CA2103666C - Products containing verapamil and trandolapril - Google Patents
Products containing verapamil and trandolapril Download PDFInfo
- Publication number
- CA2103666C CA2103666C CA002103666A CA2103666A CA2103666C CA 2103666 C CA2103666 C CA 2103666C CA 002103666 A CA002103666 A CA 002103666A CA 2103666 A CA2103666 A CA 2103666A CA 2103666 C CA2103666 C CA 2103666C
- Authority
- CA
- Canada
- Prior art keywords
- trandolapril
- verapamil
- physiologically tolerated
- tolerated salt
- salt
- 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.)
- Expired - Lifetime
Links
Classifications
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K38/00—Medicinal preparations containing peptides
- A61K38/16—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof
- A61K38/55—Protease inhibitors
- A61K38/556—Angiotensin converting enzyme inhibitors
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P9/00—Drugs for disorders of the cardiovascular system
- A61P9/12—Antihypertensives
Abstract
The description relates to a combination of verapamil and trandolapril which are useful in reducing blood pressure.
Description
Products containing verapamil and trandola~ril It has been disclosed that the Ca antagonist verapamil (Merck Index 1989, No. 9851) and the ACE
inhibitor trandolapril (= N-(1S-carbethoxy-3-phenyl-propyl)-S-alanyl-2S,3aR,7aS-octahydroindole-2-carboxylic acid, US-A 4,933,361) lower blood pressure.
Likewise, combinations of verapamil with other ACE inhibitors (EP 288 732) and of trandolapril with other Ca antagonists (EP 265 685) have been described.
The present: invention as brodly disclosed hereinafter relates to a pharmaceutical compo:~ition hereinafter called "drug", containing verapamil and trandolapril in the ratio from 500:1 to 10:1.
The invention as claimed hereinafter is however more specifically directed to a pharmaceutical compo~>ition for treating hypertension, coronary heart disease, heart failure and cardiac dysrhythmias, said compo~>ition containing verapamil or a physiologically tolerated salt thereof and trandolapril or a physiologically tolerated salt thereof in a ratio of from 500:1 to 10:1.
The stated ratio is based on weight. A ratio of from 300:1 to 50:1 is preferred.
The verapamil can be present in the combination in the form of a physiologically tolerated salt. Suitable for salt formation with verapamil are, in particular, hydrochloric acid, sulfuric acid, phosphoric acid, acetic acid, malonic acid, succinic acid, fumaric acid, malefic acid, citric acid, tartaric acid, lactic acid, sulfamic acid and oxalic acid. The hydrochloride is the preferred salt.
The trandolapril can likewise be in the form of a salt in the combination. Since trandolapril has both an acidic and a basic group it can form salts both with the abovementioned acids and with physiologically tolerated la bases such as alkali metal or alkaline earth metal hydroxides. Free trandolapril is preferred.
The novel combination is suitable for treating hypertension, coronary heart disease, heart failure and cardiac dysrhythmias, and for protecting the kidneys.
The combination according to the invention can be administered orally in a conventional manner.
The dosage depends on the age, condition and weight of the patient and on the mode of administration.
As a rule, the daily dose is from 50 to 300 mg of ,~ ~~.~i36G6 ~:1~
inhibitor trandolapril (= N-(1S-carbethoxy-3-phenyl-propyl)-S-alanyl-2S,3aR,7aS-octahydroindole-2-carboxylic acid, US-A 4,933,361) lower blood pressure.
Likewise, combinations of verapamil with other ACE inhibitors (EP 288 732) and of trandolapril with other Ca antagonists (EP 265 685) have been described.
The present: invention as brodly disclosed hereinafter relates to a pharmaceutical compo:~ition hereinafter called "drug", containing verapamil and trandolapril in the ratio from 500:1 to 10:1.
The invention as claimed hereinafter is however more specifically directed to a pharmaceutical compo~>ition for treating hypertension, coronary heart disease, heart failure and cardiac dysrhythmias, said compo~>ition containing verapamil or a physiologically tolerated salt thereof and trandolapril or a physiologically tolerated salt thereof in a ratio of from 500:1 to 10:1.
The stated ratio is based on weight. A ratio of from 300:1 to 50:1 is preferred.
The verapamil can be present in the combination in the form of a physiologically tolerated salt. Suitable for salt formation with verapamil are, in particular, hydrochloric acid, sulfuric acid, phosphoric acid, acetic acid, malonic acid, succinic acid, fumaric acid, malefic acid, citric acid, tartaric acid, lactic acid, sulfamic acid and oxalic acid. The hydrochloride is the preferred salt.
The trandolapril can likewise be in the form of a salt in the combination. Since trandolapril has both an acidic and a basic group it can form salts both with the abovementioned acids and with physiologically tolerated la bases such as alkali metal or alkaline earth metal hydroxides. Free trandolapril is preferred.
The novel combination is suitable for treating hypertension, coronary heart disease, heart failure and cardiac dysrhythmias, and for protecting the kidneys.
The combination according to the invention can be administered orally in a conventional manner.
The dosage depends on the age, condition and weight of the patient and on the mode of administration.
As a rule, the daily dose is from 50 to 300 mg of ,~ ~~.~i36G6 ~:1~
2 - o.z. 0480/01093 verapamil and from 0.2 to 4 mg of trandolapril.
The novel combination can be administered in conventional solid or liquid pharmaceutical _forms, eg.
uncoated of (film-)coated tablets, slow release tablets, capsules, powders, granules, pellets, slow release pellets or solutions. These are prepared in a conven-tional manner in which the active substances can be processed with the conventional pharmaceutical auxili-aries such as tablet binders, fillers, preservatives, tablet disintegrants, flow regulators, plasticizers, wetting agents, dispersants, emulsifiers, solvents, retardants and/or antioxidants (cf. H. Sucker et al.:
Pharmazeutische Technologie, Thieme-Verlag, Stuttgart, 1978). The pharmaceutical forms obtained in this way normally contain from 10 to 90$ by weight of the active substance [sic].
It is possible for either verapamil alone or both .
substances to be present in the combination in slow release form. It is preferable for veragamil to be in slow release form and for trandolapril to be in instant release form.
Pharmacological investigations have revealed that neither verapamil SR alone (10 mg/kg/day) nor trando lapril alone (3 ~g/kg/day) is able to lower the diastolic blood pressure of conscious normotensive dogs.
By contrast, a combination of said doses (10 mg/kglday verapamil SR + 3.0 mg/kg/day trandolapril) brought about a distinct ( 14 to 17 mm Hg ) , significant .
and persistent (> 24 h) lowering of the diastolic blood pressurQ.
We have also found that treatment o~ these .:
animals with verapamil SR alone resulted in an increase in the atrioventricular condudtion time -(PR interval) and, in some of the animals, in'a second degree AV block.
These side. effects were not. more pronounced on adminis tration of the combination.
Experiments on hypert~nsive' rats showed that 2Ifl3fi6fi O.Z. 0480/01093 repeated- oral administration of the combination lowered the blood pressure significantly more than expected from the total of the effects of the individual substances.
It is likewise possible to conclude from these results that the desired lowering of blood pressure is enhanced on administration of the combination but the side effect on atrioventricular conduction is not. This results in an increase in the therapeutic range.
This superadditive effect of the combination found in animals is also evident in patients with high blood pressure.
Furthermore, we have found, surprisingly, that trandolapril considerably increases the bioavailability of verapamil.
EXA1~RPLE
A verapamil HC1 slow release tablet containing 120 mg of active substance and trandolapril granules containing 0.5 mg of instant release trandolapril were packed into a hard gelatin capsule, which was then sealed.
The novel combination can be administered in conventional solid or liquid pharmaceutical _forms, eg.
uncoated of (film-)coated tablets, slow release tablets, capsules, powders, granules, pellets, slow release pellets or solutions. These are prepared in a conven-tional manner in which the active substances can be processed with the conventional pharmaceutical auxili-aries such as tablet binders, fillers, preservatives, tablet disintegrants, flow regulators, plasticizers, wetting agents, dispersants, emulsifiers, solvents, retardants and/or antioxidants (cf. H. Sucker et al.:
Pharmazeutische Technologie, Thieme-Verlag, Stuttgart, 1978). The pharmaceutical forms obtained in this way normally contain from 10 to 90$ by weight of the active substance [sic].
It is possible for either verapamil alone or both .
substances to be present in the combination in slow release form. It is preferable for veragamil to be in slow release form and for trandolapril to be in instant release form.
Pharmacological investigations have revealed that neither verapamil SR alone (10 mg/kg/day) nor trando lapril alone (3 ~g/kg/day) is able to lower the diastolic blood pressure of conscious normotensive dogs.
By contrast, a combination of said doses (10 mg/kglday verapamil SR + 3.0 mg/kg/day trandolapril) brought about a distinct ( 14 to 17 mm Hg ) , significant .
and persistent (> 24 h) lowering of the diastolic blood pressurQ.
We have also found that treatment o~ these .:
animals with verapamil SR alone resulted in an increase in the atrioventricular condudtion time -(PR interval) and, in some of the animals, in'a second degree AV block.
These side. effects were not. more pronounced on adminis tration of the combination.
Experiments on hypert~nsive' rats showed that 2Ifl3fi6fi O.Z. 0480/01093 repeated- oral administration of the combination lowered the blood pressure significantly more than expected from the total of the effects of the individual substances.
It is likewise possible to conclude from these results that the desired lowering of blood pressure is enhanced on administration of the combination but the side effect on atrioventricular conduction is not. This results in an increase in the therapeutic range.
This superadditive effect of the combination found in animals is also evident in patients with high blood pressure.
Furthermore, we have found, surprisingly, that trandolapril considerably increases the bioavailability of verapamil.
EXA1~RPLE
A verapamil HC1 slow release tablet containing 120 mg of active substance and trandolapril granules containing 0.5 mg of instant release trandolapril were packed into a hard gelatin capsule, which was then sealed.
Claims (5)
1. A pharmaceutical composition for treating hypertension, coronary heart disease, heart failure and cardiac dysrhythmias, said composition containing verapamil or a physiologically tolerated salt thereof and trandolapril or a physiologically tolerated salt thereof in a ratio of from 500:1 to 10:1.
2. A pharmaceutical composition as claimed in claim 1, in which verapamil or its physiologically tolerated salt is present in a slow release form.
3. Use of a pharmaceutical composition containing verapamil or a physiologically tolerated salt thereof and trandolapril or a physiologically tolerated salt thereof in a ratio of from 500:1 to 10:1, for treating hypertension, coronary heart disease, heart failure and cardiac dysrhythmias.
4. Use of a pharmaceutical composition containing verapamil or a physiologically tolerated salt thereof and trandolapril or a physiologically tolerated salt thereof in a ratio of from 500:1 to 10:1, for treating hypertension.
5. Use of claim 3 or 4, in which verapamil or its physilogically acceptable salt is present with composition in a slow release form.
Applications Claiming Priority (3)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| DE4109134A DE4109134A1 (en) | 1991-03-20 | 1991-03-20 | PRODUCTS CONTAINING VERAPAMIL AND TRANDOLAPRIL |
| DEP4109134.5 | 1991-03-20 | ||
| PCT/EP1992/000511 WO1992016229A1 (en) | 1991-03-20 | 1992-03-07 | Products containing verapamil and trandolapril |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| CA2103666A1 CA2103666A1 (en) | 1992-09-21 |
| CA2103666C true CA2103666C (en) | 2002-06-11 |
Family
ID=6427795
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CA002103666A Expired - Lifetime CA2103666C (en) | 1991-03-20 | 1992-03-07 | Products containing verapamil and trandolapril |
Country Status (17)
| Country | Link |
|---|---|
| EP (2) | EP0576452B1 (en) |
| JP (1) | JP3454430B2 (en) |
| KR (1) | KR100211914B1 (en) |
| AT (1) | ATE113844T1 (en) |
| AU (1) | AU655242B2 (en) |
| BR (1) | BR9205712A (en) |
| CA (1) | CA2103666C (en) |
| CZ (1) | CZ281286B6 (en) |
| DE (2) | DE4109134A1 (en) |
| DK (1) | DK0576452T3 (en) |
| ES (1) | ES2063581T3 (en) |
| HU (2) | HU212941B (en) |
| MX (1) | MX9201191A (en) |
| NO (1) | NO306601B1 (en) |
| TW (1) | TW257673B (en) |
| WO (1) | WO1992016229A1 (en) |
| ZA (1) | ZA922002B (en) |
Families Citing this family (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| TW197945B (en) * | 1990-11-27 | 1993-01-11 | Hoechst Ag | |
| DE4308504A1 (en) * | 1993-03-18 | 1994-09-22 | Knoll Ag | New use of a combination of verapamil and trandolapril |
| TW483763B (en) * | 1994-09-02 | 2002-04-21 | Astra Ab | Pharmaceutical composition comprising of ramipril and dihydropyridine compound |
| RU2543637C2 (en) * | 2012-12-06 | 2015-03-10 | Государственное бюджетное образовательное учреждение высшего профессионального образования "Волгоградский государственный медицинский университет" Министерства здавоохранения Российской Федерации | Prolonged antihypertension pharmaceutical composition and method for preparing it |
Family Cites Families (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| NZ202903A (en) * | 1981-12-29 | 1988-01-08 | Hoechst Ag | 1-- pe pyrrol-2-yl-carboxylic acid derivatives and pharmaceutical compositions |
| DE3633496A1 (en) * | 1986-10-02 | 1988-04-14 | Hoechst Ag | COMBINATION OF ANGIOTENSIN CONVERTING ENZYME INHIBITORS WITH CALCIUMANTAGONISTS AND THEIR USE IN MEDICINAL PRODUCTS |
| CA1323833C (en) * | 1987-04-28 | 1993-11-02 | Yatindra M. Joshi | Pharmaceutical compositions in the form of beadlets and method |
-
1991
- 1991-03-20 DE DE4109134A patent/DE4109134A1/en not_active Withdrawn
-
1992
- 1992-03-07 DK DK92905718.0T patent/DK0576452T3/en active
- 1992-03-07 JP JP50550292A patent/JP3454430B2/en not_active Expired - Lifetime
- 1992-03-07 CZ CS931450A patent/CZ281286B6/en not_active IP Right Cessation
- 1992-03-07 EP EP92905718A patent/EP0576452B1/en not_active Expired - Lifetime
- 1992-03-07 CA CA002103666A patent/CA2103666C/en not_active Expired - Lifetime
- 1992-03-07 AU AU13517/92A patent/AU655242B2/en not_active Expired
- 1992-03-07 HU HU9302650A patent/HU212941B/en unknown
- 1992-03-07 AT AT92905718T patent/ATE113844T1/en active
- 1992-03-07 BR BR9205712A patent/BR9205712A/en not_active Application Discontinuation
- 1992-03-07 EP EP92200728A patent/EP0508511B1/en not_active Expired - Lifetime
- 1992-03-07 KR KR1019930702800A patent/KR100211914B1/en not_active IP Right Cessation
- 1992-03-07 DE DE59200776T patent/DE59200776D1/en not_active Expired - Lifetime
- 1992-03-07 ES ES92905718T patent/ES2063581T3/en not_active Expired - Lifetime
- 1992-03-07 WO PCT/EP1992/000511 patent/WO1992016229A1/en active IP Right Grant
- 1992-03-18 MX MX9201191A patent/MX9201191A/en unknown
- 1992-03-19 ZA ZA922002A patent/ZA922002B/en unknown
- 1992-03-21 TW TW081102153A patent/TW257673B/zh active
-
1993
- 1993-09-17 NO NO933332A patent/NO306601B1/en not_active IP Right Cessation
-
1995
- 1995-06-30 HU HU95P/P00715P patent/HU211747A9/en unknown
Also Published As
| Publication number | Publication date |
|---|---|
| ATE113844T1 (en) | 1994-11-15 |
| AU1351792A (en) | 1992-10-21 |
| BR9205712A (en) | 1994-06-07 |
| NO306601B1 (en) | 1999-11-29 |
| DK0576452T3 (en) | 1995-04-24 |
| DE59200776D1 (en) | 1994-12-15 |
| EP0508511A1 (en) | 1992-10-14 |
| EP0576452B1 (en) | 1994-11-09 |
| DE4109134A1 (en) | 1992-09-24 |
| ZA922002B (en) | 1993-09-20 |
| HU9302650D0 (en) | 1993-12-28 |
| HUT65869A (en) | 1994-07-28 |
| CZ145093A3 (en) | 1994-02-16 |
| NO933332L (en) | 1993-09-17 |
| NO933332D0 (en) | 1993-09-17 |
| HU211747A9 (en) | 1995-12-28 |
| WO1992016229A1 (en) | 1992-10-01 |
| ES2063581T3 (en) | 1995-01-01 |
| EP0508511B1 (en) | 1997-12-10 |
| HU212941B (en) | 1996-12-30 |
| CZ281286B6 (en) | 1996-08-14 |
| EP0576452A1 (en) | 1994-01-05 |
| JPH06505720A (en) | 1994-06-30 |
| TW257673B (en) | 1995-09-21 |
| AU655242B2 (en) | 1994-12-08 |
| KR100211914B1 (en) | 1999-08-02 |
| JP3454430B2 (en) | 2003-10-06 |
| MX9201191A (en) | 1993-09-01 |
| CA2103666A1 (en) | 1992-09-21 |
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Legal Events
| Date | Code | Title | Description |
|---|---|---|---|
| EEER | Examination request | ||
| MKEX | Expiry |