original Assignee
Bayer AG
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 Bayer AG filed Critical Bayer AG
Publication of EP1140082A1 publication Critical patent/EP1140082A1/en
Withdrawn legal-status Critical Current

Links

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
    • 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
    • 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

Definitions

  • the present invention relates to the combination of the 3-hydroxy-3-methyl-glutaryl-coenzyme A inhibitor (HMG-CoA inhibitor) cerivastatin with fibrates and their use in the prophylaxis and treatment of disorders and diseases of the lipid metabolism as well as those caused thereby Diseases.
  • HMG-CoA inhibitor 3-hydroxy-3-methyl-glutaryl-coenzyme A inhibitor
  • EP-A-0 276 807 describes the combination of HMG-CoA reductase inhibitors with hexahydronaphthalene backbone with gemfibrozil and the use of this combination for regulating the lipid and cholesterol levels in the blood serum.
  • the present invention therefore relates to the combination of cerivastatin with a fibrate.
  • Cerivastatin is the INN for (+) - [3-R, 5S, (E)] - 7- [4- (4-fluorophenyl) -2,6-diisopropyl-5-methoxymethylpyrid-3-yl] -3.5 -dihydroxyhept-6-encarboxylic acid.
  • cerivastatin is also intended to include the esters, the lactone and, in particular, pharmaceutically acceptable salts. Is particularly preferred
  • Cerivastatin used in the form of its sodium salt (“Cerivastatin sodium”).
  • fibrates are understood to mean derivatives and analogs of clofibrinic acid.
  • Fenofibrate is particularly preferred.
  • the combination according to the invention comprises no further pharmaceutical active ingredients apart from cerivastatin and fibrate, in particular fenofibrate.
  • cerivastatin with fibrates according to the invention proves to be surprisingly advantageous in the treatment of disorders of the fat metabolism.
  • An example is dyslipidemia, which occurs in diabetics but also in patients who do not suffer from diabetes.
  • an additive effect which is not to be expected, for example in the lowering of the LDL (low density lipoprotein) level, is observed. This means that the amounts of cerivastatin and fibrate used can be reduced compared to monotherapy.
  • the combinations according to the invention are furthermore distinguished by surprisingly good tolerability, although there are numerous indications in the literature of disadvantageous side effects, e.g. Rhabdomyolyses are found. Serious cases of rhabdomyolysis have been described for patients who received the combination of lovastatin with gemfibrozil or nicotinic acid (Physician's Desk
  • Dyslipidemia is to be understood here as a mixed hyperlipidemia, ie a disease state with an elevated cholesterol level (LDL and total cholesterol) and an elevated triglyceride level. Dyslipidemia can also occur with normal total cholesterol level or LDL cholesterol level and / or normal triglyceride level In this case, dyslipidemia means a shift in the spectrum of the lipid particles to particularly atherogenic lipid particles. Examples of such atherogenic particles are the small dense particles (a sub-fraction of the LDL particles) or the chylomicron remnants. The combinations according to the invention are suitable for the treatment of both variants dyslipidemia.
  • the combinations according to the invention are also particularly suitable for the treatment of dyslipidemia in diabetics.
  • the combinations according to the invention are furthermore particularly suitable for the prophylaxis and treatment of atherosclerosis.
  • the combinations according to the invention are preferably used in human medicine, but are also suitable for veterinary medicine, in particular for
  • the combinations according to the invention can be administered parenterally or, preferably, orally.
  • the active compounds can be converted into the customary formulations in a known manner, which can be liquid or solid formulations. Examples are tablets, dragées, pills, capsules, granules, aerosols, syrups, emulsions, suspensions, juices.
  • Cerivastatin is effective in very low doses, a wide variety of formulation variants can be implemented.
  • the two individual components do not necessarily have to be taken at the same time, but a delayed intake of cerivastatin and fibrate can be advantageous.
  • 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 medicinal forms in which the two components are present together in a fixed quantitative ratio.
  • Such fixed combinations can be implemented, for example, as oral solutions, but are preferably solid oral medicinal preparations, for example capsules or tablets. In the context of this invention, the fixed combinations are preferred.
  • cerivastatin with fibrates according to the invention are dosed up to 3 times a day; preference is given to those combinations which allow one daily application.
  • the formulations contain 0.025 mg to 4 mg cerivastatin sodium, 0.2 mg to 1.6 mg are preferred, and 2 mg to 2000 mg of a fibrate, preferably 10 mg to 500 mg. Fibrates in the sense of the invention are in particular fenofibrate and bezafibrate.
  • the oral application of the combinations according to the invention is generally carried out in daily doses of about 1 to 60 ⁇ g / kg cerivastatin and 0.1 to 100 mg / kg fibrate; in the case of parenteral administration, the dosage is approximately 0.5 to 30 ⁇ g / kg cerivastatin and 0.05 to 50 mg / kg fibrate based on the respective body weight.
  • fenofibrate can also be administered in doses of 200 mg and less, which are comparatively low for fibrates, because of special galenical process optimizations (see e.g. EP 0 757 911 AI).
  • cerivastatin and fenofibrate are therefore particularly suitable to be formulated in a fixed combination in the form of a fixed oral dosage form. It is well known that patient compliance is critically dependent on the number of factors
  • cerivastatin is preferably administered in the evening. Fibrates, also fenofibrate or bezafibrate, are often given in the morning. Clinical studies with these preparations are usually carried out according to the dosing schedule mentioned, but other dosing schedules are possible.
  • the drug release can be controlled by combining the two preparations and modifying the composition or functionality. For example, a delayed release of active ingredient (retardation)
  • the solid oral dosage forms listed here are manufactured according to the general standard procedures.
  • Ingredients are those that are pharmaceutically accepted and are physiologically harmless, for example: as fillers cellulose derivatives (eg microcrystalline cellulose), sugar (eg lactose), sugar alcohols (eg mannitol, sorbitol), inorganic fillers (eg calcium phosphates), binders (eg polyvinylpyrrolidone) , Gelatin, starch and cellulose derivatives), and all other auxiliaries required for the preparation of pharmaceutical formulations of the desired
  • lubricants magnesium stearate
  • disintegrants e.g. cross-linked polyvinyl pyrrolidone, 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.
  • 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), wetting agents (e.g. polysorbate, sodium lauryl sulfate) ), as well as other auxiliaries that are required for the production of pharmaceutical formulations of 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
  • solvents e.g. water, alcohol, natural and synthetic oils, e.g. medium-chain triglcerides
  • solubilizers e.g. glycerol, glycol derivatives
  • wetting agents e.g. polysorbate, sodium lauryl sulfate
  • auxiliaries that are required for the production of pharmaceutical formulations of the desired properties, for example viscosity-
  • the main components of the capsule formulations are, for example, gelatin or hydroxypropylmethyl cellulose.
  • Cerivastatin tablets with an active ingredient content of 0.4 mg per tablet and the following composition are produced as described below.
  • the process is a conventional wet granulation (typical batch sizes are 5 kg - 120 kg), in which mannitol is presented as a powder base in the apparatus and granulated with a granulation liquid containing cerivastatin sodium, sodium hydroxide, polyvinylpyrrolidone and water. After drying, the granules are sieved (0.8 - 1.25 mm), mixed with magnesium stearate and crospovidone (5 - 15 min), tableted (90 mg / tablet) and if necessary with a
  • Fenofibrate tablets are manufactured using the standard method.
  • Cerivastatin tablets and fenofibrate tablets are used as a combination in a suitable primary packaging for the treatment of the lipid metabolism disorders described above.
  • Example 2 Cerivastatin tablets and fenofibrate tablets are used as a combination in a suitable primary packaging for the treatment of the lipid metabolism disorders described above.
  • Cerivastatin tablets according to Example 1 are made with capsule formulations containing granules, powder mixtures or pellets (slow-release formulation) with fenofibrate, in some cases. in special preparations or manufacturing forms (according to composition and production, as described e.g. in EP 0 330 532 AI or in French Patent No. 2 494 112) as a combination in a suitable primary packaging.
  • Cerivastatin granules (according to Example 1) are mixed with fenofibrate granules, powder mixture or pellets in appropriate proportions and tabletted; then the tablets are coated with a light protection varnish.
  • Cerivastatin granules according to Example 1 are filled with capsules (from hard gelatin or cellulose derivatives) together with fenofibrate granules, powder mixtures or pellets in appropriate proportions. This is done either on suitable capsule filling machines with 2 dosing units or on simplified machines after the two components have been previously combined and homogenized.
  • Example 5 Fixed combination Cerivastatin tablets are produced according to Example 1 and filled into capsules together with a fenofibrate formulation of the appropriate dosage, powder mixture, granules or pellets.
  • Cerivastatin sodium and fenofibrate are mixed, if necessary with the addition of other ingredients, in a joint process and, if necessary, granulated. These mixtures or granules are then filled into capsules,
  • Pellets of uniform size and load are produced from mixtures according to Example 6 by rounding out and either filled into capsules or tableted, optionally with the addition of other auxiliaries.
  • Example 9
  • Active ingredient-free pellets are loaded with a solution that contains cerivastatin sodium and other auxiliary substances. These pellets are combined with fenofibrate pellets and filled into capsules.
  • the pellets according to Example 9 are further processed into tablets, optionally with the addition of further auxiliaries.
  • a liquid formulation of cerivastatin and fenofibrate (as described in EP 0 757 911 AI) are mixed in appropriate amounts and provided as a solution for application.
  • a formulation of the two substances according to Example 11 is filled into soft gelatin capsules with a specific application volume.

Abstract

The invention relates to the combination of the 3-hydroxy-3-methyl-glutaryl-coenzyme-A inhibitor (HMG-CoA inhibitor) Cerivastatin with fibrates and to its use in the prophylaxis and treatment of disorders and diseases of lipid metabolism and of illnesses caused by such disorders and diseases.

Description

Kombination von Cerivastatin und FibratenCombination of cerivastatin and fibrates
Die vorliegende Erfindung betrifft die Kombination des 3-Hydroxy-3-methyl- glutaryl-Coenzym-A-Inhibitors (HMG-CoA-Inhibitors) Cerivastatin mit Fibraten und ihre Verwendung bei der Prophylaxe und Behandlung von Störungen und Krankheiten des Lipidstoffwechsels sowie von dadurch verursachten Erkrankungen.The present invention relates to the combination of the 3-hydroxy-3-methyl-glutaryl-coenzyme A inhibitor (HMG-CoA inhibitor) cerivastatin with fibrates and their use in the prophylaxis and treatment of disorders and diseases of the lipid metabolism as well as those caused thereby Diseases.
EP-A-0 276 807 beschreibt die Kombination von HMG-CoA-Reduktase-Inhibitoren mit Hexahydronaphthalin-Grundgerüst mit Gemfibrozil sowie die Verwendung dieser Kombination für die Regulierung des Lipid- und Cholesterinspiegels im Blutserum.EP-A-0 276 807 describes the combination of HMG-CoA reductase inhibitors with hexahydronaphthalene backbone with gemfibrozil and the use of this combination for regulating the lipid and cholesterol levels in the blood serum.
Aus EP-A-0 455 042 ist die Kombination von Pravastatin mit einem Fibrat sowie deren Verwendung zur Behandlung von Dyslipidämie bekannt. Auf die Diskussion des weiteren Standes der Technik in diesem Dokument sowie in der oben genannten EP-A-0 276 807 wird ausdrücklich hingewiesen.From EP-A-0 455 042 the combination of pravastatin with a fibrate and their use for the treatment of dyslipidemia are known. Reference is expressly made to the discussion of the further prior art in this document and in the above-mentioned EP-A-0 276 807.
Die Kombination des HMG-CoA-Reduktase-Inhibitors Cerivastatin mit Fibraten wurde bislang noch nicht beschrieben. Es wurde nun gefunden, daß die Kombination von Cerivastatin mit Fibraten vorteilhafte Eigenschaften, insbesondere bezüglich Wirkung und Verträglichkeit besitzt.The combination of the HMG-CoA reductase inhibitor cerivastatin with fibrates has not yet been described. It has now been found that the combination of cerivastatin with fibrates has advantageous properties, in particular with regard to activity and tolerance.
Die vorliegende Erfindung betrifft daher die Kombination von Cerivastatin mit einem Fibrat.The present invention therefore relates to the combination of cerivastatin with a fibrate.
Cerivastatin ist der INN für (+)-[3-R,5S,(E)]-7-[4-(4-fluorphenyl)-2,6-diisopropyl-5- methoxymethylpyrid-3-yl]-3,5-dihydroxyhept-6-encarbonsäure. Im Rahmen der vorliegenden Erfindung soll der Begriff Cerivastatin auch die Ester, das Lacton sowie insbesondere pharmazeutisch verträgliche Salze umfassen. Besonders bevorzugt wirdCerivastatin is the INN for (+) - [3-R, 5S, (E)] - 7- [4- (4-fluorophenyl) -2,6-diisopropyl-5-methoxymethylpyrid-3-yl] -3.5 -dihydroxyhept-6-encarboxylic acid. In the context of the present invention, the term cerivastatin is also intended to include the esters, the lactone and, in particular, pharmaceutically acceptable salts. Is particularly preferred
Cerivastatin in Form seines Natriumsalzes („Cerivastatin Natrium") eingesetzt. Unter Fibraten werden im Rahmen dieser Erfindung Derivate und Analoga der Clo- fibrinsäure verstanden. Im Rahmen der Erfindung sind Fenofibrat, 2-[4-(4-Chlorben- zoyl)phenoxy]-2-methylpropansäure-l-methylethylester, und Bezafibrat, 2-[4-[2-[(4- Chlorbenzoyl)amino]-ethyl]phenoxy]-2-mehtyl-propansäure, bevorzugt. Besonders bevorzugt ist Fenofibrat.Cerivastatin used in the form of its sodium salt ("Cerivastatin sodium"). In the context of this invention, fibrates are understood to mean derivatives and analogs of clofibrinic acid. Fenofibrate, 2- [4- (4-chlorobenzoyl) phenoxy] -2-methylpropanoic acid l-methylethyl ester, and bezafibrate, 2- [4- [2 - [(4-chlorobenzoyl) amino] - ethyl] phenoxy] -2-methyl propanoic acid, preferred. Fenofibrate is particularly preferred.
Gemäß einer bevorzugten Ausführungsform umfaßt die erfindungsgemäße Kombination keine weiteren pharmazeutischen Wirkstoffe außer Cerivastatin und Fibrat, insbesondere Fenofibrat.According to a preferred embodiment, the combination according to the invention comprises no further pharmaceutical active ingredients apart from cerivastatin and fibrate, in particular fenofibrate.
Die erfindungsgemäße Kombination von Cerivastatin mit Fibraten erweist sich als überraschend vorteilhaft bei der Behandlung von Störungen des Fettstoffwechsels. Als Beispiel seien Dyslipidämien genannt, wie sie bei Diabetikern aber auch bei Patienten, die nicht an Diabetes leiden, auftreten. Bei Verwendung der erfindungsgemäßen Kombinationen wird bei der Wirkung ein nicht zu erwartender additiver Effekt, beispielsweise bei der Senkung der LDL (Low Density Lipoprotein) -Spiegel, beobachtet. Damit können die eingesetzten Mengen an Cerivastatin und Fibrat im Vergleich zur Monotherapie verringert werden.The combination of cerivastatin with fibrates according to the invention proves to be surprisingly advantageous in the treatment of disorders of the fat metabolism. An example is dyslipidemia, which occurs in diabetics but also in patients who do not suffer from diabetes. When using the combinations according to the invention, an additive effect which is not to be expected, for example in the lowering of the LDL (low density lipoprotein) level, is observed. This means that the amounts of cerivastatin and fibrate used can be reduced compared to monotherapy.
Weiterhin zeichnen sich die erfindungsgemäßen Kombinationen durch eine überraschend gute Verträglichkeit aus, obwohl in der Literatur zahlreiche Hinweise auf nachteilige Nebenwirkungen wie z.B. Rhabdomyolysen zu finden sind. So wurden für Patienten, welche die Kombination von Lovastatin mit Gemfibrozil oder Nikotin- säure erhielten, schwere Fälle von Rhabdomyolyse beschrieben (Physician's DeskThe combinations according to the invention are furthermore distinguished by surprisingly good tolerability, although there are numerous indications in the literature of disadvantageous side effects, e.g. Rhabdomyolyses are found. Serious cases of rhabdomyolysis have been described for patients who received the combination of lovastatin with gemfibrozil or nicotinic acid (Physician's Desk
Reference, 52πd Ed., 1998, S. 1695).Reference, 52 πd Ed., 1998, p 1695).
Die erfindungsgemäßen Kombinationen eignen sich daher zur Prophylaxe und Behandlung von Störungen der Lipidspiegel im Blut sowie von damit im Zusammenhang stehenden Krankheiten. Bevorzugt werden die erfindungsgemäßenThe combinations according to the invention are therefore suitable for the prophylaxis and treatment of disorders of the lipid level in the blood and of diseases associated therewith. Those according to the invention are preferred
Kombinationen daher für die Behandlung von Dyslipidämie eingesetzt. Unter „Dyslipidämie" soll hier eine gemischte Hyperlipidämie verstanden werden, d.h. ein Krankheitszustand mit erhöhtem Cholesterinspiegel (LDL und Gesamt- cholesterin) und erhöhtem Triglyceridspiegel. Dyslipidämien können aber auch bei normalem Gesamtcholesterinspiegel bzw. LDL-Cholesterinspiegel und/oder normalem Triglyceridspiegel auftreten. In diesem Fall versteht man unter Dyslipidämie eine Verschiebung des Spektrums der Lipidpartikel zu besonders atherogenen Lipidpartikeln. Als Beispiele für solche atherogenen Partikel seien die small dense Partikel (eine Unterfraktion der LDL-Partikel) oder die Chylomikronremnants genannt. Die erfindungsgemäßen Kombinationen eignen sich für die Behandlung beider Varianten der Dyslipidämie.Combinations are therefore used for the treatment of dyslipidemia. “Dyslipidemia” is to be understood here as a mixed hyperlipidemia, ie a disease state with an elevated cholesterol level (LDL and total cholesterol) and an elevated triglyceride level. Dyslipidemia can also occur with normal total cholesterol level or LDL cholesterol level and / or normal triglyceride level In this case, dyslipidemia means a shift in the spectrum of the lipid particles to particularly atherogenic lipid particles. Examples of such atherogenic particles are the small dense particles (a sub-fraction of the LDL particles) or the chylomicron remnants. The combinations according to the invention are suitable for the treatment of both variants dyslipidemia.
Von einem erhöhten Cholesterinspiegel spricht man in diesem Zusammenhang bei Werten von über 200mg/dl für Gesamtcholesterin bzw. über 130mg/dl für LDL- Cholesterin, ein erhöhter Triglyceridspiegel liegt bei Werten von über 150mg/dl vor.In this context, one speaks of an increased cholesterol level with values of over 200 mg / dl for total cholesterol or over 130 mg / dl for LDL cholesterol; an increased triglyceride level is present with values of over 150 mg / dl.
Die erfindungsgemäßen Kombinationen eignen sich insbesondere auch zur Behandlung von Dyslipidämien bei Diabetikern.The combinations according to the invention are also particularly suitable for the treatment of dyslipidemia in diabetics.
Aufgrund ihrer Wirkung auf die Serumlipidspiegel eignen sich die erfindungsgemäßen Kombinationen weiterhin besonders zur Prophylaxe und Behandlung von Atherosklerose.Because of their effect on serum lipid levels, the combinations according to the invention are furthermore particularly suitable for the prophylaxis and treatment of atherosclerosis.
Die erfindungsgemäßen Kombinationen werden bevorzugt in der Humanmedizin eingesetzt, eignen sich jedoch auch für die Veterinärmedizin, insbesondere zurThe combinations according to the invention are preferably used in human medicine, but are also suitable for veterinary medicine, in particular for
Behandlung von Säugetieren.Treatment of mammals.
Die Verabreichung der erfindungsgemäßen Kombinationen kann parenteral oder bevorzugt oral erfolgen. Die Wirkstoffe können in bekannter Weise in die üblichen Formulierungen überführt werden, wobei es sich um flüssige oder feste Formulierungen handeln kann. Beispiele sind Tabletten, Dragees, Pillen, Kapseln, Granulate, Aerosole, Sirupe, Emulsionen, Suspensionen, Säfte.The combinations according to the invention can be administered parenterally or, preferably, orally. The active compounds can be converted into the customary formulations in a known manner, which can be liquid or solid formulations. Examples are tablets, dragées, pills, capsules, granules, aerosols, syrups, emulsions, suspensions, juices.
Da Cerivastatin in sehr niedrigen Dosierungen wirksam ist, lassen sich die verschiedensten Formulierungsvarianten realisieren. So besteht zum einen die Möglichkeit die Einzelkomponenten getrennt zu fomulieren. In diesem Fall müssen die beiden Einzelkomponenten nicht unbedingt zur gleichen Zeit eingenommen werden, vielmehr kann eine zeitlich versetzte Einnahme von Cerivastatin und Fibrat vorteilhaft sein. Bei einer solchen getrennten Darreichung bietet es sich an, die Formulierungen der beiden Einzelkomponenten, beispielsweise Tabletten oder Kapseln, gleichzeitig nebeneinander in einem geeigneten Primärpackmittel zu kombinieren.Since Cerivastatin is effective in very low doses, a wide variety of formulation variants can be implemented. On the one hand, there is the possibility of formulating the individual components separately. In this case, the two individual components do not necessarily have to be taken at the same time, but a delayed intake of cerivastatin and fibrate can be advantageous. In the case of such a separate administration, it makes sense to combine the formulations of the two individual components, for example tablets or capsules, simultaneously in a suitable primary packaging.
Als weitere Formulierungsvariante für die erfindungsgemäßen Kombinationen eigenen sich auch fixe Kombinationen. Unter „fixe Kombination" sollen hier solche Arzneiformen verstanden werden, in denen die beiden Komponenten gemeinsam in einem festgelegten Mengenverhältnis vorliegen. Solche fixen Kombinationen können beispielsweise als perorale Lösungen realisiert werden, bevorzugt handelt es sich jedoch um feste orale Arzneizubereitungen, z.B. Kapseln oder Tabletten. Im Rahmen dieser Erfindung sind die fixen Kombinationen bevorzugt.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 medicinal forms in which the two components are present together in a fixed quantitative ratio. Such fixed combinations can be implemented, for example, as oral solutions, but are preferably solid oral medicinal preparations, for example capsules or tablets. In the context of this invention, the fixed combinations are preferred.
Die erfindungsgemäßen Kombinationen von Cerivastatin mit Fibraten werden bis zu 3x täglich dosiert, bevorzugt sind solche Kombinationen, die eine lx tägliche Appli- kation erlauben.The combinations of cerivastatin with fibrates according to the invention are dosed up to 3 times a day; preference is given to those combinations which allow one daily application.
Die Formulierungen enthalten 0,025 mg bis 4 mg Cerivastatin Natrium, bevorzugt sind 0,2 mg bis 1,6 mg, sowie 2 mg bis 2000 mg eines Fibrates, bevorzugt 10 mg bis 500 mg. Fibrate im Sinne der Erfindung sind insbesondere Fenofibrat und Bezafibrat. Die orale Applikation der erfindungsgemäßen Kombinationen erfolgt zur Erzielung wirksamer Ergebnisse im allgemeinen in Tagesdosen von etwa 1 bis 60 μg/kg Cerivastatin und 0,1 bis 100 mg/kg Fibrat; bei parenteraler Applikation beträgt die Dosierung etwa 0,5 bis 30 μg/kg Cerivastatin und 0,05 bis 50 mg/kg Fibrat bezogen auf das jeweilige Körpergewicht.The formulations contain 0.025 mg to 4 mg cerivastatin sodium, 0.2 mg to 1.6 mg are preferred, and 2 mg to 2000 mg of a fibrate, preferably 10 mg to 500 mg. Fibrates in the sense of the invention are in particular fenofibrate and bezafibrate. To achieve effective results, the oral application of the combinations according to the invention is generally carried out in daily doses of about 1 to 60 μg / kg cerivastatin and 0.1 to 100 mg / kg fibrate; in the case of parenteral administration, the dosage is approximately 0.5 to 30 μg / kg cerivastatin and 0.05 to 50 mg / kg fibrate based on the respective body weight.
Gegebenenfalls kann es erforderlich sein, von den genannten Mengen abzuweichen, und zwar in Abhängigkeit vom Körpergewicht bzw. der Art des Applikationsweges, vom individuellen Verhalten gegenüber den Medikamenten, der Art von deren Formulierung und dem Zeitpunkt bzw. Intervall, zu welchem die Verabreichung erfolgt. So kann es in einigen Fällen ausreichend sein, mit weniger als der vorgenannten Mindestmenge auszukommen, während in anderen Fällen die genannte obere Grenze überschritten werden muß. Im Falle der Applikation größerer Mengen kann es empfehlenswert sein, diese in mehreren Einzelgaben über den Tag zu ver- teilen.It may be necessary to deviate from the amounts mentioned, depending on the body weight or the type of application route, on the individual behavior towards the medication, the type of its formulation and the time or interval at which the administration takes place. In some cases it may be sufficient to make do with less than the aforementioned minimum quantity, while in other cases the above upper limit must be exceeded. In the case of application of larger quantities, it may be advisable to distribute them in several single doses over the day.
In diesem Zusammenhang erweist sich weiterhin als vorteilhaft, daß Fenofibrat ggf. ebenfalls - aufgrund besonderer galenischer Verfahrensoptimierungen (siehe z.B. EP 0 757 911 AI) - in für Fibrate vergleichsweise niedrigen Dosierungen von 200 mg und weniger verabreicht werden kann.In this context, it also proves to be advantageous that fenofibrate can also be administered in doses of 200 mg and less, which are comparatively low for fibrates, because of special galenical process optimizations (see e.g. EP 0 757 911 AI).
Die beiden Wirkstoffe Cerivastatin und Fenofibrat sind demnach besonders geeignet, in einer fixen Kombination in Form einer festen peroralen Darreichungsform formuliert zu werden. Es ist allgemein bekannt, daß die Einnahmezuverlässigkeit (Compliance) bei Patienten in entscheidendem Maße von den Faktoren Anzahl derThe two active substances cerivastatin and fenofibrate are therefore particularly suitable to be formulated in a fixed combination in the form of a fixed oral dosage form. It is well known that patient compliance is critically dependent on the number of factors
Darreichungsformen pro Einnahmezeitpunkt und Größe und Gewicht der (festen peroralen) Arzneiform abhängig ist. Daher sollte sowohl die Anzahl der verschiedenen getrennt einzunehmenden Arzneimittel so gering wie möglich sein (Vorteil einer fixen Kombination), als auch die Größe und das Gewicht einer festen peroralen Darreichungsform so klein wie möglich sein, um die Einnahme für den Patienten so angenehm wie möglich zu gestalten. Keine andere derzeit bekannte fixe Kombination von Statinen mit Fibraten läßt sich - bei voller therapeutischer Wirkstärke - niedriger dosieren als die von Cerivastatin mit Fenofibrat. Damit lassen sich fixe Kombinationen in Form von festen peroralen Arzneiformulierungen mit minimaler Größe und minimalem Gewicht realisieren. Die erfindungsgemäßen fixen Kombinationen von Cerivastatin und Fenofibrat bieten demnach eine höchstmöglicheDosage forms depend on the time of ingestion and the size and weight of the (fixed oral) dosage form. Therefore, the number of different medicines 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 in order to make the intake as comfortable as possible for the patient shape. No other currently known fixed combination Statins with fibrates can be dosed lower than those of cerivastatin with fenofibrate - with full therapeutic potency. This enables fixed combinations in the form of solid oral pharmaceutical formulations to be implemented with a minimal size and minimal weight. The fixed combinations of cerivastatin and fenofibrate according to the invention therefore offer the highest possible
Patienten Compliance und verbessern dadurch die Sicherheit und Zuverlässigkeit einer Therapie entscheidend.Patient compliance and thereby decisively improve the safety and reliability of a therapy.
Die Applikation von Cerivastatin erfolgt aus pharmakologischen Gründen bevorzugt am Abend. Fibrate, auch Fenofibrat oder Bezafibrat, werden häufig am Morgen gegeben. Klinische Studien mit diesen Präparaten werden in der Regel nach dem genannten Dosierungsschema durchgeführt, andere Dosierungsschemata sind jedoch möglich. Durch Kombination der beiden Präparate und Modifizierung der Zusammensetzung bzw. der Funktionalität läßt sich die Wirkstofffreisetzung steuern. Beispielsweise läßt sich durch verzögerte Wirkstofffreisetzung (Retardierung) einerFor pharmacological reasons, cerivastatin is preferably administered in the evening. Fibrates, also fenofibrate or bezafibrate, are often given in the morning. Clinical studies with these preparations are usually carried out according to the dosing schedule mentioned, but other dosing schedules are possible. The drug release can be controlled by combining the two preparations and modifying the composition or functionality. For example, a delayed release of active ingredient (retardation)
Komponente die oben angeführte zeitliche Entkopplung des Wirkeintritts realisieren. Eine Form der Retardierung von Fenofibrat ist z.B. in WO 82/01649 beschrieben.Realize the above-mentioned decoupling of the onset of action. One form of retardation of fenofibrate is e.g. described in WO 82/01649.
Die hier angeführten festen peroralen Dareichungsformen werden hergestellt nach den allgemeinen Standardverfahren. Inhaltsstoffe sind solche, die pharmazeutisch akzeptiert und physiologisch unbedenklich sind, beispielsweise: als Füllstoffe Cellu- losederivate (z.B. Mikrokristalline Cellulose), Zucker (z.B. Lactose), Zuckeralkohole (z.B. Mannitol, Sorbitol), anorganische Füllstoffe (z.B. Calciumphosphate), Bindemittel (z.B. Polyvinylpyrrolidon, Gelatine, Stärke- und Cellulosederivate), sowie alle weiteren Hilfsstoffe, die zur Herstellung von Arzneiformulierungen der gewünschtenThe solid oral dosage forms listed here are manufactured according to the general standard procedures. Ingredients are those that are pharmaceutically accepted and are physiologically harmless, for example: as fillers cellulose derivatives (eg microcrystalline cellulose), sugar (eg lactose), sugar alcohols (eg mannitol, sorbitol), inorganic fillers (eg calcium phosphates), binders (eg polyvinylpyrrolidone) , Gelatin, starch and cellulose derivatives), and all other auxiliaries required for the preparation of pharmaceutical formulations of the desired
Eigenschaften benötigt werden, z.B. Schmiermittel (Magnesiumstearat), z.B. Sprengmittel (z.B. quervernetztes Polyvinylpyrrolidon, Natriumcarboxymethylcellulose), z.B. Netzmittel (z.B. Natriumlaurylsulfat), z.B. Retardierungsmittel (z.B. Cellulosederivate, Polyacrylsäurederivate), z.B. Stabilisatoren, z.B. Aromen, z .B. Farbpig- mente. Flüssige Formulierungen werden ebenfalls nach Standardmethode mit pharmazeutisch gebräuchlichen Hilfsstoffen hergestellt und enthalten den Wirkstoff bzw. die beiden Wirkstoffe entweder gelöst oder suspendiert. Typische Applikationsvolumen dieser Arzneizubereitungen sind 1 bis 10 ml. Beispiele für Hilfsstoffe in diesen flüssigen Formulierungen sind: Lösungsmittel (z.B. Wasser, Alkohol, natürliche und synthetische Öle, z.B. Mittelkettige Triglceride), Lösungsvermittler (z.B. Glycerol, Glykolderivate), Netzmittel (z.B. Polysorbat, Natriumlaurylsulfat), sowie weitere Hilfsstoffe, die zur Herstellung von Arzneiformulierungen der gewünschten Eigenschaften benötigt werden, z.B. viskositätserhöhende Mittel, z.B. pH-Wert-Korri- genzien, z.B. Süßstoffe und Aromen, z.B. Antioxidantien, z.B. Stabilisatoren, z.B.Properties are required, e.g. lubricants (magnesium stearate), e.g. disintegrants (e.g. cross-linked polyvinyl pyrrolidone, sodium carboxymethyl cellulose), e.g. wetting agents (e.g. sodium lauryl sulfate), e.g. retardants (e.g. cellulose derivatives, polyacrylic acid derivatives), e.g. 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.Examples of 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), wetting agents (e.g. polysorbate, sodium lauryl sulfate) ), as well as other auxiliaries that are required for the production of pharmaceutical formulations of 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
Konservierungsmittel.Preservative.
Hauptbestandteile der Hüllen von Kapselformulierungen sind beispielsweise Gelatine oder Hydroxypropylmethylcellulose.The main components of the capsule formulations are, for example, gelatin or hydroxypropylmethyl cellulose.
Pharmazeutische Hilfsstoffe, wie sie dem Fachmann geläufig sind, sind beispielsweise auch in folgendem Handbuch beschrieben: "Handbook of Pharmaceutical Excipients", Wade, A. & Weller, P.J., American Pharmaceutical Association, Washington, 2nd edition 1994. Pharmaceutical auxiliaries as are known to the person skilled in the art are also described, for example, in the following manual: "Handbook of Pharmaceutical Excipients", Wade, A. & Weller, PJ, American Pharmaceutical Association, Washington, 2nd edition 1994.
BeispieleExamples
Beispiel 1example 1
Getrennte FormulierungSeparate wording
Cerivastatin Tabletten mit einem Wirkstoffanteil von 0,4 mg pro Tablette und der folgenden Zusammensetzung werden wie unten beschrieben hergestellt.Cerivastatin tablets with an active ingredient content of 0.4 mg per tablet and the following composition are produced as described below.
Das Verfahren ist eine konventionelle Feuchtgranulation (typische Chargengrößen sind 5 kg - 120 kg), bei der Mannitol als Pulvergrundlage in der Appararatur vorgelegt und mit einer Granulationsflüssigkeit, enthaltend Cerivastatin Natrium, Natriumhydroxid, Polyvinylpyrrolidon und Wasser granuliert wird. Nach der Trocknung wird das Granulat gesiebt (0,8 - 1,25 mm), nach Zugabe von Magnesiumstearat und Crospovidone gemischt (5 - 15 min), tablettiert (90 mg/Tablette) und ggf. mit einemThe process is a conventional wet granulation (typical batch sizes are 5 kg - 120 kg), in which mannitol is presented as a powder base in the apparatus and granulated with a granulation liquid containing cerivastatin sodium, sodium hydroxide, polyvinylpyrrolidone and water. After drying, the granules are sieved (0.8 - 1.25 mm), mixed with magnesium stearate and crospovidone (5 - 15 min), tableted (90 mg / tablet) and if necessary with a
Lichtschutzlack überzogen. Durch Variation der Anteile Wirkstoff und Mannitol in der Zusammensetzung sind Wirkstärken der Tabletten von 0,025 mg bis 4 mg möglich.Sunscreen varnish coated. By varying the proportions of active ingredient and mannitol in the composition, the strengths of the tablets from 0.025 mg to 4 mg are possible.
Fenofibrat-Tabletten werden nach Standardmethode hergestellt.Fenofibrate tablets are manufactured using the standard method.
Cerivastatin Tabletten und Fenofibrat Tabletten werden als Kombination in einer geeigneten Primärverpackung gemeinsam zur Behandlung der oben beschriebenen Fettstoffwechselerkrankungen eingesetzt. Beispiel 2Cerivastatin tablets and fenofibrate tablets are used as a combination in a suitable primary packaging for the treatment of the lipid metabolism disorders described above. Example 2
Getrennte FormulierungSeparate wording
Cerivastatin Tabletten gemäß Beispiel 1 werden mit Kapselformulierungen, enthaltend Granulate, Pulvermischungen oder Pellets (Retardformulierung) mit Fenofibrat, z.T. in besonderen Zubereitungen bzw. Herstellungsformen (gemäß Zusammensetzung und Herstellung, wie z.B. beschrieben in EP 0 330 532 AI oder im Franz. Patent Nr. 2 494 112) als Kombination in einer geeigneten Primärverpackung eingesetzt.Cerivastatin tablets according to Example 1 are made with capsule formulations containing granules, powder mixtures or pellets (slow-release formulation) with fenofibrate, in some cases. in special preparations or manufacturing forms (according to composition and production, as described e.g. in EP 0 330 532 AI or in French Patent No. 2 494 112) as a combination in a suitable primary packaging.
Beispiel 3Example 3
Fixe KombinationFixed combination
Cerivastatin Granulat (gemäß Beispiel 1) wird mit Fenofibrat Granulat, Pulvermischung oder Pellets in entsprechenden Mengenverhältnissen gemischt und tablettiert; anschließend werden die Tabletten mit einem Lichtschutzlack überzogen.Cerivastatin granules (according to Example 1) are mixed with fenofibrate granules, powder mixture or pellets in appropriate proportions and tabletted; then the tablets are coated with a light protection varnish.
Beispiel 4 Fixe KombinationExample 4 Fixed combination
Cerivastatin-Granulate gemäß Beispiel 1 werden mit Fenofibrat-Granulaten, Pulvermischungen bzw. Pellets in entsprechenden Mengenverhältnissen gemeinsam in Kapseln (aus Hartgelatine bzw. Cellulosederivaten) abgefüllt. Dies geschieht ent- weder auf geeigneten Kapselabfüllmaschinen mit 2 Dosiereinheiten oder auf vereinfachten Maschinen nach vorheriger Vereinigung und Homogenisierung der beiden Komponenten.Cerivastatin granules according to Example 1 are filled with capsules (from hard gelatin or cellulose derivatives) together with fenofibrate granules, powder mixtures or pellets in appropriate proportions. This is done either on suitable capsule filling machines with 2 dosing units or on simplified machines after the two components have been previously combined and homogenized.
Beispiel 5 Fixe Kombination Cerivastatin Tabletten werden gemäß Beispiel 1 hergestellt und zusammen mit einer Fenofibrat Formulierung der entsprechenden Dosierung, Pulvermischung, Granulat oder Pellets, in Kapseln abgefüllt.Example 5 Fixed combination Cerivastatin tablets are produced according to Example 1 and filled into capsules together with a fenofibrate formulation of the appropriate dosage, powder mixture, granules or pellets.
Beispiel 6Example 6
Fixe Kombination (Kapseln)Fixed combination (capsules)
Cerivastatin Natrium und Fenofibrat werden, ggf. unter Zusatz weiterer Bestandteile, in einem gemeinsamen Prozeß gemischt und ggf. granuliert. Diese Mischungen bzw. Granulate werden anschließend in Kapseln abgefüllt,Cerivastatin sodium and fenofibrate are mixed, if necessary with the addition of other ingredients, in a joint process and, if necessary, granulated. These mixtures or granules are then filled into capsules,
Beispiel 7Example 7
Fixe Kombination (Tabletten)Fixed combination (tablets)
Die Mischungen bzw. Granulate gemäß Beispiel 6 werden, ggf. unter Zusatz weitererThe mixtures or granules according to Example 6 are, if appropriate with the addition of further
Hilfsstoffe, tablettiert; anschließend werden die Tabletten mit einem Lichtschutzlack überzogen.Excipients, tableted; then the tablets are coated with a light protection varnish.
Beispiel 8 Fixe Kombination (Pellets)Example 8 Fixed combination (pellets)
Aus Mischungen gemäß Beispiel 6 werden in besonderen Verfahren durch Ausrunden Pellets einheitlicher Größe und Beladung hergestellt und entweder in Kapseln abgefüllt oder, ggf. unter Zusatz weiterer Hilfsstoffe, tablettiert. Beispiel 9Pellets of uniform size and load are produced from mixtures according to Example 6 by rounding out and either filled into capsules or tableted, optionally with the addition of other auxiliaries. Example 9
Fixe Kombination (Pellets)Fixed combination (pellets)
Wirkstofffreie Pellets (Nonpareils) werden mit einer Lösung, die Cerivastatin Natrium und weitere Hilfsstoffe enthält, beladen. Diese Pellets werden mit Feno- fibrat-Pellets kombiniert und in Kapseln abgefüllt.Active ingredient-free pellets (nonpareils) are loaded with a solution that contains cerivastatin sodium and other auxiliary substances. These pellets are combined with fenofibrate pellets and filled into capsules.
Beispiel 10Example 10
Fixe KombinationFixed combination
Die Pellets entsprechend Beispiel 9 werden, ggf. unter Zugabe weiterer Hilfsstoffe zu Tabletten weiterverarbeitet.The pellets according to Example 9 are further processed into tablets, optionally with the addition of further auxiliaries.
Beispiel 11 Fixe Kombination (flüssig)Example 11 Fixed combination (liquid)
Eine flüssige Formulierung von Cerivastatin und Fenofibrat (gemäß der Beschreibung in EP 0 757 911 AI) werden in entsprechenden Mengen gemischt und als Lösung zur Applikation bereitgestellt.A liquid formulation of cerivastatin and fenofibrate (as described in EP 0 757 911 AI) are mixed in appropriate amounts and provided as a solution for application.
Beispiel 12Example 12
Fixe KombinationFixed combination
Eine Formulierung der beiden Stoffe gemäß Beispiel 11 wird in Weichgelatine- kapseln mit bestimmtem Applikationsvolumen abgefüllt.A formulation of the two substances according to Example 11 is filled into soft gelatin capsules with a specific application volume.
Beispiel 13Example 13
Formulierungen gemäß den Beispielen 1 bis 12, wobei Bezafibrat - statt Fenofibrat - in einer geeigneten Dosierung von bis zu 500 mg zusammen mit Cerivastatin kombiniert wird. Beispiel 14Formulations according to Examples 1 to 12, wherein bezafibrate - instead of fenofibrate - is combined in a suitable dosage of up to 500 mg together with cerivastatin. Example 14
Wirkung auf die LipidspiegelEffect on lipid levels
Im Rahmen einer diätkontrollierten klinischen Doppelblind-Studie wurden Patienten einmal täglich abends mit 0,3 mg Cerivastatin in Form von Tabletten sowie mit 200 mg Fenofibrat (Kapseln/mikronisiert) behandelt.In a diet-controlled double-blind clinical study, patients were treated with 0.3 mg cerivastatin in the form of tablets and with 200 mg fenofibrate (capsules / micronized) once a day in the evening.
Die Ergebnisse nach 16 Wochen sind in der folgenden Tabelle für die Behandlung mit Fenofibrat bzw. Cerivastatin alleine sowie mit der Kombination zusammengefaßt. Angegeben ist jeweils die prozentuale Änderung bezogen auf den Ausgangswert.The results after 16 weeks are summarized in the following table for the treatment with fenofibrate or cerivastatin alone as well as with the combination. The percentage change in relation to the initial value is given in each case.
Cholesterin LDL- HDL- TriglycerideCholesterol LDL-HDL triglycerides
(gesamt) Cholesterin Cholesterin(total) cholesterol cholesterol
Cerivastatin 0,3 mg -20,7% -29,3% +6,5% -10,8%Cerivastatin 0.3 mg -20.7% -29.3% + 6.5% -10.8%
Fenofibrat 200mg -16,2% -21,8% +13,0% -32,2%Fenofibrate 200mg -16.2% -21.8% + 13.0% -32.2%
Cerivastatin 0,3 mg + -30,4% -41,3% +13,0% -38,7%Cerivastatin 0.3 mg + -30.4% -41.3% + 13.0% -38.7%
Fenofibrat 200 mg Fenofibrate 200 mg

Claims

Patentansprüche claims
1. Kombination von Cerivastatin mit einem Fibrat.1. Combination of cerivastatin with a fibrate.
2. Kombination gemäß Anspruch 1, dadurch gekennzeichnet, daß das Fibrat2. Combination according to claim 1, characterized in that the fibrate
Fenofibrat oder Bezafibrat ist.Fenofibrate or bezafibrate is.
3. Kombination gemäß Anspruch 1 von Cerivastatin mit Fenofibrat.3. Combination according to claim 1 of cerivastatin with fenofibrate.
4. Kombination gemäß einem der Ansprüche 1 bis 3, dadurch gekenzeichnet, daß sie außer Cerivastatin und dem Fibrat keine weiteren pharmazeutischen Wirkstoffe umfaßt.4. Combination according to one of claims 1 to 3, characterized in that it comprises no other pharmaceutical active substances apart from cerivastatin and the fibrate.
5. Kombination gemäß einem der Ansprüche 1 bis 4, dadurch gekennzeichnet, daß Cerivastatin in einer Menge von 0,025 mg bis 4 mg enthalten ist.5. Combination according to one of claims 1 to 4, characterized in that cerivastatin is contained in an amount of 0.025 mg to 4 mg.
6. Kombination gemäß einem der Ansprüche 1 bis 5, dadurch gekennzeichnet, daß das Fibrat in einer Menge von 2 mg bis 2000 mg enthalten ist.6. Combination according to one of claims 1 to 5, characterized in that the fibrate is contained in an amount of 2 mg to 2000 mg.
7. Verwendung der Kombinationen gemäß einem der Ansprüche 1 bis 6 zur7. Use of the combinations according to one of claims 1 to 6 for
Herstellung von Arzneimitteln zur Behandlung von KrankheitenManufacture of medicines for the treatment of diseases
8. Arzneimittel, enthaltend die Kombination gemäß einem der Ansprüche 1 bis 6.8. Medicament containing the combination according to one of claims 1 to 6.
9. Arzneimittel gemäß Anspruch 8, dadurch gekennzeichnet, daß es als fixe Kombination formuliert ist.9. Medicament according to claim 8, characterized in that it is formulated as a fixed combination.
10. Arzneimittel gemäß Anspruch 9, dadurch gekennzeichnet, daß das Fibrat, bevorzugt Fenofibrat, so formuliert ist, daß die Wirkung des Fibrats gesteuert eintritt. 10. Medicament according to claim 9, characterized in that the fibrate, preferably fenofibrate, is formulated such that the effect of the fibrate occurs in a controlled manner.
1. Verfahren zur Herstellung von Arzneimitteln gemäß Anspruch 8, dadurch gekennzeichnet, daß man die Wirkstoffe nach üblichen Verfahren mit geeigneten pharmazeutischen Hilfsstoffen mischt und die Mischung in eine geeignete Formulierung überführt. 1. A process for the preparation of medicaments according to claim 8, characterized in that the active ingredients are mixed by customary processes with suitable pharmaceutical auxiliaries and the mixture is converted into a suitable formulation.
EP99964522A 1998-12-18 1999-12-06 Combination of cerivastatin and fibrates Withdrawn EP1140082A1 (en)

Applications Claiming Priority (3)

Application Number Priority Date Filing Date Title
DE19858789A DE19858789A1 (en) 1998-12-18 1998-12-18 Medicament combination of cerivastatin and fibrate, has additive effect in the treatment of lipid metabolism disorders, e.g. dyslipidemia or atherosclerosis
DE19858789 1998-12-18
PCT/EP1999/009524 WO2000037078A1 (en) 1998-12-18 1999-12-06 Combination of cerivastatin and fibrates

Publications (1)

Publication Number Publication Date
EP1140082A1 true EP1140082A1 (en) 2001-10-10

Family

ID=7891784

Family Applications (1)

Application Number Title Priority Date Filing Date
EP99964522A Withdrawn EP1140082A1 (en) 1998-12-18 1999-12-06 Combination of cerivastatin and fibrates

Country Status (19)

Country Link
US (1) US6511985B1 (en)
EP (1) EP1140082A1 (en)
KR (1) KR20010093845A (en)
CN (1) CN1330544A (en)
AR (1) AR021643A1 (en)
AU (1) AU3035600A (en)
BR (1) BR9916270A (en)
CA (1) CA2355295A1 (en)
CO (1) CO5160272A1 (en)
DE (1) DE19858789A1 (en)
GT (1) GT199900214A (en)
HN (1) HN1999000208A (en)
IL (1) IL143221A0 (en)
PE (1) PE20001325A1 (en)
PL (1) PL349389A1 (en)
SV (1) SV1999000250A (en)
TR (1) TR200101722T2 (en)
WO (1) WO2000037078A1 (en)
ZA (1) ZA200103918B (en)

Families Citing this family (16)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP1322289B1 (en) 2000-09-20 2007-07-25 Jagotec AG Spray drying process of compositions containing fenofibrate
WO2002067901A1 (en) * 2001-02-22 2002-09-06 Skyepharma Canada Inc. Fibrate-statin combinations with reduced fed-fasted effects
WO2003013607A1 (en) * 2001-08-07 2003-02-20 Galephar M/F ORAL PHARMACEUTICAL COMPOSITION CONTAINING A COMBINATION OF FENOFIBRATE AND A HMG-CoA REDUCTASE INHIBITOR
WO2003013608A1 (en) 2001-08-07 2003-02-20 Galephar M/F ORAL PHARMACEUTICAL COMPOSITION CONTAINING A COMBINAITION OF PPARα AND A HMG-COA REDUCTASE INHIBITOR
DE10200138A1 (en) * 2002-01-04 2003-07-17 Karl Winkler Composition, useful for the treatment of the atherogenic lipid phenotype found in e.g. type II diabetics, comprises agonist of peroxisome proliferator-activated receptor and inducer of low density lipoprotein receptor
US7411045B2 (en) * 2002-11-19 2008-08-12 A&G Pharmaceutical, Inc. Autocrine growth factor receptor antibodies and methods
US7923467B2 (en) * 2003-05-30 2011-04-12 Ranbaxy Laboratories, Inc. Substituted pyrrole derivatives and their use as HMG-CO inhibitors
DE602004020649D1 (en) * 2003-11-07 2009-05-28 Jj Pharma Inc HDL REINFORCING COMBINATION THERAPY COMPLEXES
EP1853249A2 (en) * 2005-02-10 2007-11-14 LifeCycle Pharma A/S A stable pharmaceutical composition comprising a fixed dose combination of fenofibrate and an hmg-coa reductase inhibitor
WO2007054896A1 (en) * 2005-11-08 2007-05-18 Ranbaxy Laboratories Limited Process for (3r, 5r)-7-[2-(4-fluorophenyl)-5-isopropyl-3-phenyl-4- [(4-hydroxy methyl phenyl amino) carbonyl]-pyrrol-1-yl]-3, 5-dihydroxy-heptanoic acid hemi calcium salt
CL2007000667A1 (en) * 2006-03-14 2008-03-14 Ranbaxi Lab Ltd PHARMACEUTICAL COMPOSITION THAT INCLUDES ACID 7- [2- (4-FLUOROPHENYL) -5-ISOPROPIL-3-PHENYL-4 - [(4-HYDROXIMETHYLPHENAMINE) CARBONYL] PIRROL-1-IL] -3,5-DIHYDROXI-HEPTANOIC OR A SALT AND AT LEAST A STABILIZING AGENT; PREPARATION PROCEDURE, USEFUL IN E
US20070269503A1 (en) * 2006-05-16 2007-11-22 James Walter Burgess Combinations of HMG CoA reductase inhibitors and negatively charged phospholipids and uses thereof
CL2007002044A1 (en) * 2006-07-14 2008-06-13 Ranbaxy Lab Ltd CRYSTALLINE POLYMORPH OF HEMICALCIC ACID SALT (3R, 5R) -7- [2- (4-FLUOROPHENYL) -5-ISOPROPIL-3-PHENYL-4 - [(4-HYDROXIMETHYLPHENYLAMINE) CARBON]] -PIRROL-1-IL] -3,5-DIHYDROXIHEPTANOIC; PHARMACEUTICAL COMPOSITION; AND USE FOR THE TREATMENT OF DIABETES, ENF
EP2047851A4 (en) 2006-08-04 2009-09-23 Aska Pharm Co Ltd Drug formulation containing fibrate medicament and process for producing the same
TWI407955B (en) 2007-03-29 2013-09-11 Kowa Co A preventive and/or therapeutical agent of hyperlipemia
WO2023146320A1 (en) * 2022-01-28 2023-08-03 동광제약 주식회사 Capsule formulation containing rosuvastatin or pharmaceutically acceptable salt thereof and fenofibrate

Family Cites Families (7)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
FR2494112B1 (en) 1980-11-19 1986-01-10 Laruelle Claude
AU1422388A (en) 1987-01-27 1988-08-10 Warner-Lambert Company Lipid regulating compositions
FR2627696B1 (en) 1988-02-26 1991-09-13 Fournier Innovation Synergie NEW GALENIC FORM OF FENOFIBRATE
CA2039763A1 (en) * 1990-04-30 1991-10-31 Henry Y. Pan Combination of pravastatin and a fibric acid derivative, and method for treating dyslipidemia using such combination
US5177080A (en) * 1990-12-14 1993-01-05 Bayer Aktiengesellschaft Substituted pyridyl-dihydroxy-heptenoic acid and its salts
FR2737121B1 (en) 1995-07-27 1997-10-03 Cl Pharma NEW GALENIC FORMULATIONS OF FENOFIBRATE AND THEIR APPLICATIONS
DK1017390T3 (en) * 1997-07-31 2007-06-11 Kos Life Sciences Inc Coated tablet comprising nicotinic acid or a compound metabolized to nicotinic acid in a sustained-release form and an HMG-CoA reductase inhibitor in an immediate-release form

Non-Patent Citations (1)

* Cited by examiner, † Cited by third party
Title
See references of WO0037078A1 *

Also Published As

Publication number Publication date
PE20001325A1 (en) 2000-12-30
TR200101722T2 (en) 2001-11-21
PL349389A1 (en) 2002-07-15
KR20010093845A (en) 2001-10-29
ZA200103918B (en) 2002-05-15
AU3035600A (en) 2000-07-12
DE19858789A1 (en) 2000-06-21
US6511985B1 (en) 2003-01-28
HN1999000208A (en) 2000-11-22
BR9916270A (en) 2001-09-04
SV1999000250A (en) 2000-10-16
GT199900214A (en) 2001-06-08
CO5160272A1 (en) 2002-05-30
IL143221A0 (en) 2002-04-21
CN1330544A (en) 2002-01-09
WO2000037078A1 (en) 2000-06-29
AR021643A1 (en) 2002-07-31
CA2355295A1 (en) 2000-06-29

Similar Documents

Publication Publication Date Title
DE69720985T3 (en) ADMINISTRATION OF NICOTIN IN THICK DARM FOR THE TREATMENT OF INFLAMMATORY INFUSION DISEASE
DE69829097T2 (en) Cholesterol lowering composition containing coenzyme Q.
EP1140082A1 (en) Combination of cerivastatin and fibrates
EP1509207B1 (en) Pharmaceutical composition containing oxcarbazepine and having a controlled active substance release
DE69929703T2 (en) NEW ORAL FORMULATIONS FOR 5-HT4 AGONISTS OR ANTAGONISTS
AT400521B (en) METHOD FOR PRODUCING A SOLID ORAL PHARMACEUTICAL KETOTIFIC COMPOSITION
US3978216A (en) Method for treating schizophrenia and method and composition for potentiating neuroleptic drugs
US4138484A (en) Method for treating schizophrenia and method and composition for potentiating neuroleptic drugs
US4129652A (en) Method for potentiating neuroleptic drugs
US4084000A (en) Method of treating schizophrenia
DE2950154C2 (en)
EP1513533A2 (en) Pharmaceutical active substance combination and the use thereof
EP1001756B1 (en) Synergistically acting compositions for selectively combating tumor tissue
DE60125062T2 (en) Quetiapine for the treatment of dyskinesia in non-psychotic patients
EP1196194A2 (en) COMBINATION OF MTP INHIBITORS AND HMG-CoA REDUCTASE INHIBITORS AND THE USE THEREOF IN MEDICAMENTS
WO2004080488A2 (en) Combined preparations of acetyl salicylic acid with an hmg-coa reductase inhibitor
WO2001000184A2 (en) Combination of mtp inhibitors and lipid reducers and the use thereof in medicaments
DE3040042A1 (en) PHARMACEUTICAL PREPARATION OF TIARAMID OR ITS PHARMACEUTICAL TOLERABLE SALTS
DE4140172A1 (en) RETARD FORM FOR A MEDICINAL PRODUCT CONTAINING AN IBUPROFEN AND ITS PRODUCTION
EP0315197A1 (en) Medicinal form for oral application for the once-a-day treatment of hypertension by diltiazem hydrochloride
EP1225889A2 (en) Medicament combinations of nifedipine and cerivastatin
WO2001089525A1 (en) Combination of cerivastatin with ace inhibitors and the use thereof in medicaments
EP1638576A1 (en) Combination of acetylsalicylic acid and alpha-glucosidase inhibitors
EP0291751B1 (en) Pharmaceutical mixture preparation
MXPA01006136A (en) Combination of cerivastatin and fibrates

Legal Events

Date Code Title Description
PUAI Public reference made under article 153(3) epc to a published international application that has entered the european phase

Free format text: ORIGINAL CODE: 0009012

17P Request for examination filed

Effective date: 20010718

AK Designated contracting states

Kind code of ref document: A1

Designated state(s): AT BE CH CY DE DK ES FI FR GB GR IE IT LI LU MC NL PT SE

AX Request for extension of the european patent

Free format text: AL;LT;LV;MK;RO;SI

17Q First examination report despatched

Effective date: 20030718

RAP1 Party data changed (applicant data changed or rights of an application transferred)

Owner name: BAYER HEALTHCARE AG

STAA Information on the status of an ep patent application or granted ep patent

Free format text: STATUS: THE APPLICATION IS DEEMED TO BE WITHDRAWN

18D Application deemed to be withdrawn

Effective date: 20031201