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WO1992019270A1 - Novel combination of medicaments - Google Patents

Novel combination of medicaments Download PDF

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Publication number
WO1992019270A1
WO1992019270A1 PCT/EP1992/000908 EP9200908W WO9219270A1 WO 1992019270 A1 WO1992019270 A1 WO 1992019270A1 EP 9200908 W EP9200908 W EP 9200908W WO 9219270 A1 WO9219270 A1 WO 9219270A1
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WO
WIPO (PCT)
Prior art keywords
calcium
acid
antagonist
serotonin
txä2
Prior art date
Application number
PCT/EP1992/000908
Other languages
German (de)
French (fr)
Inventor
Aktiengesellschaft Basf
Original Assignee
Kirchengast, Michael
Ruebsamen, Klaus
Schmied, Bernhard
Seitz, Werner
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 Kirchengast, Michael, Ruebsamen, Klaus, Schmied, Bernhard, Seitz, Werner filed Critical Kirchengast, Michael
Publication of WO1992019270A1 publication Critical patent/WO1992019270A1/en

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    • 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
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/275—Nitriles; Isonitriles

Definitions

  • the present invention describes a new pharmaceutical combination for the prophylaxis and treatment of coronary heart disease and arterial occlusive disease
  • Calciu antagonists are an integral part of advanced therapy for coronary artery disease and myocardial infarction (Manual of Internal Medicine Volume IX / 3: Coronary Diseases Chapter 33, Springer Verlag 1984; Spektrum Koronartherapeutika, Aesopus Verlag, Switzerland, 1985).
  • the therapeutic effect of calcium antagonists is primarily based on a vasodilatory effect, caused by inhibition of the
  • the cause of vascular contraction is primarily the vasoactive substances serotonin and thromboxane-A2, which are released as a result of platelet activation in the area of a pathologically altered blood vessel.
  • This process is pathophysiologically relevant due to its cascade-like course, because even the smallest amounts of thromboxane-A2 are sufficient to activate platelets.
  • this pathophysiological process can be simulated by a mechanically induced locally limited lesion on an arterial blood vessel in connection with a defined stenosis (Circulation 54, 365 (1976).
  • Carculation 54, 365 (1976) a mechanically induced locally limited lesion on an arterial blood vessel in connection with a defined stenosis.
  • this model it could be shown that both calcium antagonists alone and a combination, Consisting of serotonin and TX ⁇ 2 receptor antagonists which reduce cyclic blood flow changes as a result of the thrombocyte adhesion and. -rAggregation and especially completely prevent them in high doses
  • the invention relates to medicaments which contain a calcium / serotonin antagonist and a thromboxane A2 receptor antagonist.
  • the medicaments can be in the form of combination preparations for simultaneous use in a fixed combination or separately for simultaneous or staggered use.
  • Calcium / serotonin receptor antagonists are substances that act simultaneously as calcium and serotonin receptor antagonists. Such substances can easily be found in a screening system in which the substances are first tested for calcium-antagonistic and then for serotonin-antagonistic effects.
  • Calcium serotonin receptor antagonists are gallopamil (Merck Index, 11th edition, No. 4257), Verapamil (Merck Index, 11th edition, No. 9851) l [4- [3- [4- [bis (4th -fluorophenyl) hydroxymethyl] -l-piperidinyl] propoxy] phenyl] -2-methyl-lp ropanone (J. Med. Chem. 3_2, 105 (1989)) and especially the substances mentioned in EP-OS 345 572 , preferably that
  • thromboxane A2 receptor antagonists examples include Daltroban (Merck Index 11th edition, No. 2807), Sulotroban (Clin. Pharm. Therapeutics 39 (1986) 145), (3R) -3 (4-fluorophenylsulfonamido) -l , 2,3,4-tetrahydro-9-carbazolpropanoic acid (Bay U 3405, Arzneistoff-Forsch.
  • Both the calcium / serotonin receptor antagonists and the TXA2 receptor antagonists can contain acidic or basic groups. If so, they can be present in the drug in the form of salts.
  • physiologically tolerated acids such as hydrochloric acid, sulfuric acid, phosphoric acid, acetic acid, citric acid, malonic acid, salicylic acid, maleic acid, fumaric acid, succinic acid, ascorbic acid, malic acid, methanesulfonic acid, lactic acid, gluconic acid, glucuronic acid, amimosulfonic acid or benzoic acid or tartaric acid physiologically compatible bases such as the hydroxides and hydrogen carbonates of aluminum, calcium, potassium, sodium, lithium, magnesium, diethanolamine, ethylenediamine or meglumine are possible.
  • Calcium / serotonin antagonist and TXA2 receptor antagonist are present in the mixture in amounts which are a factor of 2 to 5 below the lower limit of the individual doses.
  • the ratio of the amounts of TX ⁇ 2 receptor antagonist to calcium serotonin antagonist is in the range from 10: 1 to 1:10.
  • this ratio is preferably 5: 1 to 1: 5.
  • the new drug combination improves the thrombosis-inhibiting and antivasospastic properties compared to the individual components of the combination in unexpected, super-additive strength.
  • the combination can drastically reduce the dose of the individual components and thus the intensity and frequency of undesirable side effects. It is therefore suitable for the therapy and prophylaxis of symptoms which are caused by disorders of the myocardial blood flow in coronary heart disease, i.e. all
  • angina pectoris for the treatment of myocardial infarction, for use before and after balloon dilatation and bypass surgery, and as concomitant medication during and after thrombolytic therapy.
  • the products according to the invention can be administered parenterally, but preferably orally. Tablets, coated tablets and capsules are particularly suitable for oral administration. Retard forms are particularly suitable.
  • the known processes are suitable for the production of the forms mentioned, as described, for example, in H. Sucker et al., Pharmaceutical Technology, Thie e-Verlag, Stuttgart 1978. It is also possible to process the individual components of the mixture into application forms and to package them together, for example in a blister pack.
  • Tablets of the following composition are pressed in a conventional manner on a tablet press:
  • the core mass consists of 9 parts of corn starch, 3 parts of milk sugar and 1 part of Luviskol® VA 64 (vinyl pyrrolidone-vinyl acetite copolymer 60:40, see Pharm. Ind. 1962, 586).
  • the film coating layer consists of

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  • Health & Medical Sciences (AREA)
  • Animal Behavior & Ethology (AREA)
  • Medicinal Chemistry (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Epidemiology (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Chemical & Material Sciences (AREA)
  • General Health & Medical Sciences (AREA)
  • Public Health (AREA)
  • Veterinary Medicine (AREA)
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  • Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)
  • Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)

Abstract

Il est décrit des combinaisons de médicaments renfermant des antagonistes du calcium et de la sérotonine et des antagonistes des récepteurs du thromboxane A2, utilisées pour combattre des maladies.Drug combinations containing antagonists of calcium and serotonin and antagonists of thromboxane A2 receptors are used which are used to combat diseases.

Description

Neue ArzneimittelkombinationNew drug combination
Beschreibungdescription
Die vorliegende Erfindung beschreibt eine neue Arzneimittel¬ kombination zur Prophylaxe und Behandlung von koronarer Herz¬ krankheit und arterieller VerschlußkrankheitThe present invention describes a new pharmaceutical combination for the prophylaxis and treatment of coronary heart disease and arterial occlusive disease
Calciu antagonisten sind ein wesentlicher Bestandteil fortschrittlicher Therapie der koronaren Herzkrankheit und des Myokardinfarktes (Handbuch der Inneren Medizin Band IX/3: Koronarerkrankungen Kapitel 33, Springer Verlag 1984; Spektrum Koronartherapeutika, Aesopus Verlag, Zug, 1985). Die therapeutische Wirkung der Calciumantagonisten beruht primär auf einer gefäßerweiternden Wirkung, bedingt durch Hemmung desCalciu antagonists are an integral part of advanced therapy for coronary artery disease and myocardial infarction (Manual of Internal Medicine Volume IX / 3: Coronary Diseases Chapter 33, Springer Verlag 1984; Spektrum Koronartherapeutika, Aesopus Verlag, Zug, 1985). The therapeutic effect of calcium antagonists is primarily based on a vasodilatory effect, caused by inhibition of the
Calcium-Einstroms. Ursache der Gefäßkontraktion, insbesondere bei der koronaren Herzkrankheit, sind primär die vasoaktiven Substanzen Serotonin und Thromboxan-A2, die als Folge einer Thrombozytenaktivierung im Bereich eines pathologisch veränderten Blutgefäßes freigesetzt werden. Pathophysiologisch relevant ist dieser Prozeß durch seinen kaskadenartigen Verlauf, denn bereits geringste Mengen Thromboxan-A2 reichen zur Aktivierung von Thrombozyten aus. Diese wiederum setzen Serotonin und TXA2 in erheblicher Menge frei, wobei dieser Vorgang im Endstadium durch die gleichzeitige Aktivierung der Gerinnungskaskade zum stabilen thro botisehen Gefäßverschluß führen kann. Im Tierexperiment kann dieser pathophysiologische Prozeß durch eine mechanisch induziert lokal begrenzte Läsion an einem arteriellen Blutgefäß in Verbindung mit einer definierten Stenose simuliert werden (Circulation 54, 365 (1976). In diesem Modell konnte gezeigt werden, daß sowohl Calciumantagonisten allein als auch eine Kombination, bestehend aus Serotonin- und TXÄ2-Rezep- tor-Antagonisten die als Folge der Thro bozytenadhäsion und .-rAggregation entstehenden zyklischen Blutflußveränderungen reduzieren und besonders in hohen Dosen ganz verhindernCalcium influx. The cause of vascular contraction, especially in coronary artery disease, is primarily the vasoactive substances serotonin and thromboxane-A2, which are released as a result of platelet activation in the area of a pathologically altered blood vessel. This process is pathophysiologically relevant due to its cascade-like course, because even the smallest amounts of thromboxane-A2 are sufficient to activate platelets. These, in turn, release serotonin and TXA2 in considerable quantities, whereby this process in the final stage can lead to a stable thrombotic vascular occlusion due to the simultaneous activation of the coagulation cascade. In animal experiments, this pathophysiological process can be simulated by a mechanically induced locally limited lesion on an arterial blood vessel in connection with a defined stenosis (Circulation 54, 365 (1976). In this model it could be shown that both calcium antagonists alone and a combination, Consisting of serotonin and TXÄ2 receptor antagonists which reduce cyclic blood flow changes as a result of the thrombocyte adhesion and. -rAggregation and especially completely prevent them in high doses
(Circulation 78, 701 (1988), Circulation 79, 911 (1989), J. Phar acol. Exper. Ther. 244, 1164 (1988). Es wurde nun gefunden, daß sich durch Kombination der drei Wirk¬ prinzipien in Form eines Calcium-/Serotonin-Antagonisten mit einem TXA2-Rezeptorantagonisten eine Potenzierung der Wirkungen der Einzelsubstanzen erzielen läßt, die durch Addition der Einzeleffekte nicht zu erklären ist.(Circulation 78, 701 (1988), Circulation 79, 911 (1989), J. Phar acol. Exper. Ther. 244, 1164 (1988). It has now been found that by combining the three active principles in the form of a calcium / serotonin antagonist with a TXA2 receptor antagonist, the effects of the individual substances can be potentiated, which cannot be explained by adding the individual effects.
Gegenstand der Erfindung sind Arzneimittel, die einen Calcium-/Serotonin-Antagonisten und einen Thromboxan-A2-Rezeptor- antagonisten enthalten.The invention relates to medicaments which contain a calcium / serotonin antagonist and a thromboxane A2 receptor antagonist.
Die Arzneimittel können als Kombinationspräparate zur gleich¬ zeitigen Anwendung in fixer Kombination oder getrennt zur gleich¬ zeitigen oder zeitlich abgestuften Anwendung vorliegen.The medicaments can be in the form of combination preparations for simultaneous use in a fixed combination or separately for simultaneous or staggered use.
Calcium-/Serotonin-Rezeptorantagonisten sind solche Substanzen, die gleichzeitig als Calcium- und Serotonin-Rezeptorantagonisten wirken. Solche Substanzen lassen sich leicht in einem Screening- Syste finden, in dem die Substanzen zuerst auf calciumanta- gonistische und anschließend auf serotoninantagonistische Wirkung geprüft werden. Als Calcium-Serotonin-Rezeptorantagonisten sind Gallopamil (Merck-Index, 11. Auflage, Nr. 4257), Verapamil (Merck-Index, 11. Auflage, Nr. 9851) l[4-[3-[4-[Bis(4-fluor- phenyl)-hydroxymethyl]-l-piperidinyl]propoxy]phenyl]-2-methyl-l-p ropanon (J. Med. Chem. 3_2, 105 (1989)) und besonders die in der EP-OS 345 572 genannten Substanzen, vorzugsweise dasCalcium / serotonin receptor antagonists are substances that act simultaneously as calcium and serotonin receptor antagonists. Such substances can easily be found in a screening system in which the substances are first tested for calcium-antagonistic and then for serotonin-antagonistic effects. Calcium serotonin receptor antagonists are gallopamil (Merck Index, 11th edition, No. 4257), Verapamil (Merck Index, 11th edition, No. 9851) l [4- [3- [4- [bis (4th -fluorophenyl) hydroxymethyl] -l-piperidinyl] propoxy] phenyl] -2-methyl-lp ropanone (J. Med. Chem. 3_2, 105 (1989)) and especially the substances mentioned in EP-OS 345 572 , preferably that
(2S)-5-Hexylmethylamino-2-isopropyl-2-(3,4,5-trimethoxyphenyl)- valeronitril (= A) zu nennen.(2S) -5-Hexylmethylamino-2-isopropyl-2- (3,4,5-trimethoxyphenyl) valeronitrile (= A).
Als Thromboxan-A2-Rezeptorantagonisten kommen beispielsweise Daltroban (Merck-Index 11. Auflage, Nr. 2807), Sulotroban (Clin. Pharm. Therapeutics 39 (1986) 145), (3R)-3(4-Fluorophenylsulfon- amido)-l,2,3,4-tetrahydro-9-carbazolpropansäure (Bay U 3405, Arzneim-Forsch. (1989) 1519), [lR-[lα(Z),2ß,3ß,
Figure imgf000004_0001
CClrl'BiphenyU-^-yll-methoxyll-S-h ydroxy-2-(l-piperidinyl)- cyclopentyl]-4-heptansäure (GR 32191, Thrombosis and Haemastasis, 61 (1989) 429), [(lα(Z),2ß,5α]-7-J5-[[(1, r-Biphenyl)-4yl-] meth- oxy]-2-(4-morpholinyl)-3-oxocyclopentyl]-4-heptansäure), (AH 23848, Circulation 72 (1985) 1208), [lß,2α(5Z),3α(lE)4ß]-7- [3-(3-cyclohexyl-3-hydroxy-l-propenyl)-7-oxabicyclo[2.2.1]- hept-2-yl]-5-heptensäure (SQ 29548, 0. Pharm. exp. Therapeutics 234 (1985), 435), insbesondere aber die in der EP-OS 271 013 genannten Verbindungen, vorzugsweise die R(-)-4-[l-Methoxy- 2-(4-chlorphenylsulfonamido)ethyl]-phenylessigsäure (= B) in Betracht.Examples of thromboxane A2 receptor antagonists are Daltroban (Merck Index 11th edition, No. 2807), Sulotroban (Clin. Pharm. Therapeutics 39 (1986) 145), (3R) -3 (4-fluorophenylsulfonamido) -l , 2,3,4-tetrahydro-9-carbazolpropanoic acid (Bay U 3405, Arzneimittel-Forsch. (1989) 1519), [lR- [lα (Z), 2ß, 3ß,
Figure imgf000004_0001
CClrl'BiphenyU - ^ - yll-methoxyll-Sh ydroxy-2- (l-piperidinyl) - cyclopentyl] -4-heptanoic acid (GR 32191, Thrombosis and Haemastasis, 61 (1989) 429), [(lα (Z), 2ß , 5α] -7-J5 - [[(1, r-biphenyl) -4yl-] methoxy] -2- (4-morpholinyl) -3-oxocyclopentyl] -4-heptanoic acid), (AH 23848, Circulation 72 (1985) 1208), [lß, 2α (5Z), 3α (lE) 4ß] -7- [3- (3-cyclohexyl-3-hydroxy-l-propenyl) -7-oxabicyclo [2.2.1] - hept -2-yl] -5-heptenoic acid (SQ 29548, 0. Pharm. Exp. Therapeutics 234 (1985), 435), but especially the compounds mentioned in EP-OS 271 013, preferably the R (-) - 4- [l-methoxy-2- (4-chlorophenylsulfonamido) ethyl] phenylacetic acid (= B) into consideration.
Sowohl die Calcium-/Serotonin-Rezeptorantagonisten als auch die TXA2-Rezeptorantagonisten können saure oder basische Gruppen enthalten, ist das der Fall, können sie in Form von Salzen in dem Arzneimittel vorliegen. Zur Salzbildung kommen physiologisch verträgliche Säuren wie Salzsäure, Schwefelsäure, Phosphorsäure, Essigsäure, Zitronensäure, Malonsäure, Salicylsäure, Maleinsäure, Fumarsäure, Bernsteinsäure, Ascorbinsäure, Äpfelsäure, Methan- sulfonsäure, Milchsäure, Gluconsäure, Glucuronsäure, Amimdo- sulfonsäure, Benzoesäure oder Weinsäure oder aber physiologisch verträgliche Basen wie die Hydroxide und Hydrogencarbonate von Aluminium, Calcium, Kalium, Natrium, Lithium, Magnesium, Di- ethanolamin, Ethylendiamin oder Meglumin in Frage.Both the calcium / serotonin receptor antagonists and the TXA2 receptor antagonists can contain acidic or basic groups. If so, they can be present in the drug in the form of salts. For the formation of salt there are physiologically tolerated acids such as hydrochloric acid, sulfuric acid, phosphoric acid, acetic acid, citric acid, malonic acid, salicylic acid, maleic acid, fumaric acid, succinic acid, ascorbic acid, malic acid, methanesulfonic acid, lactic acid, gluconic acid, glucuronic acid, amimosulfonic acid or benzoic acid or tartaric acid physiologically compatible bases such as the hydroxides and hydrogen carbonates of aluminum, calcium, potassium, sodium, lithium, magnesium, diethanolamine, ethylenediamine or meglumine are possible.
Calcium-/Serotonin-Antagonist und TXA2-Rezeptorantagonist liegen in der Mischung in Mengen vor, die um den Faktor 2 bis 5 unter der unteren Grenze der Einzeldosierungen liegen. In der Regel liegt das Verhältnis der Mengen TXÄ2-Rezeptorantagonist zu Calcium-Serotonin-Antagonist im Bereich von 10:1 bis 1:10. Für eine Kombination aus A und B liegt dieses Verhältnis vorzugsweise bei 5:1 bis 1:5.Calcium / serotonin antagonist and TXA2 receptor antagonist are present in the mixture in amounts which are a factor of 2 to 5 below the lower limit of the individual doses. As a rule, the ratio of the amounts of TXÄ2 receptor antagonist to calcium serotonin antagonist is in the range from 10: 1 to 1:10. For a combination of A and B, this ratio is preferably 5: 1 to 1: 5.
Die neue Arzneimittelkombination verbessert die thrombose¬ hemmenden und antivasospastischen Eigenschaften im Vergleich zu den Einzelbestandteilen der Kombination in unerwarteter, über- additiver Stärke. Insbesondere kann durch die Kombination die Dosis der Einzelbestandteile und somit die Intensität und Häufigkeit unerwünschter Nebenwirkungen drastisch vermindert werden. Sie eignet sich daher zur Therapie und Prophylaxe von Symptomen, die durch Störungen der Myokarddurchblutung bei koronarer Herzerkrankung bedingt sind, d.h. allerThe new drug combination improves the thrombosis-inhibiting and antivasospastic properties compared to the individual components of the combination in unexpected, super-additive strength. In particular, the combination can drastically reduce the dose of the individual components and thus the intensity and frequency of undesirable side effects. It is therefore suitable for the therapy and prophylaxis of symptoms which are caused by disorders of the myocardial blood flow in coronary heart disease, i.e. all
Angina-pectoris-Formen, zur Nachbehandlung des Herzinfarktes, zur Anwendung vor und nach Ballondilatation und Bypass-Operationen, sowie als Begleitmedikation während und nach thrombolytischer Therapie. Die erfindungsgemäßen Erzeugnisse können parenteral, vorzugsweise aber oral verabfolgt werden. Zur oralen Applikation eignen sich insbesondere Tabletten, Dragees und Kapseln. Besonders geeignet sind Retardformen. Für die Herstellung der genannten Formen eignen sich die bekannten Verfahren, wie sie beispielsweise in H. Sucker et al., Pharmazeutische Technologie, Thie e-Verlag, Stuttgart 1978, beschrieben sind. Es ist auch möglich, die Einzelbestandteile der Mischung zu Applikationsformen zu verarbeiten und diese zusammen zu verpacken, beispielsweise in einer Durchdrückpackung.Forms of angina pectoris, for the treatment of myocardial infarction, for use before and after balloon dilatation and bypass surgery, and as concomitant medication during and after thrombolytic therapy. The products according to the invention can be administered parenterally, but preferably orally. Tablets, coated tablets and capsules are particularly suitable for oral administration. Retard forms are particularly suitable. The known processes are suitable for the production of the forms mentioned, as described, for example, in H. Sucker et al., Pharmaceutical Technology, Thie e-Verlag, Stuttgart 1978. It is also possible to process the individual components of the mixture into application forms and to package them together, for example in a blister pack.
Beispiel 1example 1
Auf einer Tablettenpresse werden in üblicher Weise Tabletten folgender Zusammensetzung gepreßt:Tablets of the following composition are pressed in a conventional manner on a tablet press:
10 mg Substanz A 50 mg Substanz B 80 mg Maisstärke 5 mg PVP10 mg substance A 50 mg substance B 80 mg maize starch 5 mg PVP
45 mg Milchzucker 1 mg Magnesium-Stearat45 mg milk sugar 1 mg magnesium stearate
Beispiel 2Example 2
Es wurden Filmtabletten folgender Zusammensetzung hergestellt:Film-coated tablets of the following composition were produced:
10 mg Substanz A 50 mg Substanz B 60 mg Kernmasse10 mg substance A 50 mg substance B 60 mg core mass
10 mg Filmcoatingschicht.10 mg film coating layer.
Die Kernmasse besteht aus 9 Teilen Maisstärke, 3 Teilen Milch¬ zucker und 1 Teil Luviskol® VA 64 (Vinylpyrrolidon-Vinyl- acetit-Mischpolymerisat 60:40, vgl. Pharm. Ind. 1962, 586). Die Filmcoatingschicht besteht ausThe core mass consists of 9 parts of corn starch, 3 parts of milk sugar and 1 part of Luviskol® VA 64 (vinyl pyrrolidone-vinyl acetite copolymer 60:40, see Pharm. Ind. 1962, 586). The film coating layer consists of
50 % Methylhydroxypropylcellulose 10 % PEG 400 20 % Talkum 15 % PEG 8000 5 % Farbanteil (davon 4 % Tiθ2)50% methylhydroxypropyl cellulose 10% PEG 400 20% talc 15% PEG 8000 5% color (including 4% TiO2)
Beispiel 3Example 3
Herstellung von Retardtabletten:Production of prolonged-release tablets:
10 mg Substanz A 50 mg Substanz B 200 mg Natriumalginat10 mg substance A 50 mg substance B 200 mg sodium alginate
20 mg Eudragit®RS (Methyl-Acrylsäurepolymerisat)20 mg Eudragit®RS (methyl acrylic acid polymer)
20 mg PVP20 mg PVP
17 mg Cellulose17 mg cellulose
3 mg Magnesium-Stearat 1155 mmgg LLaacckk ((FFiillmmccooaattiinnggsscchhiicchhtt wie in Beispiel 2) 3 mg magnesium stearate 1155 mmgg LLaacckk ((FFiillmmccooaattiinnggsschchiicchhtt as in Example 2)

Claims

Patentansprüche Claims
1. Erzeugnisse, enthaltend einen Calciüm-/Serotonin-Anta- gonisten und einen TXÄ2-Rezeptorantagonisten.1. Products containing a calcium / serotonin antagonist and a TXÄ2 receptor antagonist.
2. Erzeugnisse gemäß Anspruch 1 als Kombinationspräparat zur gleichzeitigen Anwendung in fixer Kombination oder getrennt zur gleichzeitigen oder zeitlichen abgestuften Anwendung.2. Products according to claim 1 as a combination preparation for simultaneous use in a fixed combination or separately for simultaneous or temporal graded application.
3. Erzeugnisse gemäß Anspruch 1, dadurch gekennzeichnet, daß das Verhältnis von Calcium-/Serotonin-Antagonist zu TXÄ2-Rezeptorantagonist im Bereich von 10:1 bis 1:10 liegt.3. Products according to claim 1, characterized in that the ratio of calcium / serotonin antagonist to TXÄ2 receptor antagonist is in the range of 10: 1 to 1:10.
4. Verfahren zur Herstellung eins Erzeugnisses enthaltend einen Calcium-/Serotonϊn-Antagonisten und einen TXÄ2-Rezeptoranta- gonisten, dadurch gekennzeichnet, daß man die beiden Anta- gonisten im Verhältnis 10:1 bis 1:10 miteinander mischt und die so erhaltene Mischung zu einer galanischen Applikations¬ form verarbeitet. 4. A process for producing a product containing a calcium / seroton Sern antagonist and a TXÄ2 receptor antagonist, characterized in that the two antagonists are mixed together in a ratio of 10: 1 to 1:10 and the mixture thus obtained is added processed a Galanic application form.
PCT/EP1992/000908 1991-05-02 1992-04-24 Novel combination of medicaments WO1992019270A1 (en)

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Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO1999045905A3 (en) * 1998-03-13 1999-10-21 Pozen Inc Prophylaxis and treatment of migraine headaches with thromboxane synthetase inhibitors and/or receptor antagonists

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* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US6358981B1 (en) 1998-07-31 2002-03-19 Eli Lilly And Company Sulphonamide derivatives
PE20000944A1 (en) * 1998-07-31 2000-09-20 Lilly Co Eli SULFONAMIDE DERIVATIVES

Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP0351755A1 (en) * 1988-07-21 1990-01-24 E.R. SQUIBB & SONS, INC. Combination of a calcium channel blocker and thromboxane A2 receptor antagonist or synthetase inhibitor and method for treating ischemia employing such combination
EP0405391A1 (en) * 1989-06-28 1991-01-02 Ciba-Geigy Ag Certain (arylsulfonamido- and pyridyl- or imidazolyl-)-substituted carboxylic acids and derivatives thereof

Patent Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP0351755A1 (en) * 1988-07-21 1990-01-24 E.R. SQUIBB & SONS, INC. Combination of a calcium channel blocker and thromboxane A2 receptor antagonist or synthetase inhibitor and method for treating ischemia employing such combination
EP0405391A1 (en) * 1989-06-28 1991-01-02 Ciba-Geigy Ag Certain (arylsulfonamido- and pyridyl- or imidazolyl-)-substituted carboxylic acids and derivatives thereof

Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO1999045905A3 (en) * 1998-03-13 1999-10-21 Pozen Inc Prophylaxis and treatment of migraine headaches with thromboxane synthetase inhibitors and/or receptor antagonists

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