CA1255596A - Pharmaceutical compositions containing dihydropyridine - Google Patents
Pharmaceutical compositions containing dihydropyridineInfo
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- CA1255596A CA1255596A CA000485285A CA485285A CA1255596A CA 1255596 A CA1255596 A CA 1255596A CA 000485285 A CA000485285 A CA 000485285A CA 485285 A CA485285 A CA 485285A CA 1255596 A CA1255596 A CA 1255596A
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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
- A61K31/33—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
- 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
- A61K31/535—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with at least one nitrogen and one oxygen as the ring hetero atoms, e.g. 1,2-oxazines
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
-
- 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
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- Chemical Kinetics & Catalysis (AREA)
- Cardiology (AREA)
- Heart & Thoracic Surgery (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)
- Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)
- Medicinal Preparation (AREA)
- Hydrogenated Pyridines (AREA)
Abstract
ABSTRACT OF THE DISCLOSURE
An antihypertensive and antianginal combination comprising (A) 0.1 to 10 parts by weight of an asymmetrical dihydropyridine of the formula
An antihypertensive and antianginal combination comprising (A) 0.1 to 10 parts by weight of an asymmetrical dihydropyridine of the formula
Description
~ss~
The invent;on relates to a new act;ve compound comb;nation ~ith an antihypertensive and antianginal action, which contains dihydropyridines (component A), some of which are known, and certain ~-blockers ~compon-ent B), and which has a long duration of action and agood tolerance.
It is already known that comb;nations of var;ous ~-blockers with various calcium antagonists can be used in the treatment of circulatory diseases, in particular 1n hypertension and coronary diseases~ However, from the action mechanis~s of calcium antagonists and of ~-blockers, a higher risk in comparison with monotherapy can be deduced in respect of possible undesirable side effects. For e)~ample, V.S. Wayne et al., in Australia N.Z.JOMed. 1Z, ~o. 4, 285 - 289 (1982), report serious side effects of a combination of the calcium antagonist verapamil and the ~-blockers metoprolol and pindolol.
M~D. Winniford et al. (Zirkulation 66, No. 4 Part 2, page 120 (1982) Dallas USA) also report possible serious side 2û effects in connection ~ith the treatment of 13 angina patients with a combination of the ~-blocker propanolol and the calcium antagonist verapamil. In contrast, the calcium antagonists selected accord;ng to the invention from the 1,4-dihydropyridine group are distinguished by a clearly better tolerance in this respect; if suitable ~ -blockers are chosen as combination partners, the benefit/risk ratio is further optimised.
The present invention relates to a new antihyper-tensive and antianginal combination product containing a combination of a dihydropyridine with an unsymmetric ester grouping (component A), of the general formula I
Le A 22 709 31 2SS5~6
The invent;on relates to a new act;ve compound comb;nation ~ith an antihypertensive and antianginal action, which contains dihydropyridines (component A), some of which are known, and certain ~-blockers ~compon-ent B), and which has a long duration of action and agood tolerance.
It is already known that comb;nations of var;ous ~-blockers with various calcium antagonists can be used in the treatment of circulatory diseases, in particular 1n hypertension and coronary diseases~ However, from the action mechanis~s of calcium antagonists and of ~-blockers, a higher risk in comparison with monotherapy can be deduced in respect of possible undesirable side effects. For e)~ample, V.S. Wayne et al., in Australia N.Z.JOMed. 1Z, ~o. 4, 285 - 289 (1982), report serious side effects of a combination of the calcium antagonist verapamil and the ~-blockers metoprolol and pindolol.
M~D. Winniford et al. (Zirkulation 66, No. 4 Part 2, page 120 (1982) Dallas USA) also report possible serious side 2û effects in connection ~ith the treatment of 13 angina patients with a combination of the ~-blocker propanolol and the calcium antagonist verapamil. In contrast, the calcium antagonists selected accord;ng to the invention from the 1,4-dihydropyridine group are distinguished by a clearly better tolerance in this respect; if suitable ~ -blockers are chosen as combination partners, the benefit/risk ratio is further optimised.
The present invention relates to a new antihyper-tensive and antianginal combination product containing a combination of a dihydropyridine with an unsymmetric ester grouping (component A), of the general formula I
Le A 22 709 31 2SS5~6
- 2 -4 ~ (I) R 00 ~ COOR2 ll ~
~' N ~R1 in which R1 and R5 are identical or different and repre-sent methyl, hydroxymethyl or cyano, R2 and R4 are always different from one another and represent alkyl ~ith 1 to 10 carbon atoms, which i~ optionally substituted by alkoxy with 1 to 4 carbon atoms, fluorine, chlorine or N-methyl-benzylamino, and R3 represents 1 or 2 identical or different substituents fro~ the group comprising ni~ro, chlorine and trifluoromethyl, or represents the radical =N-O-N=
and a ~-blocker without a local anaesthetic action, in a weight ratio of 0.1 to 10 parts by we;ght of co~ponent A
and 10 to 200 parts by weight of component B.
The invention preferably relates to an antihyper-tensive and antianginal combination product which con-tains the dihydropyridine isobutyl ~ethyl 1,4-dihYdro-2,6-dimethyl-4-(2-nitrophenyl)-pyridin~-3,5-dicarboxylatP (nisol-dip;ne) or the ~ihydropyridine 3-methyl 5-ethyl Z,6-di-methyl-4-(3'-nitrophenyl~-1,4-dihydropyridine-305-dicar-boxylate tnitrendipine) as component A and a~ -blocker from the group ~comprising atenolol, sotalol, timolol or 5 nadolol as component B.
The two dihydropyridines and their action on the blood pressure ~and their coronary action are known (com-pare DOS ~German Published Spec;fication) 2,117,571;
British Patent 1,358,951; DOS tGerman Published Specifi-cation) 2,549,568; and British Patent 1,516,793). TheirLe A 22 709 -:l~S5i~96 use as combination partners w;th the ~-blockers mentioned is new.
The~ -blockers ~hich can be used according to the invention and halve no local anaesthetic action are also known (compare Llloth et al., J. Med. Chem. 9, 8$ ~1966), and U.S. Patents 3,663~607, 3,836,671, 3,619,370,
~' N ~R1 in which R1 and R5 are identical or different and repre-sent methyl, hydroxymethyl or cyano, R2 and R4 are always different from one another and represent alkyl ~ith 1 to 10 carbon atoms, which i~ optionally substituted by alkoxy with 1 to 4 carbon atoms, fluorine, chlorine or N-methyl-benzylamino, and R3 represents 1 or 2 identical or different substituents fro~ the group comprising ni~ro, chlorine and trifluoromethyl, or represents the radical =N-O-N=
and a ~-blocker without a local anaesthetic action, in a weight ratio of 0.1 to 10 parts by we;ght of co~ponent A
and 10 to 200 parts by weight of component B.
The invention preferably relates to an antihyper-tensive and antianginal combination product which con-tains the dihydropyridine isobutyl ~ethyl 1,4-dihYdro-2,6-dimethyl-4-(2-nitrophenyl)-pyridin~-3,5-dicarboxylatP (nisol-dip;ne) or the ~ihydropyridine 3-methyl 5-ethyl Z,6-di-methyl-4-(3'-nitrophenyl~-1,4-dihydropyridine-305-dicar-boxylate tnitrendipine) as component A and a~ -blocker from the group ~comprising atenolol, sotalol, timolol or 5 nadolol as component B.
The two dihydropyridines and their action on the blood pressure ~and their coronary action are known (com-pare DOS ~German Published Spec;fication) 2,117,571;
British Patent 1,358,951; DOS tGerman Published Specifi-cation) 2,549,568; and British Patent 1,516,793). TheirLe A 22 709 -:l~S5i~96 use as combination partners w;th the ~-blockers mentioned is new.
The~ -blockers ~hich can be used according to the invention and halve no local anaesthetic action are also known (compare Llloth et al., J. Med. Chem. 9, 8$ ~1966), and U.S. Patents 3,663~607, 3,836,671, 3,619,370,
3,655,663, 3,657,237 and 3,9~5,267).
Their use as combination partners w;th the un-symmetric dihydropyridines mentioned is new.
The g -bLockers mentiorled according to the inven-tion are selected from the large group of knownf~-blockers. In the prior art, there are numerous indica-tions that combînations o~ ~-blockers with many calcium antagonists have the risk of undesirable side effects and can thus be used to only a limited degree for therapy of coronary and circulatory diseases. Knowledge of the mechanisms of the automaticity in cardiac pacemaker tissue and of the influences of calcium antagonists and ~-blockers on these shows that, for example in animals treated with ~-blockers, the spontaneous excitation of the cardiac pacemaker tissue may be lost if relatively high doses of calcium antagonists are s;multaneously administered.
It could not be predicted that a combination of selected~Y-blockers without a local anaesthetic or sodium antagonistic action with the calc;um antagonists selected according to the invention from the 1,4-dihydropyridine group shows such an advantageous action and is particu-larly distinguished by a good tolerance.
It is therefore decidedly surprising that the combinations according to the invention of selected calc;um antagonists with selected ~-blockers without a local anaesthetic (sodium antagonistic) action have a considerably better tolerance, cou~led with an advantage-ous antihypertensive and antianginal action, than combina-tions with other ~-blockers which have a local anaesthetic ~e A Z2 709 12S~S~
or sodium antagonistic action.
This applies all the more so since all the known electrophysiological investigations suggest that the sodium system plays no part in the automaticity of ~he pacemaker cells in the heart ~compare, for example, Brown, H.F., Physiol~ Rev. 62:505-530 (1982)).
In the combination according to the invention, 1 part by weight of component A is advantageously brought together with 1 to 10, in particular 2 to 6, parts by weight of component B. The daily dose of the comb;nation according to the invention advantageously contains 1 to 100 mg, preferably 2 to 50 mg and ;n particular 5 to 30 mg, of component A and 1 to Z00 mg, preferably 10 to 100 mg and ;n part;cular 30 to 80 mg, of component B.
The combination product according to the inven-tion is preferably used as a solid formulation, for example in the form of tablets, pills, dragees, granules, powders, capsules or sachets~
The galenical formulations can be prepared in a known manner using known auxiliaries and excipients and, if appropriate, with the addition of other suitable active compounds, such as saluretics, in particular the active compounds mefruside or muzolimine.
Those combination products in ~hich the active compound of component A is employed in a sustained release formulation, such as, for example, in the form of active compound crystals with a specific surface area of 0.5 to 4 m~/g, are to be particularly singled OUtr Another possibility for component A ;s the use of a di-hydropyridine which is in crystalline form to the extent of 60 to 100% and in amorphous form to the extent of 0 to 40%, for exarnple as a co-precipitate with polyvinyl-pyrrolidone tPVP), methylcellulose, hydroxypropylcellu-lose or hydroxypropylmethylcellulose.
By using a mixture of amorphous dihydropyridine and crystalline dihydropyridine, the advantage of a rapid Le A 22 709 ~2S5596 onset of action is combined with the advantage of a long duration of action.
The combination according to the invention is very well tolerated. Rats which had been beta-blocked by pre-treatment with propranolol show the occurence of ECG-abnormalties (loss of artrial excitation) after intravenous infusion of a cummulative dose of nitrendipine of 2,5 mg/kg (infusion rate: 300 ~g/kg/min). Rats which have been b~ta-blocked by pretreatment with sotalo, tolerate a five-times higher dose of rlitrendipine which is 12,2 mg/kg. If the rats were beta-blocked by pretreatment with atenolol a dosis of 6,8 mg/kg of nitrendipine was tolerated.
Besides the unexpectedly good tolerance of the combination according to the invention, which leads to a clear reduction in risk to the patient to be treated, the administration of the fixed combination according to the invention facilitates handling by the patient (improved patient compliance).
Other advantages of the combination according to the invention are to be seen in the fact that, in the case of serious circulatory diseases, i~ par-ticular severe hypertension or coronar.~ heart disease, ~hen therapy with monoproducts is no longer successful, the combination product according to the invention can be conveniently and reLiably used. Even if the handling abiLity of the patient is limited, ;ntake of both active compounds in the combined form in the correct dosage is ensured and can be controlled more easily by the treating physician.
The following formulation examples are intended to illustrate the subject of the invention.
Example 1 20 mg of nitrendipine, consisting of 15 ~9 of m;crocrystalline active compound ~ith a specific crystal surface area of about 3 m2/g and 5 mg of nitrendipine co-precipitate with PVP, are mixed toget~er with 53 mg of crystalline atenolol, 370 mg of microcrystalline cellulose, 85 rng of lactose and 7 mg of magnesium stear-ate and the mixture is pressed to tablets.
Le A 22 709 , .
~S~;~6 Example 2 20 mg of nitrendipine, consisting of S mg of microcrystalline active compound with a specific crystal surface area of about 3 m2/g and 15 mg of nitrendipine co-precipitate with PVP, are mixed together with 25 mg of crystalline atenolol, 150 mg of microcrYstalline cellulose, 110 mg of maize starch, 30 mg of crospovidone and 5 mg of magnesium stearate and the mixture is pressed to tablets.
~xample 3 30 mg of nitrendipine, consisting of 10 mg of microcrystalline active compound with a specific crystal surface area of about 3 m2/g and 20 mg of nitrendipine co-precipitate with PVP, are mixed ~ith 60 mg of crystal-line timolol, 200 mg of microcrystalline ceLlulose~
150 mg of maize starch, 35 mg of crospovidone and S mg of magnesium stearate and the mixture is pressed to tab-lets.
Example 4 (only for n;trendipine) 50 mg of nitrendipine as a microcrystalline active compound with a specific crystal surface area of about 3.5 m2/g are mixed with 10û mg of crystalline timolol, 50 mg of microcrystalline cellulose, 70 mg of maize starch, 26 mg of lactose, 20 mg of PVP, 2 mg of sodium lauryl-sulphate and 2 mg of magnesium stearate and the mixture is pressed to tablets.
Fxample 5 10 mg of nitrendipine as a microcrystalline active compound with a specific crystal surface area of about 3 m2/g are mixed with 50 mg of crystalline sotalol, 27.5 mg of maize starch, 20 mg of microcrystal-line cellulose, 16 mg of calcium hydrogen phosphate, 5 mg of PVP~ 1 mg of polysorbate and 0.5 mg of magnesium stearate and the mixture is pressed to tablets.
Example 6 20 mg of nitrendipine as a microcrystalline active compound ~ith a specific crystal surface area of about 3 m2/g are mixed with 30 mg of crystalline nadolol, 28.5 mg of maize starch, 25 mg of microcrystal line cellulose, 20 mg of magnesium carbonate, 5 mg of PVP, 1 rg of sodium lauryl-sulphate and 0.5 mg of mag-nesium stearate and the mixture is pressed to tablets.
Le A 2~ 709 1~5~59~
Example 7 - Z0 mg of nisoldipine as a microcrystalline active compound with a specific crystal surface area of about 2~5 m2/g are mixed with 120 mg of crystalline atenolol, 80 mg of microcrystalline cellulose, 66 mg of maize starch, 40 mg of lactose, 10 mg of PVP, 2 mg of sodium lauryl-sulphate and Z mg of magnesium stearate and the mixture is pressed to tablets~
Example 8 10 mg of nitrendipine as a microcrystalline active compound ~ith a specific crystal surface area of about 2.5 m2/g are mixed with 60 mg of crystalline sotalol, 40 mg of microcrystalline cellulose, 33 mg of maize starch, 20 mg of lactose, 5 mg of PVP, 1 mg of sodium lauryl-sulphate and 1 mg of magnesium stearate and the mixture is pressed to tablets.
Example 9 5 mg of nitrendipine as a microcrystalline active compound with a specific crystal surface area of about 3 m2/g are mixed with 40 mg of crystalline nadolol, 30 mg of microcrystall;ne cellulose, 29 mg of maize starch, 20 mg of magnesium carbonate, 5 mg of PVP, 0.5 mg of polysorbate and 0.5 mg of magnesium stearate and the mixture is pressed to tablets.
Example ~0 1 mg of n;trendipine as a microcrystalline active compound ~ith a specific crystal surface area of about 2.5 m2/g are mixed with 70 mg of crystalline timolol, 20 mg of microcrystalline cellulose~ 15 mg of calc;um hydrogen phosphate, 8 mg of maize starch, 0.5 mg of sod;um lauryl-sulphate and 0.5 mg of magnesium stearate and the mixture is pressed to tablets.
Example 11 (only for nisoldipine) 0.5 mg of nisoldipine as a microcrystalline active compound ~ith a specific crystal surface area of about 3.5 m2/g are mixed with 25 mg of crystalline Le A 22 709 atenolol, 20 mg of cellulose powder, 1D mg of lactose, 19.7 mg of ma;ze starch, 4 mg of PVP~ 0O5 mg of sodium lauryl-sulphate and 0.3 mg of magnes;um stearate and the mixture is pressed to tablets.
Le A 22 7D9
Their use as combination partners w;th the un-symmetric dihydropyridines mentioned is new.
The g -bLockers mentiorled according to the inven-tion are selected from the large group of knownf~-blockers. In the prior art, there are numerous indica-tions that combînations o~ ~-blockers with many calcium antagonists have the risk of undesirable side effects and can thus be used to only a limited degree for therapy of coronary and circulatory diseases. Knowledge of the mechanisms of the automaticity in cardiac pacemaker tissue and of the influences of calcium antagonists and ~-blockers on these shows that, for example in animals treated with ~-blockers, the spontaneous excitation of the cardiac pacemaker tissue may be lost if relatively high doses of calcium antagonists are s;multaneously administered.
It could not be predicted that a combination of selected~Y-blockers without a local anaesthetic or sodium antagonistic action with the calc;um antagonists selected according to the invention from the 1,4-dihydropyridine group shows such an advantageous action and is particu-larly distinguished by a good tolerance.
It is therefore decidedly surprising that the combinations according to the invention of selected calc;um antagonists with selected ~-blockers without a local anaesthetic (sodium antagonistic) action have a considerably better tolerance, cou~led with an advantage-ous antihypertensive and antianginal action, than combina-tions with other ~-blockers which have a local anaesthetic ~e A Z2 709 12S~S~
or sodium antagonistic action.
This applies all the more so since all the known electrophysiological investigations suggest that the sodium system plays no part in the automaticity of ~he pacemaker cells in the heart ~compare, for example, Brown, H.F., Physiol~ Rev. 62:505-530 (1982)).
In the combination according to the invention, 1 part by weight of component A is advantageously brought together with 1 to 10, in particular 2 to 6, parts by weight of component B. The daily dose of the comb;nation according to the invention advantageously contains 1 to 100 mg, preferably 2 to 50 mg and ;n particular 5 to 30 mg, of component A and 1 to Z00 mg, preferably 10 to 100 mg and ;n part;cular 30 to 80 mg, of component B.
The combination product according to the inven-tion is preferably used as a solid formulation, for example in the form of tablets, pills, dragees, granules, powders, capsules or sachets~
The galenical formulations can be prepared in a known manner using known auxiliaries and excipients and, if appropriate, with the addition of other suitable active compounds, such as saluretics, in particular the active compounds mefruside or muzolimine.
Those combination products in ~hich the active compound of component A is employed in a sustained release formulation, such as, for example, in the form of active compound crystals with a specific surface area of 0.5 to 4 m~/g, are to be particularly singled OUtr Another possibility for component A ;s the use of a di-hydropyridine which is in crystalline form to the extent of 60 to 100% and in amorphous form to the extent of 0 to 40%, for exarnple as a co-precipitate with polyvinyl-pyrrolidone tPVP), methylcellulose, hydroxypropylcellu-lose or hydroxypropylmethylcellulose.
By using a mixture of amorphous dihydropyridine and crystalline dihydropyridine, the advantage of a rapid Le A 22 709 ~2S5596 onset of action is combined with the advantage of a long duration of action.
The combination according to the invention is very well tolerated. Rats which had been beta-blocked by pre-treatment with propranolol show the occurence of ECG-abnormalties (loss of artrial excitation) after intravenous infusion of a cummulative dose of nitrendipine of 2,5 mg/kg (infusion rate: 300 ~g/kg/min). Rats which have been b~ta-blocked by pretreatment with sotalo, tolerate a five-times higher dose of rlitrendipine which is 12,2 mg/kg. If the rats were beta-blocked by pretreatment with atenolol a dosis of 6,8 mg/kg of nitrendipine was tolerated.
Besides the unexpectedly good tolerance of the combination according to the invention, which leads to a clear reduction in risk to the patient to be treated, the administration of the fixed combination according to the invention facilitates handling by the patient (improved patient compliance).
Other advantages of the combination according to the invention are to be seen in the fact that, in the case of serious circulatory diseases, i~ par-ticular severe hypertension or coronar.~ heart disease, ~hen therapy with monoproducts is no longer successful, the combination product according to the invention can be conveniently and reLiably used. Even if the handling abiLity of the patient is limited, ;ntake of both active compounds in the combined form in the correct dosage is ensured and can be controlled more easily by the treating physician.
The following formulation examples are intended to illustrate the subject of the invention.
Example 1 20 mg of nitrendipine, consisting of 15 ~9 of m;crocrystalline active compound ~ith a specific crystal surface area of about 3 m2/g and 5 mg of nitrendipine co-precipitate with PVP, are mixed toget~er with 53 mg of crystalline atenolol, 370 mg of microcrystalline cellulose, 85 rng of lactose and 7 mg of magnesium stear-ate and the mixture is pressed to tablets.
Le A 22 709 , .
~S~;~6 Example 2 20 mg of nitrendipine, consisting of S mg of microcrystalline active compound with a specific crystal surface area of about 3 m2/g and 15 mg of nitrendipine co-precipitate with PVP, are mixed together with 25 mg of crystalline atenolol, 150 mg of microcrYstalline cellulose, 110 mg of maize starch, 30 mg of crospovidone and 5 mg of magnesium stearate and the mixture is pressed to tablets.
~xample 3 30 mg of nitrendipine, consisting of 10 mg of microcrystalline active compound with a specific crystal surface area of about 3 m2/g and 20 mg of nitrendipine co-precipitate with PVP, are mixed ~ith 60 mg of crystal-line timolol, 200 mg of microcrystalline ceLlulose~
150 mg of maize starch, 35 mg of crospovidone and S mg of magnesium stearate and the mixture is pressed to tab-lets.
Example 4 (only for n;trendipine) 50 mg of nitrendipine as a microcrystalline active compound with a specific crystal surface area of about 3.5 m2/g are mixed with 10û mg of crystalline timolol, 50 mg of microcrystalline cellulose, 70 mg of maize starch, 26 mg of lactose, 20 mg of PVP, 2 mg of sodium lauryl-sulphate and 2 mg of magnesium stearate and the mixture is pressed to tablets.
Fxample 5 10 mg of nitrendipine as a microcrystalline active compound with a specific crystal surface area of about 3 m2/g are mixed with 50 mg of crystalline sotalol, 27.5 mg of maize starch, 20 mg of microcrystal-line cellulose, 16 mg of calcium hydrogen phosphate, 5 mg of PVP~ 1 mg of polysorbate and 0.5 mg of magnesium stearate and the mixture is pressed to tablets.
Example 6 20 mg of nitrendipine as a microcrystalline active compound ~ith a specific crystal surface area of about 3 m2/g are mixed with 30 mg of crystalline nadolol, 28.5 mg of maize starch, 25 mg of microcrystal line cellulose, 20 mg of magnesium carbonate, 5 mg of PVP, 1 rg of sodium lauryl-sulphate and 0.5 mg of mag-nesium stearate and the mixture is pressed to tablets.
Le A 2~ 709 1~5~59~
Example 7 - Z0 mg of nisoldipine as a microcrystalline active compound with a specific crystal surface area of about 2~5 m2/g are mixed with 120 mg of crystalline atenolol, 80 mg of microcrystalline cellulose, 66 mg of maize starch, 40 mg of lactose, 10 mg of PVP, 2 mg of sodium lauryl-sulphate and Z mg of magnesium stearate and the mixture is pressed to tablets~
Example 8 10 mg of nitrendipine as a microcrystalline active compound ~ith a specific crystal surface area of about 2.5 m2/g are mixed with 60 mg of crystalline sotalol, 40 mg of microcrystalline cellulose, 33 mg of maize starch, 20 mg of lactose, 5 mg of PVP, 1 mg of sodium lauryl-sulphate and 1 mg of magnesium stearate and the mixture is pressed to tablets.
Example 9 5 mg of nitrendipine as a microcrystalline active compound with a specific crystal surface area of about 3 m2/g are mixed with 40 mg of crystalline nadolol, 30 mg of microcrystall;ne cellulose, 29 mg of maize starch, 20 mg of magnesium carbonate, 5 mg of PVP, 0.5 mg of polysorbate and 0.5 mg of magnesium stearate and the mixture is pressed to tablets.
Example ~0 1 mg of n;trendipine as a microcrystalline active compound ~ith a specific crystal surface area of about 2.5 m2/g are mixed with 70 mg of crystalline timolol, 20 mg of microcrystalline cellulose~ 15 mg of calc;um hydrogen phosphate, 8 mg of maize starch, 0.5 mg of sod;um lauryl-sulphate and 0.5 mg of magnesium stearate and the mixture is pressed to tablets.
Example 11 (only for nisoldipine) 0.5 mg of nisoldipine as a microcrystalline active compound ~ith a specific crystal surface area of about 3.5 m2/g are mixed with 25 mg of crystalline Le A 22 709 atenolol, 20 mg of cellulose powder, 1D mg of lactose, 19.7 mg of ma;ze starch, 4 mg of PVP~ 0O5 mg of sodium lauryl-sulphate and 0.3 mg of magnes;um stearate and the mixture is pressed to tablets.
Le A 22 7D9
Claims (14)
1. Antihypertensive and antianginal combination product containing a combination of a dihydropyridine with an unsymmetric ester grouping (component A), of the general formula I
(I) in which R1 and R1 are identical or different and repre-sent methyl, hydroxymethyl or cyano, R2 and R4 are always different from one another and represent alkyl with 1 to 10 carbon atoms, which is optionally substituted by alkoxy with 1 to 4 carbon atoms, fluorine, chlorine or N-methyl-benzylamino, and R3 represents 1 or 2 identical or different substituents from the group comprising nitro, chlorine and trifluoromethyl, or represents the radical =N-0-N=
and a .beta.-blocker without a local anaesthetic action (com-ponent B), in a weight ratio of 0.1 to 10 parts by weight of component A and 10 to 200 parts by weight of component B.
(I) in which R1 and R1 are identical or different and repre-sent methyl, hydroxymethyl or cyano, R2 and R4 are always different from one another and represent alkyl with 1 to 10 carbon atoms, which is optionally substituted by alkoxy with 1 to 4 carbon atoms, fluorine, chlorine or N-methyl-benzylamino, and R3 represents 1 or 2 identical or different substituents from the group comprising nitro, chlorine and trifluoromethyl, or represents the radical =N-0-N=
and a .beta.-blocker without a local anaesthetic action (com-ponent B), in a weight ratio of 0.1 to 10 parts by weight of component A and 10 to 200 parts by weight of component B.
2. Antihypertensive and antianginal combination pro-duct according to Claim 1, characterised in that a .beta.-blocker from the group comprising atenolol, sotalol, timolol and nadolol is used as component B.
3. Antihypertensive and antianginal combination pro-duct according to Claim 1, characterised in that nitren-dipine or nisoldipine is used as component A.
4. Combination product according to claim 1 or 2 characterised in that components A and B are used in a weight ratio of 1:2-6.
5. Combination product according to claim 1, 2 or 3, characterised in that a daily dose contains 1 to 100 mg of component A and 1 to 200 mg of component B.
6. Combination product according to claim 1, 2 or 3, characterised in that it contains 5 to 30 mg of component A and 30 to 80 mg of component B.
7. Combination product according to claim 1, 2 or 3, in the form of powders, granules, tablets, capsules or dragees.
8. A process for the preparation of the combination product according to claim 1, which comprises admixing the component A and the component B together with a pharmaceutically acceptable auxiliary or excipient.
9. A process according to claim 8, wherein the component A
is used in a crystalline or amorphous form.
is used in a crystalline or amorphous form.
10. Antihypertensive and antianginal combination product according to claim 2, characterised in that nitrendipine or nisoldipine is used as component A.
11. Combination product according to claim 10 characterised in that components A and B are used in a weight ratio of 1:2-6.
12. Combination product according to claim 10 or 11 characterised in that it contains 5 to 30 mg of component A and 30 to 80 mg of component B.
13. Combination product according to claim 1, 2 or 3, which further comprises a pharmaceutically acceptable auxiliary or excipient.
14. Combination product according to claim 10 or 11, which further comprises a pharmaceutically acceptable auxiliary or excipient.
Applications Claiming Priority (2)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| DEP3427402.2 | 1984-07-25 | ||
| DE19843427402 DE3427402A1 (en) | 1984-07-25 | 1984-07-25 | NEW COMBINATION DEVICE, METHOD FOR THE PRODUCTION THEREOF AND ITS USE AS A MEDICINAL PRODUCT |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| CA1255596A true CA1255596A (en) | 1989-06-13 |
Family
ID=6241524
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CA000485285A Expired CA1255596A (en) | 1984-07-25 | 1985-06-26 | Pharmaceutical compositions containing dihydropyridine |
Country Status (12)
| Country | Link |
|---|---|
| EP (1) | EP0169470A3 (en) |
| JP (1) | JPS6144816A (en) |
| KR (1) | KR860000870A (en) |
| AU (1) | AU576608B2 (en) |
| CA (1) | CA1255596A (en) |
| DE (1) | DE3427402A1 (en) |
| DK (1) | DK338185A (en) |
| ES (1) | ES8608887A1 (en) |
| GR (1) | GR851823B (en) |
| IL (1) | IL75873A (en) |
| PT (1) | PT80852B (en) |
| ZA (1) | ZA855584B (en) |
Families Citing this family (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| DE3424553A1 (en) * | 1984-07-04 | 1986-01-09 | Bayer Ag, 5090 Leverkusen | SOLID DRUG PREPARATIONS WITH DIHYDROPYRIDINE AND METHOD FOR THE PRODUCTION THEREOF |
| DE3447170A1 (en) * | 1984-12-22 | 1986-07-03 | Bayer Ag, 5090 Leverkusen | MIXTURE OF DIFFERENT DIHYDROPYRIDINE, METHOD FOR THE PRODUCTION THEREOF AND THEIR USE IN MEDICINAL PRODUCTS |
| DE3610037A1 (en) * | 1986-03-21 | 1987-09-24 | Schering Ag | NIFEDIPINE COMBINATION PRODUCT |
| IE59540B1 (en) * | 1987-01-09 | 1994-03-09 | Elan Corp | Sustained release capsule or tablet formulation |
Family Cites Families (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| GB2084017B (en) * | 1980-09-18 | 1984-08-22 | Sandoz Ltd | Pharmaceutical compositions effective against coronary heat disease and hypertension |
| DE3419130A1 (en) * | 1984-05-23 | 1985-11-28 | Bayer Ag, 5090 Leverkusen | NIFEDIPINE COMBINATION PREPARATIONS AND METHOD FOR THEIR PRODUCTION |
| DE3419131A1 (en) * | 1984-05-23 | 1985-11-28 | Bayer Ag, 5090 Leverkusen | DIHYDROPYRIDINE COMBINATION PREPARATIONS AND METHOD FOR THE PRODUCTION THEREOF |
-
1984
- 1984-07-25 DE DE19843427402 patent/DE3427402A1/en not_active Withdrawn
-
1985
- 1985-06-26 CA CA000485285A patent/CA1255596A/en not_active Expired
- 1985-07-15 EP EP85108806A patent/EP0169470A3/en not_active Withdrawn
- 1985-07-22 IL IL75873A patent/IL75873A/en unknown
- 1985-07-23 PT PT80852A patent/PT80852B/en not_active IP Right Cessation
- 1985-07-23 GR GR851823A patent/GR851823B/el unknown
- 1985-07-23 AU AU45285/85A patent/AU576608B2/en not_active Ceased
- 1985-07-23 KR KR1019850005239A patent/KR860000870A/en not_active Application Discontinuation
- 1985-07-24 JP JP60162170A patent/JPS6144816A/en active Pending
- 1985-07-24 ES ES545522A patent/ES8608887A1/en not_active Expired
- 1985-07-24 DK DK338185A patent/DK338185A/en not_active Application Discontinuation
- 1985-07-24 ZA ZA855584A patent/ZA855584B/en unknown
Also Published As
| Publication number | Publication date |
|---|---|
| AU4528585A (en) | 1986-01-30 |
| GR851823B (en) | 1985-11-26 |
| ES545522A0 (en) | 1986-07-16 |
| EP0169470A2 (en) | 1986-01-29 |
| JPS6144816A (en) | 1986-03-04 |
| DK338185A (en) | 1986-01-26 |
| EP0169470A3 (en) | 1988-11-02 |
| ES8608887A1 (en) | 1986-07-16 |
| ZA855584B (en) | 1986-03-26 |
| PT80852B (en) | 1987-11-30 |
| AU576608B2 (en) | 1988-09-01 |
| KR860000870A (en) | 1986-02-20 |
| DE3427402A1 (en) | 1986-01-30 |
| PT80852A (en) | 1985-08-01 |
| IL75873A0 (en) | 1985-11-29 |
| DK338185D0 (en) | 1985-07-24 |
| IL75873A (en) | 1988-11-30 |
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Legal Events
| Date | Code | Title | Description |
|---|---|---|---|
| MKEX | Expiry |