WO1999016446A1 - Pharmaceutical combination preparations containing endothelin antagonists and calcium antagonists - Google Patents
Pharmaceutical combination preparations containing endothelin antagonists and calcium antagonists Download PDFInfo
- Publication number
- WO1999016446A1 WO1999016446A1 PCT/EP1998/005916 EP9805916W WO9916446A1 WO 1999016446 A1 WO1999016446 A1 WO 1999016446A1 EP 9805916 W EP9805916 W EP 9805916W WO 9916446 A1 WO9916446 A1 WO 9916446A1
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- Prior art keywords
- antagonists
- calcium
- antagonist
- endothelin
- combination
- Prior art date
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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
Definitions
- the present invention relates to new pharmaceutical combination preparations which are suitable for the treatment of cardiovascular diseases and which contain a calcium antagonist and an endothelin antagonist and which have improved properties compared to single administration.
- the subject of the present invention is a
- R 2 C ⁇ -C 4 alkyl, C ! -C 4 alkoxy
- R 3 -C 8 alkyl which may be substituted by a phenyl radical, which in turn may be substituted by one or two C 1 -C alkoxy radicals,
- Calcium antagonists suitable for the purpose of the invention are all T-channel blockers, in particular mibefradil and derivatives.
- preference is given to all L-channel blockers for the combination such as dihydropyridine derivatives and preferably phenylalkylamines such as gallopamil and nexopamil and in particular verapamil.
- Diltiazem and its active derivatives are also suitable for the combination.
- a calcium channel blocker with an ET system inhibitor can be used as a means of treating diseases based on vasoconstriction or associated with pathological vasoconstriction. Examples include: All forms of high blood pressure (including pulmonary hypertension), coronary heart disease, heart failure ciency, renal and myocardial ischemia, acute and chronic renal failure.
- the weight ratio of calcium antogonist to endothelin antagonist is normally in the range from 50: 1 to 1: 500, preferably 10: 1 to 1: 100 and in particular 2: 1 to 1:50.
- the combinations according to the invention are generally administered orally, e.g. administered in the form of tablets, coated tablets, coated tablets, hard and soft gelatin capsules, solutions, emulsions or suspensions.
- administration can also be rectal, e.g. in the form of suppositories, or parenterally, e.g. in the form of injection solutions.
- the active ingredient can be administered in the form of preparations which contain both active ingredients together, such as tablets or capsules, or separately as ad hoc
- a combination according to the invention with pharmaceutically inert, inorganic or organic excipients can be processed to produce tablets, coated tablets, coated tablets and hard gelatin capsules.
- Lactose, corn starch or derivatives thereof, talc, stearic acid or salts thereof can be used as such excipients for tablets, dragees and hard gelatin capsules.
- Vegetable oils, waxes, fats, semi-solid and liquid polyols are suitable excipients for soft gelatin capsules.
- Suitable excipients for the production of solutions and syrups are e.g. Water, polyols, sucrose, invert sugar, glucose and the like.
- Suitable excipients for injection solutions are water, alcohols, polyols, glycerin, vegetable oils. Natural or hardened oils, waxes, fats, semi-liquid or liquid polyols and the like are suitable as excipients for suppositories.
- the pharmaceutical preparations can also contain preservatives, solubilizers, stabilizers. Wetting agents, emulsifying agents, sweetening agents, coloring agents, flavoring agents. Contain salts for changing the osmotic pressure, buffers, coating agents and / or antioxidants.
- preservatives solubilizers, stabilizers.
- Wetting agents emulsifying agents, sweetening agents, coloring agents, flavoring agents.
- Contain salts for changing the osmotic pressure, buffers, coating agents and / or antioxidants Contain salts for changing the osmotic pressure, buffers, coating agents and / or antioxidants.
- Lacquer tablets of the following composition were produced:
- Compound A verapramil, the lactose, the cellulose and the polyvinylpyrrolidone are wet-granulated and dried.
- the sieved granules are mixed with the magnesium stearate, and the ready-to-press mixture is compressed into oval tablet cores of 370 mg each.
- the cores are then coated using a coating process until the coating tablets have reached a final weight of 380 mg.
- the first five ingredients are wet granulated and dried.
- the granules are mixed with the sodium carboxymethyl starch, the talc and the magnesium stearate and the mixture is filled into size 1 hard gelatin capsules.
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- Health & Medical Sciences (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)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)
Abstract
The invention relates to a mixture of endothelin antagonists and calcium antagonists. Said mixture is suitable for combating diseases.
Description
PHARMAZEUTISCHE KOMBINATIONSPRÄPARATE, ENDOTHELIN-ANTAGONISTEN UND CALCIUM-ANTAGONISTEN ENTHALTENDCONTAINING PHARMACEUTICAL COMBINATIONS, ENDOTHELINE ANTAGONISTS AND CALCIUM ANTAGONISTS
Beschreibungdescription
Die vorliegende Erfindung betrifft neue pharmazeutische Kombinationspräparate, die sich zur Behandlung von Herz-Kreislauf-Erkrankungen eignen und einen Calciumantagonisten und einen Endothelin-Antagonisten enthalten und die verbesserte Eigenschaf - ten gegenüber Einzelgabe aufweisen.The present invention relates to new pharmaceutical combination preparations which are suitable for the treatment of cardiovascular diseases and which contain a calcium antagonist and an endothelin antagonist and which have improved properties compared to single administration.
Gegenstand der vorliegenden Erfindung istThe subject of the present invention is
eine Kombination aus einem Endothelin-Antagonisten der Formel Ia combination of an endothelin antagonist of the formula I.
in der die Substituenten folgende Bedeutung haben:in which the substituents have the following meaning:
R1 Cι-C4-Alkyl, Cι-C4-Alkoxy;R 1 -C 4 alkyl, -C 4 alkoxy;
R2 Cι-C4-Alkyl, C!-C4-Alkoxy;R 2 Cι-C 4 alkyl, C ! -C 4 alkoxy;
R3 Cι-C8-Alkyl, welches durch einen Phenylrest substituiert sein kann, der seinerseits durch einen oder zwei Cι- -Alkoxyreste substituiert sein kann,R 3 -C 8 alkyl, which may be substituted by a phenyl radical, which in turn may be substituted by one or two C 1 -C alkoxy radicals,
Z Sauerstoff oder eine Einfachbindung,Z oxygen or a single bond,
und einem Calcium-Antagonisten.and a calcium antagonist.
Als Endothelin-Antagonisten der Formel I eignen sich vorzugsweise die folgenden Verbindungen:
The following compounds are preferably suitable as endothelin antagonists of the formula I:
Für den Zweck der Erfindung geeignete Calciumantagonisten sind alle T-Kanal-Blocker, insbesondere Mibefradil und Derivate. Vorzugsweise kommen jedoch für die Kombination sämtliche L-Kanal- Blocker in Betracht, wie Dihydropyridin-Derivate und vorzugsweise Phenylalkylamine wie Gallopamil und Nexopamil und insbesondere Verapamil. Auch Diltiazem und dessen aktive Derivate eignen sich für die Kombination.Calcium antagonists suitable for the purpose of the invention are all T-channel blockers, in particular mibefradil and derivatives. However, preference is given to all L-channel blockers for the combination, such as dihydropyridine derivatives and preferably phenylalkylamines such as gallopamil and nexopamil and in particular verapamil. Diltiazem and its active derivatives are also suitable for the combination.
Die Kombination eines Calciumantagonisten mit einem Hemmstoff des ET-Systems kann als Mittel zur Behandlung von Erkrankungen verwendet werden, die auf einer Vasokonstriktion beruhen oder mit einer pathologischen Vasokonstriktion einhergehen. Beispiele sind: Sämtliche Formen des Bluthochdrucks (einschließlich pulmonale Hypertonie) , Koronare Herzerkrankungen, Herzinsuffi-
zienz, renale und myokardiale Ischämie, akute und chronische Niereninsuffizienz .The combination of a calcium channel blocker with an ET system inhibitor can be used as a means of treating diseases based on vasoconstriction or associated with pathological vasoconstriction. Examples include: All forms of high blood pressure (including pulmonary hypertension), coronary heart disease, heart failure ciency, renal and myocardial ischemia, acute and chronic renal failure.
Aufgrund der Potenzierung der Wirkung der Einzelkomponenten ist die Kombination der beiden Wirkklassen eine ideale Ergänzung. Ein weiterer Vorteil ist, daß durch die Dosisreduktion unerwünschte Nebenwirkungen seltener auftreten.Due to the potentiation of the action of the individual components, the combination of the two action classes is an ideal addition. Another advantage is that the dose reduction reduces undesirable side effects.
Das Gewichtsverhältnis vom Calciumantogonisten zum Endothelin- Antagonisten liegt normalerweise im Bereich von 50:1 bis 1:500, vorzugsweise 10:1 bis 1:100 und insbesonders 2:1 bis 1:50.The weight ratio of calcium antogonist to endothelin antagonist is normally in the range from 50: 1 to 1: 500, preferably 10: 1 to 1: 100 and in particular 2: 1 to 1:50.
Die erfindungsgemässen Kombinationen werden im allgemeinen oral, z.B. in Form von Tabletten, Lacktabletten, Dragees, Hart- und Weichgelatinekapseln, Lösungen, Emulsionen oder Suspensionen verabreicht. Die Verabreichung kann aber auch rektal, z.B. in Form von Suppositorien, oder parenteral, z.B. in Form von Injektionslösungen, erfolgen. Die Verabreichung der Wirkstoff kann in Form von Präparaten erfolgen, die beide Wirkstoffe zusammen, wie Tabletten oder Kapseln enthalten, oder getrennt als ad-hoc-The combinations according to the invention are generally administered orally, e.g. administered in the form of tablets, coated tablets, coated tablets, hard and soft gelatin capsules, solutions, emulsions or suspensions. However, administration can also be rectal, e.g. in the form of suppositories, or parenterally, e.g. in the form of injection solutions. The active ingredient can be administered in the form of preparations which contain both active ingredients together, such as tablets or capsules, or separately as ad hoc
Kombination von EinzelSubstanzen, die gleichzeitig oder zeitlich abgestuft appliziert werden können.Combination of individual substances that can be applied at the same time or at different times.
Zur Herstellung von Tabletten, Lacktabletten, Dragees und Hartgelatinekapseln kann eine erfindungsgemäße Kombination mit pharmazeutisch inerten, anorganischen oder organischen Excipientien verarbeitet werden. Als solche Excipientien kann man für Tabletten, Dragees und Hartgelatinekapseln Lactose, Maisstärke oder Derivate davon, Talk, Stearinsäure oder deren Salze verwenden. Für Weichgelatinekapseln eignen sich als Excipientien pflanzliche Öle, Wachse, Fette, halbfeste und flüssige Polyole.A combination according to the invention with pharmaceutically inert, inorganic or organic excipients can be processed to produce tablets, coated tablets, coated tablets and hard gelatin capsules. Lactose, corn starch or derivatives thereof, talc, stearic acid or salts thereof can be used as such excipients for tablets, dragees and hard gelatin capsules. Vegetable oils, waxes, fats, semi-solid and liquid polyols are suitable excipients for soft gelatin capsules.
Zur Herstellung von Lösungen und Sirupen eignen sich als Excipientien z.B. Wasser, Polyole, Saccharose, Invertzucker, Glukose und dergleichen. Für Injektionslösungen eignen sich als Excipientien Wasser, Alkohole, Polyole, Glyzerin, vegetabile Öle. Für Suppositorien eignen sich als Excipientien natürliche oder gehärtete Öle, Wachse, Fette, halbflüssige oder flüssige Polyole und dergleichen.Suitable excipients for the production of solutions and syrups are e.g. Water, polyols, sucrose, invert sugar, glucose and the like. Suitable excipients for injection solutions are water, alcohols, polyols, glycerin, vegetable oils. Natural or hardened oils, waxes, fats, semi-liquid or liquid polyols and the like are suitable as excipients for suppositories.
Die pharmazeutischen Zubereitungen können daneben noch Konservierungsmittel, Lösevermittler, Stabilisierungsmittel. Netzmittel, Emulgiermittel, Süssmittel, Färbemittel, Aromatisierungs- mittel. Salze zur Veränderung des osmotischen Druckes, Puffer, Überzugsmittel und/oder Antioxidantien enthalten.
Die nachfolgenden Beispiele erläutern die Erfindung.The pharmaceutical preparations can also contain preservatives, solubilizers, stabilizers. Wetting agents, emulsifying agents, sweetening agents, coloring agents, flavoring agents. Contain salts for changing the osmotic pressure, buffers, coating agents and / or antioxidants. The following examples illustrate the invention.
Beispiel 1example 1
Es wurden Lacktabletten folgender Zusammensetzung hergestellt:Lacquer tablets of the following composition were produced:
Verbindung A 100,0 mgCompound A 100.0 mg
Verapamil 180,0 mg Lactose wasserfrei 30,0 mgVerapamil 180.0 mg lactose anhydrous 30.0 mg
Mikrokristalline Cellulose 30,0 mgMicrocrystalline cellulose 30.0 mg
Polyvinylpyrrolidon 20,0 mgPolyvinyl pyrrolidone 20.0 mg
Magnesiumstearat 5, 0 mg Polyethylenglykol 6000 0,8 mgMagnesium stearate 5.0 mg polyethylene glycol 6000 0.8 mg
Eisenoxid gelb 1,2 mgIron oxide yellow 1.2 mg
Titandioxid 0,3 mgTitanium dioxide 0.3 mg
Talk 0 , 7 mgTalc 0.7 mg
Verbindung A, Verapramil, die Lactose, die Cellulose und das Polyvinylpyrrolidon werden feuchtgranuliert und getrocknet. Das gesiebte Granulat wird mit dem Magnesiumstearat gemischt, und die preßfertige Mischung zu ovalen Tablettenkernen zu je 370 mg verpreßt. Anschließend werden die Kerne mit Hilfe eines Lackier- Verfahrens überzogen, bis die Lacktabletten ein Endgewicht von 380 mg erreicht haben.Compound A, verapramil, the lactose, the cellulose and the polyvinylpyrrolidone are wet-granulated and dried. The sieved granules are mixed with the magnesium stearate, and the ready-to-press mixture is compressed into oval tablet cores of 370 mg each. The cores are then coated using a coating process until the coating tablets have reached a final weight of 380 mg.
Beispiel 2Example 2
Herstellung von Hartgelatinekapseln folgender Zusammensetzung:Production of hard gelatin capsules with the following composition:
Verbindung A 100,0 mgCompound A 100.0 mg
Gallopamil 75,0 mg Lactose krist. 18,0 mgGallopamil 75.0 mg lactose krist. 18.0 mg
Polyvinylpyrrolidon 15,0 mgPolyvinyl pyrrolidone 15.0 mg
Microkristalline Cellulose 17,5 mgMicrocrystalline cellulose 17.5 mg
Natrium-carboxymethylstärke 10,0 mgSodium carboxymethyl starch 10.0 mg
Talk 9 , 0 mgTalc 9.0 mg
Magnesiumstearat 3,0 mgMagnesium stearate 3.0 mg
Die ersten fünf Bestandteile werden feuchtgranuliert und getrocknet. Das Granulat wird mit der Natrium-carboxymethylstärke, dem Talk und dem Magnesiumstearat gemischt und die Mischung in Hartgelatinekapseln der Größe 1 abgefüllt.
The first five ingredients are wet granulated and dried. The granules are mixed with the sodium carboxymethyl starch, the talc and the magnesium stearate and the mixture is filled into size 1 hard gelatin capsules.
Claims
1. Kombination aus einem Endothelin-Antagonisten der Formel I1. Combination of an endothelin antagonist of the formula I
in der die Substituenten folgende Bedeutung haben:in which the substituents have the following meaning:
R1 Cι-C4-Alkyl, Cι-C-Alkoxy;R 1 -C 4 alkyl, -C -C alkoxy;
R2 Cx-C-Alkyl, Cι-C-Alkoxy;R 2 C x -C alkyl, -C -C alkoxy;
R3 Cι-C8-Alkyl, welches durch einen Phenylrest substituiert sein kann, der seinerseits durch einen oder zwei Cι-4-Alkoxyreste substituiert sein kann,R 3 -C 8 alkyl, which may be substituted by a phenyl radical, which in turn may be substituted by one or two C 4 alkoxy radicals,
Z Sauerstoff oder eine Einfachbindung,Z oxygen or a single bond,
und einem Calcium-Antagonisten.and a calcium antagonist.
2. Pharmazeutische Zubereitung, enthaltend eine Kombination gemäß Anspruch 1.2. Pharmaceutical preparation containing a combination according to claim 1.
3. Herstellung einer pharmazeutischen Zubereitung, dadurch gekennzeichnet, daß man ein Gemisch aus einem Calcium- Antagonisten und einem Endothelin-Antagonisten gemäß Anspruch 1 in eine galenische Darreichungsform bringt.3. Preparation of a pharmaceutical preparation, characterized in that a mixture of a calcium antagonist and an endothelin antagonist according to claim 1 is brought into a pharmaceutical dosage form.
4. Verwendung einer Kombination von einem Calcium-Antagonisten und einem Endothelin-Antagonisten gemäß Anspruch 1 bzw. einer pharmazeutischen Zubereitung, enthaltend einen Calcium-Antagonisten und einen Endothelin-Antagonisten gemäß Anspruch 1 zur gleichzeitigen, getrennten oder zeitlich abgestuften Anwendung bei der Behandlung von Erkrankungen, die mit einer Vasokonstriktion oder anderen biologischen Wirkungen von Endothelin assoziiert sind.
4. Use of a combination of a calcium antagonist and an endothelin antagonist according to claim 1 or a pharmaceutical preparation containing a calcium antagonist and an endothelin antagonist according to claim 1 for simultaneous, separate or graduated use in the treatment of diseases that are associated with vasoconstriction or other biological effects of endothelin.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| AU97447/98A AU9744798A (en) | 1997-09-30 | 1998-09-17 | Pharmaceutical combination preparations containing endothelin antagonists and calcium antagonists |
Applications Claiming Priority (2)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| DE1997143142 DE19743142A1 (en) | 1997-09-30 | 1997-09-30 | Combination pharmaceutical preparations |
| DE19743142.9 | 1997-09-30 |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| WO1999016446A1 true WO1999016446A1 (en) | 1999-04-08 |
Family
ID=7844114
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| PCT/EP1998/005916 WO1999016446A1 (en) | 1997-09-30 | 1998-09-17 | Pharmaceutical combination preparations containing endothelin antagonists and calcium antagonists |
Country Status (3)
| Country | Link |
|---|---|
| AU (1) | AU9744798A (en) |
| DE (1) | DE19743142A1 (en) |
| WO (1) | WO1999016446A1 (en) |
Families Citing this family (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| EP1604656A1 (en) | 2004-06-09 | 2005-12-14 | Schwarz Pharma Ag | Novel use of peptide compounds for treating amyotrophic lateral sclerosis (ALS) |
| CA2697057A1 (en) | 2007-08-22 | 2009-02-26 | Gilead Colorado, Inc. | Therapy for complications of diabetes |
Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO1996011914A1 (en) * | 1994-10-14 | 1996-04-25 | Basf Aktiengesellschaft | New carboxylic acid derivatives, their preparation and their use |
| WO1996019233A2 (en) * | 1994-12-12 | 1996-06-27 | Omeros Medical Systems, Inc. | Irrigation solution and method for inhibition of pain, inflammation and spasm |
| WO1996022978A1 (en) * | 1995-01-27 | 1996-08-01 | Rhone Poulenc Rorer Limited | Substituted phenyl compounds as endothelin antagonists |
-
1997
- 1997-09-30 DE DE1997143142 patent/DE19743142A1/en not_active Withdrawn
-
1998
- 1998-09-17 AU AU97447/98A patent/AU9744798A/en not_active Abandoned
- 1998-09-17 WO PCT/EP1998/005916 patent/WO1999016446A1/en active Application Filing
Patent Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO1996011914A1 (en) * | 1994-10-14 | 1996-04-25 | Basf Aktiengesellschaft | New carboxylic acid derivatives, their preparation and their use |
| WO1996019233A2 (en) * | 1994-12-12 | 1996-06-27 | Omeros Medical Systems, Inc. | Irrigation solution and method for inhibition of pain, inflammation and spasm |
| WO1996022978A1 (en) * | 1995-01-27 | 1996-08-01 | Rhone Poulenc Rorer Limited | Substituted phenyl compounds as endothelin antagonists |
Non-Patent Citations (1)
| Title |
|---|
| RIECHERS H ET AL: "DISCOVERY AND OPTIMIZATION OF A NOVEL CLASS OF ORALLY ACTIVE NONPEPTIDIC ENDOTHELIN-A RECEPTOR ANTAGONISTS", JOURNAL OF MEDICINAL CHEMISTRY, vol. 39, no. 11, May 1996 (1996-05-01), pages 2123 - 2128, XP002034887 * |
Also Published As
| Publication number | Publication date |
|---|---|
| DE19743142A1 (en) | 1999-04-01 |
| AU9744798A (en) | 1999-04-23 |
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