WO1995028919A1 - MEDICAMENT CONTENANT UN DERIVE D'ACIDE p-OXYBENZOIQUE ET UN FIBRATE - Google Patents

MEDICAMENT CONTENANT UN DERIVE D'ACIDE p-OXYBENZOIQUE ET UN FIBRATE Download PDF

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Publication number
WO1995028919A1
WO1995028919A1 PCT/EP1995/001565 EP9501565W WO9528919A1 WO 1995028919 A1 WO1995028919 A1 WO 1995028919A1 EP 9501565 W EP9501565 W EP 9501565W WO 9528919 A1 WO9528919 A1 WO 9528919A1
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WO
WIPO (PCT)
Prior art keywords
fibrate
oxybenzoic acid
acid derivative
cooh
medicament
Prior art date
Application number
PCT/EP1995/001565
Other languages
German (de)
English (en)
Inventor
Matthias Heil
Michael Schliack
Klaus Seibel
Original Assignee
Klinge Pharma Gmbh
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 Klinge Pharma Gmbh filed Critical Klinge Pharma Gmbh
Priority to AU35562/95A priority Critical patent/AU3556295A/en
Publication of WO1995028919A1 publication Critical patent/WO1995028919A1/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
    • A61K31/21—Esters, e.g. nitroglycerine, selenocyanates
    • A61K31/215—Esters, e.g. nitroglycerine, selenocyanates of carboxylic acids
    • A61K31/235—Esters, e.g. nitroglycerine, selenocyanates of carboxylic acids having an aromatic ring attached to a carboxyl group

Definitions

  • the invention relates to preparations for the therapy of combined hyperlipidemia and in particular combination preparations containing a p-oxybenzoic acid derivative, such as lifibrol (4- (4'-tert.-butylphenyl) -1- (4'-carboxyphenoxy) -2-butanol). and a fibrate.
  • a p-oxybenzoic acid derivative such as lifibrol (4- (4'-tert.-butylphenyl) -1- (4'-carboxyphenoxy) -2-butanol).
  • Atherosclerosis and heart attacks are among the leading causes of death.
  • the main risk factors here are high concentrations of serum cholesterol, high concentrations of LDL cholesterol (low density lipoprotein cholesterol), high concentrations of LP.a) (lipoprotein (a)), and low concentrations of HDL cholesterol (high density lipoprotein cholesterol) ), high concentrations of triglycerides in the serum, increased concentrations of fibrinogen in the serum as well as increased blood pressure and smoking.
  • HMG-CoA reductase inhibitors such as lovastatin, pravastatin, simvastatin and other statins, reduce the concentrations of total cholesterol and LDL cholesterol in the serum, but they only reduce the concentration of triglycerides in the serum to a small extent (cf. H. Vanhanen and TA Wunschn, Euro. J. Clin. Pharmacol., Vol. 42 (1992), pp. 127-130).
  • Substances from the class of fibrates primarily reduce the triglycerides and increase the HDL concentration, but have only a minor influence on the serum cholesterol (cf. P. Zimetbaum et al., J. Clin. Pharmacol. , Vol. 31 (1991), pp. 25-37).
  • the concentration of LP (a) remains unaffected by both classes of substances.
  • Certain p-oxybenzoic acid derivatives are known from EP-A-0 133 935 as lipid-lowering agents.
  • An example of these compounds is Lifibrol, which primarily lowers LDL cholesterol, triglycerides and LP (a) (P. Schwandt, 62nd EAS Congress, Jerusalem, September 5-9, 1993).
  • the present invention is intended to provide a means that, if possible
  • Another object is to provide a method for producing a drug with the above-mentioned properties.
  • a medicament is provided according to the invention which is a combination of a p-oxybenzoic acid derivative of the general formula
  • X -CH (OH) -,.-C0-
  • R 2 -OH, -NHCH 2 COOH, or a physiologically tolerable salt thereof and a fibrate and conventional carriers, auxiliaries and / or additives.
  • R 1 preferably has the meaning -CH (CH 3 ) 2 , -C (CH 3 ) 3 , or -C (CH 3 ) 2 CH 2 OH or -C (CH 3 ) 2 -COOH.
  • the p-oxybenzoic acid derivative is lifibrol (4- (4'-tert.-butylphenyl) -1- (4'-carboxyphenoxy) -2-butanol).
  • p-Oxybenzoic acid derivatives such as Lifibrol
  • Lifibrol have a complex mechanism of action that has not been fully elucidated.
  • the effect of such expresses itself Substances in an inhibition of cholesterol biosynthesis and an inhibition of cholesterol absorption.
  • fibrates are understood to mean all substances belonging to the group of substances having a hypotriglyceridemic effect. Without being bound by theory, it is believed that fibrates increase the activity of lipoprotein lipase and therefore, above all, reduce triglycerides. A reduction in LDL cholesterol has also been observed in some fibrates.
  • the fibrate is preferably selected from bezafibrate, clofibrate, ciprofibrate, gemfibrozil and fenofibrate.
  • the combined therapy with substances from the series of fibrates (these are all substances belonging to the group of hypotriglyceridemic substances, such as bezafibrate, clofibrate, ciprofibrate, gemfibrozil, fenofibrate etc.) and substances from the class of p-oxybenzoic urederivate, such as Lifibrol, as well as Lifibrol metabolites, result in a completely new activity profile for the treatment of the multifactorial disease of arteriosclerosis.
  • substances from the series of fibrates (these are all substances belonging to the group of hypotriglyceridemic substances, such as bezafibrate, clofibrate, ciprofibrate, gemfibrozil, fenofibrate etc.) and substances from the class of p-oxybenzoic urederivate, such as Lifibrol, as well as Lifibrol metabolites, result in a completely new activity profile for the treatment of the multifactorial disease of arteriosclerosis.
  • the exact dosage of the active ingredients depends on the age, body weight and condition of the patient. In particular, it depends on the desired degree of reduction in the concentration of LDL cholesterol in the serum. Accordingly, the dosage can be set individually for a patient by the doctor.
  • the range of doses for the Lifibrol derived from the clinical studies is between 100 and 400 mg per day.
  • the application range of the fibrates is the recommended base dose.
  • the preparations according to the invention can be administered in any manner for therapeutic use as a medicament in the case of combined hyperlipidemia; however, they are preferably administered orally. Administration can be in one or more divided doses per day. Both active ingredients can be combined in one preparation or administered in separate preparations. A capsule or tablet is preferred as the galenic form. For this, the active ingredients' with conventional carriers, adjuvants and / or additives can be mixed. Common excipients such as lactose, sucrose, man are suitable as pharmaceutical carriers. ., Potato or corn starch, cellulose derivatives or gelatin, optionally with the addition of lubricants, such as magnesium or calcium stearate, and polyethylene glycols.
  • Preferred forms of administration are push-fit capsules made of hard gelatin and closed soft gelatin capsules.
  • the pure active ingredient possibly with a small addition of lubricants, may be present in push-fit capsules.
  • processing into granules is possible, potato or corn starch, microcrystalline cellulose, cellulose derivatives, gelatin or highly disperse silicas also being used as auxiliaries.
  • the pure active ingredient When packaged in soft gelatin capsules, the pure active ingredient is dissolved or suspended in suitable liquids, e.g. in liquid polyethylene glycols or vegetable oils.
  • R 1 H or a straight-chain or branched Cl-C4-alkyl group, in particular -CH (CH3) 2 and -C (CH3) 3, or -C (CH 3 ) 2CH 2 OH, or -C (CH 3 ) 2 - COOH.
  • n 1, 2

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  • Health & Medical Sciences (AREA)
  • Emergency Medicine (AREA)
  • Chemical & Material Sciences (AREA)
  • Medicinal Chemistry (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Epidemiology (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Animal Behavior & Ethology (AREA)
  • General Health & Medical Sciences (AREA)
  • Public Health (AREA)
  • Veterinary Medicine (AREA)
  • Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)

Abstract

L'invention concerne un médicament contenant une combinaison d'un dérivé d'acide p-oxybenzoïque de la formule générale (I), dans laquelle R1 représente hydrogène ou un groupe alkyle à chaîne droite ou ramifiée C1-C4, n vaut 1 ou 2, X représente -CH(OH)-, -CO-, et R2 représente -OH, -NHCH¿2?COOH, ou d'un sel physiologiquement compatible de ce dérivé, et d'un fibrate, ainsi des excipients, des substances auxiliaires et/ou des additifs usuels. Une préparation de ce type convient au traitement de l'hyperlipidémie combinée. L'invention concerne en outre un procédé permettant de produire le médicament décrit.
PCT/EP1995/001565 1994-04-26 1995-04-25 MEDICAMENT CONTENANT UN DERIVE D'ACIDE p-OXYBENZOIQUE ET UN FIBRATE WO1995028919A1 (fr)

Priority Applications (1)

Application Number Priority Date Filing Date Title
AU35562/95A AU3556295A (en) 1994-04-26 1995-04-25 Medicament containing p-oxybenzoic acid derivative and fibrate

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
DE4414538A DE4414538A1 (de) 1994-04-26 1994-04-26 Präparate zur Therapie der kombinierten Hyperlipidämie mit einem Gehalt an einem p-Oxybenzoesäurederivat und einem Fibrat
DEP4414538.1 1994-04-26

Publications (1)

Publication Number Publication Date
WO1995028919A1 true WO1995028919A1 (fr) 1995-11-02

Family

ID=6516473

Family Applications (1)

Application Number Title Priority Date Filing Date
PCT/EP1995/001565 WO1995028919A1 (fr) 1994-04-26 1995-04-25 MEDICAMENT CONTENANT UN DERIVE D'ACIDE p-OXYBENZOIQUE ET UN FIBRATE

Country Status (5)

Country Link
AU (1) AU3556295A (fr)
DE (1) DE4414538A1 (fr)
EE (1) EE9400266A (fr)
WO (1) WO1995028919A1 (fr)
ZA (1) ZA953416B (fr)

Citations (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP0133935A2 (fr) * 1983-07-20 1985-03-13 Klinge Pharma GmbH Dérivés d'acides p-oxybenzoiques, procédés pour leur préparation et leur utilisation pour la préparation de médicaments ayant une activité hypolipémique

Patent Citations (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP0133935A2 (fr) * 1983-07-20 1985-03-13 Klinge Pharma GmbH Dérivés d'acides p-oxybenzoiques, procédés pour leur préparation et leur utilisation pour la préparation de médicaments ayant une activité hypolipémique

Non-Patent Citations (2)

* Cited by examiner, † Cited by third party
Title
DINH, D.M. ET AL: "Lifibrol increases hepatic cholesterol 7Ó-hydroxylase activity in Sprague-Dawley rats", DRUG DEVELOPMENT RESEARCH, vol. 33, pages 439 - 447 *
ILLINGWORTH, D.R. ET AL: "The hypolipidemic effects of lovastatin and clofibrate alone and in combination in patients with type III hyperlipoproteinemia", METABOLISM, vol. 39, no. 4, pages 403 - 409 *

Also Published As

Publication number Publication date
DE4414538A1 (de) 1995-11-02
EE9400266A (et) 1996-02-15
AU3556295A (en) 1995-11-16
ZA953416B (en) 1996-01-11

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