CA1212326A - Liquid formulations of dihydropyridines, a process for their preparation, and their use in combating diseases - Google Patents
Liquid formulations of dihydropyridines, a process for their preparation, and their use in combating diseasesInfo
- Publication number
- CA1212326A CA1212326A CA000448601A CA448601A CA1212326A CA 1212326 A CA1212326 A CA 1212326A CA 000448601 A CA000448601 A CA 000448601A CA 448601 A CA448601 A CA 448601A CA 1212326 A CA1212326 A CA 1212326A
- Authority
- CA
- Canada
- Prior art keywords
- dihydropyridine
- dimethyl
- dicarboxylate
- liquid formulation
- nitrophenyl
- 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
Links
Classifications
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/10—Dispersions; Emulsions
-
- 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
- A61K31/435—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
- A61K31/455—Nicotinic acids, e.g. niacin; Derivatives thereof, e.g. esters, amides
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
- A61K47/06—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
- A61K47/08—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite containing oxygen, e.g. ethers, acetals, ketones, quinones, aldehydes, peroxides
- A61K47/10—Alcohols; Phenols; Salts thereof, e.g. glycerol; Polyethylene glycols [PEG]; Poloxamers; PEG/POE alkyl ethers
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
- A61K47/06—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
- A61K47/08—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite containing oxygen, e.g. ethers, acetals, ketones, quinones, aldehydes, peroxides
- A61K47/14—Esters of carboxylic acids, e.g. fatty acid monoglycerides, medium-chain triglycerides, parabens or PEG fatty acid esters
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
- A61K47/06—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
- A61K47/26—Carbohydrates, e.g. sugar alcohols, amino sugars, nucleic acids, mono-, di- or oligo-saccharides; Derivatives thereof, e.g. polysorbates, sorbitan fatty acid esters or glycyrrhizin
Abstract
ABSTRACT
A rapidly absorbable liquid formulation of a dihydropyridine comprising, by weight, about 0.5 to 10 parts of a dihydropyridine of the formula
A rapidly absorbable liquid formulation of a dihydropyridine comprising, by weight, about 0.5 to 10 parts of a dihydropyridine of the formula
Description
The ;nvent;on relates to l;qu;d formulat;ons of dihydropyridines, in particular drop formulations, a pro-cess for their preparat;on, and their use in combating diseases.
It is known thaw dihydropyridines have very powerful actions which influence the circulation (com-pare 8ritish Patent 1,173,862). eecause they are sensi-tive to light and spar;ngly soluble, a number of d;ff;-cuLties ar;se dur;ng galen;cal formulat;on of drug special;ties, which can be seen from the numerous patents and patent appl;cations for part;cular formulat;ons ox th;s active compound. Thus, for example, U.S. Patent 3,784,6~ relates to particular gela~ine biteable capsules contain;n~ n;fed;pine, by means of wh;ch the coronary act;on of n;fedipine can advantageously be utilised.
British Patent 1,45~,618 moreover describes sol;d med;ca-ment formulat;ons wh;ch l;kew;se ensure good b;oava;l-ab;l;ty of n;fed;pine. Solid medicament forms in which the spar;ngly soluble character;st;cs of n;fedip;ne are sa;d to be compensated by using certain solub;l;s;ng agents and surface-act;ve substances are also described in DE-OS (German Published Specification 2,&22,882. In European OffenlPgungsschr;ft (European Publ;shed Speci-~;cat;on) 1,247, the absorbency of nifed;pine is also sa;d to be ;mproved by us;ng polyethylene glycol and certain porous carrier substances.
All the attempts which have hitherto been made to compensate the poor solubility of nifedipine by certa;n measures and at the same t;re to ensure good b;oava;l-ab;lity have a number of disadvantages. The use of~urface-act;ve substances, solubilising agents and certa;n carrier substances wh;ch have a part;cular surface, for example are porous, frequently leads to adm;n;strat;on , 3~S
. .
It is known thaw dihydropyridines have very powerful actions which influence the circulation (com-pare 8ritish Patent 1,173,862). eecause they are sensi-tive to light and spar;ngly soluble, a number of d;ff;-cuLties ar;se dur;ng galen;cal formulat;on of drug special;ties, which can be seen from the numerous patents and patent appl;cations for part;cular formulat;ons ox th;s active compound. Thus, for example, U.S. Patent 3,784,6~ relates to particular gela~ine biteable capsules contain;n~ n;fed;pine, by means of wh;ch the coronary act;on of n;fedipine can advantageously be utilised.
British Patent 1,45~,618 moreover describes sol;d med;ca-ment formulat;ons wh;ch l;kew;se ensure good b;oava;l-ab;l;ty of n;fed;pine. Solid medicament forms in which the spar;ngly soluble character;st;cs of n;fedip;ne are sa;d to be compensated by using certain solub;l;s;ng agents and surface-act;ve substances are also described in DE-OS (German Published Specification 2,&22,882. In European OffenlPgungsschr;ft (European Publ;shed Speci-~;cat;on) 1,247, the absorbency of nifed;pine is also sa;d to be ;mproved by us;ng polyethylene glycol and certain porous carrier substances.
All the attempts which have hitherto been made to compensate the poor solubility of nifedipine by certa;n measures and at the same t;re to ensure good b;oava;l-ab;lity have a number of disadvantages. The use of~urface-act;ve substances, solubilising agents and certa;n carrier substances wh;ch have a part;cular surface, for example are porous, frequently leads to adm;n;strat;on , 3~S
. .
- 2 -forms in wh;ch the products are undesirably large. To facilitate swallowing, such tablets or capsules are frequently converted into specific shapes, such 35, for example, elypsoids or longitudinal shapes, but this still no longer gives satisfactory results for products ~e;gh;ng more than 400 mg. More frequent intake of smaller products is also not a satisfactory solution.
A tablet containing nifedipine which is charac-terised ;n that the crystalline active compound has a lQ certain specific surface area is also known (DE-OS (German Published Specif;cat;on) 3,û33,919). Follow;ng oral adm;nistration of the tablet, the plasma concentrat;on rises and remains at a high value for many hours.
There is still a need to provide a formulation for dihydropyridines which has a very rapid absorption of active compound. When the active compound is adminis-tered as a tablet, the plasma concentration rises only slowly, because the compound is sparingly soluble.
Accord;ngly, a more rap;d onset of act;on cannot be achieved.
Adm;nistration of the act;ve compound ;n capsule Norm, in the core of which the active compound ;s dis-solved, leads to a more rapid build-up of the plasma con-- centrat;on ;n compar;son w;th the tablet administration form but in many cases an even more rapid onset of act;on is des;rable.
Moreover, there is a need in med;c;ne also to provide drop formulations, since in particular older pat;ents can be mot;vated more eas;ly to take drops than capsules or tablets.
furthermore, drop formulations can also be adm;n;stered to unconsc;ous patients w;thout compl;ca-tions. The active compound can l;kewise be fed to the body by infus;on.
hs already ment;oned above, all dihydropyr;d;nes are sparlngly soluble in an aqueous med;um. For example, .
A tablet containing nifedipine which is charac-terised ;n that the crystalline active compound has a lQ certain specific surface area is also known (DE-OS (German Published Specif;cat;on) 3,û33,919). Follow;ng oral adm;nistration of the tablet, the plasma concentrat;on rises and remains at a high value for many hours.
There is still a need to provide a formulation for dihydropyridines which has a very rapid absorption of active compound. When the active compound is adminis-tered as a tablet, the plasma concentration rises only slowly, because the compound is sparingly soluble.
Accord;ngly, a more rap;d onset of act;on cannot be achieved.
Adm;nistration of the act;ve compound ;n capsule Norm, in the core of which the active compound ;s dis-solved, leads to a more rapid build-up of the plasma con-- centrat;on ;n compar;son w;th the tablet administration form but in many cases an even more rapid onset of act;on is des;rable.
Moreover, there is a need in med;c;ne also to provide drop formulations, since in particular older pat;ents can be mot;vated more eas;ly to take drops than capsules or tablets.
furthermore, drop formulations can also be adm;n;stered to unconsc;ous patients w;thout compl;ca-tions. The active compound can l;kewise be fed to the body by infus;on.
hs already ment;oned above, all dihydropyr;d;nes are sparlngly soluble in an aqueous med;um. For example, .
3~
. .
the solubility of nimodipine in water is 0.2 mg per 1C0 ml It has now been found that when certain solu-b;lising agents are added to the drop solution in a con-centration of 20%-60X, based on the total amount of solu-tion, the very sparingly soluble active compound readilydissolves and also remains in solution. It has further-more been found that when the drop solution according to the invention is d;luted with aqueous media, such a dilu-tion rema;ns stable and clear over a relatively long period, depending on the degree of dilution.
The invent;on thus relates to liquid formulations of dihydropyrid;nes of the formula l OX
Cd3 H R3 in which R1 denotes C1-C4-alkyl, opt;onally substituted by C1-C3-alkoxy, R2 denotes C1-C10-alkyl, optionally substituted by C1-C3-alkoxy, trifluorome~hyl or N-methyl-N-benzylamino, ~3 denotes C1-C~-alkyl, cyano or hydroxymethyl and X denotes 2- or 3-nitro, 2-chloro, 2,3-dichloro or-a 2,3-ring member cons;sting of =N-0-N=, which are character;sed in that the dihydropyridines are dissolved in amounts of 0.5-1CX by weight, preferably 1-5Y by weight, based on 100 parts by weight of a solution consisting of 20 Jo 60% by weight, preferably 30-50% by weight, of a solubilising agent and 8Q to 40YO by weight, preferably 70-50X by weight, of a diluent.
z~
The compounds in the table which follows may be mentioned as preferred dihydropyridines:
a C C
.,~ .,, ., I,, .,, I, h I 'C5 h a) :~ hO O l 0 ,_ E
Z Z Z Z Z Z
O
Z
V V C) U V O U V V V V V U V V
.
.. V~
V
f r_ V to U I _~_ . V _ O O Z l I V I -- V
V V O U
O I) i Lr) U V Us h r? _ o l X
l C:._ V U r I Us _ I:; V C U -- -- V U U C V V V V V V
~.~
X O V
V _ _ I- rt /~\ o Us V Us X ::
V U V V O U V V U V
I:
tZ ~Z
O O
N N l N t l ~J O
ZZZZZZUUZZ~I~ZZ
I t X l N l ll l Ll ,~ . . O tot _ Z; I- or us U7 l CO O -- . _ C
.. , . . . .
. , , 3~
Compounds Nos.1, 3, 4, 5 and 7 may by ment;oned as preferred.
Solubilising agents is understood as meaning substances which solubil;se active compounds ~h;ch are ;nsufficiently soluble in an aqueous medium, usually with the formation of micelles. Non-ionic surface-active agents are used for this. The following compounds are suitable solubil;sing agents for the drop solutions accord;ng to the invention: sorbitan monolaurate, sor-l bitan monopalmitate, sorbitan monostearate, sorbitanmonooleate and sorbitan sesquioleate; polyethylene gly-col (20)-sorbitan monolaurate, polyethylene glycol (4)-sorbitan monolaurate, polyethylene glycol ~20)-sorbitan monopalmit3te, polyethylene glycol (Z0)-sorbitan tri-stearate, polyethylene glycol (20)-sorbitan monooleate and polyethylene glycol (20)-sorb;tan trioleate, but especially glycerol polyethylene glycol oxystearate oxyethylated with about 35 mols of ethylene oxide, glycerol polyethylene glycol oxystearate oxyethylated with about 45 mols of ethylene ox;de and glycerol poly-ethylene glycol oxystearate oxyethylated with about 60 mols of ethylene oxide.
D;luents which can be used in combination with the solubil;sing agents are water and all the solvents which are m;scible with water or the solub;l;s;ng agents an are suitable for oral purposes. Examples ox suitable - solvents are: ethanol, glycerol, 1,2-propylene glycol, polyethylene glycol 20n, polyethylene glycol 4~0 and polyethylene glycol 600.
The drops can also be aromatised. Examples of su;table aromas are: pepperm;nt o;l, contramarum aroma, cinnamon aroma, boonekamp aroma, orange aroma or lemon aroma Sweeteners, such as, for example, sacchar;n or the sod;um salt of saccharin can also be added.
Since the d;hydropyr;dine derivatives are very 3Z~
sensitive to light, it may prove to be necessary or cer-tain dyestuffs to be added to the drop solutions to pro-tect them from light and for the purpose of stabil;sation.
Suitable dyestuffs can be, for example, apocarotenal, canthaxanthine, tartrazine (E 102), amaranth YE 123) and erythrosine YE 127), but in particular Yellow Orange S
tE 110). The concentration ox the particular dyestuff is 0.01-0.5Y~ by we;ght, preferably 0.1-0.4X by weight, based on the liquid formulation.
The liquid formulations can be prepared by warming the solubilising agents, for exampLe to temperatures of 30 to 70C, d;ssolving the dihydropyridine therein, for example with stirring, adding the diluent and, if appro-pr;ate, add;ng the rema;n;ng const;tuents.
Example 1 Nimodip;ne 4û.000 9 Glycerol polyethylene glycol oxystearate oxyethylated w;th about 45 mols of ethylene ox;de 400.000 9 Ethanol 500.600 9 Example 2 N;modip;ne 40.000 9 6lycerol polyethylene glycol oxystearate oxyethylated w;th about ~5 mols of ethylene ox;de 400.000 9 Contramarum aroma 0.750 9 Ethanol 500.600 9 Example 3 N;modipine 40.000 9 Glycerol polyethylene glycol oxystearate oxyethylated w;th about 35 mols ox ethylene oxide 435.000 9 DemineraL;sed water 50.000 9 the sod;um salt of sacchar;n 9.000 9 3S Cinnamon aroma 0.500 9 Ethanol 529.200 9 3~
. - 8 -Example 4 Nisold;p;ne 20.000 g GLycerol polyethylene glycol oxystearate oxyethylated with about 60 mols of ethylene ox;de 300.000 9 Demineralised water 100.000 9 Ethanol 533.700 9 Example 5 N;sold;p;ne 25.000 9 Polyethylene glycol (20)~sorbitan monolaurate 360-000 9 Sacchar;n 5.000 9 Ethanol 700.000 9 Example 6 Nifedipine 40.000 9 Glycerol polyethylene glycol oxystearate oxyethylated w;th about 45 mols of ethylene ox;de 450.000 9 Polyethylene glycol 400 80.000 9 Dem;neralised water 80.00û 9 Boonekamp aroma 0.~00 9 Ethanol 530.600 g Example 7 Nifedipine 4Q.000 9 Glycerol polyethylene glycol oxystearate oxyethylated w;th about 45 mols of ethylene oxide 420.000 9 OranQe aroma 20.000 9 Sacchar;n 9.000 9 Ethanol 600.200 9 Example 8 M;mod;p;ne 20.000 9 Polyethylene glycol t20)-sorbitan monolaurate 380.000 9 Polyethylene glycol 400 80.000 9 Ethanol 6C7.300 9 _ 9 _ Example 9 3~Methyl 5-trifluoroethyl diester of
. .
the solubility of nimodipine in water is 0.2 mg per 1C0 ml It has now been found that when certain solu-b;lising agents are added to the drop solution in a con-centration of 20%-60X, based on the total amount of solu-tion, the very sparingly soluble active compound readilydissolves and also remains in solution. It has further-more been found that when the drop solution according to the invention is d;luted with aqueous media, such a dilu-tion rema;ns stable and clear over a relatively long period, depending on the degree of dilution.
The invent;on thus relates to liquid formulations of dihydropyrid;nes of the formula l OX
Cd3 H R3 in which R1 denotes C1-C4-alkyl, opt;onally substituted by C1-C3-alkoxy, R2 denotes C1-C10-alkyl, optionally substituted by C1-C3-alkoxy, trifluorome~hyl or N-methyl-N-benzylamino, ~3 denotes C1-C~-alkyl, cyano or hydroxymethyl and X denotes 2- or 3-nitro, 2-chloro, 2,3-dichloro or-a 2,3-ring member cons;sting of =N-0-N=, which are character;sed in that the dihydropyridines are dissolved in amounts of 0.5-1CX by weight, preferably 1-5Y by weight, based on 100 parts by weight of a solution consisting of 20 Jo 60% by weight, preferably 30-50% by weight, of a solubilising agent and 8Q to 40YO by weight, preferably 70-50X by weight, of a diluent.
z~
The compounds in the table which follows may be mentioned as preferred dihydropyridines:
a C C
.,~ .,, ., I,, .,, I, h I 'C5 h a) :~ hO O l 0 ,_ E
Z Z Z Z Z Z
O
Z
V V C) U V O U V V V V V U V V
.
.. V~
V
f r_ V to U I _~_ . V _ O O Z l I V I -- V
V V O U
O I) i Lr) U V Us h r? _ o l X
l C:._ V U r I Us _ I:; V C U -- -- V U U C V V V V V V
~.~
X O V
V _ _ I- rt /~\ o Us V Us X ::
V U V V O U V V U V
I:
tZ ~Z
O O
N N l N t l ~J O
ZZZZZZUUZZ~I~ZZ
I t X l N l ll l Ll ,~ . . O tot _ Z; I- or us U7 l CO O -- . _ C
.. , . . . .
. , , 3~
Compounds Nos.1, 3, 4, 5 and 7 may by ment;oned as preferred.
Solubilising agents is understood as meaning substances which solubil;se active compounds ~h;ch are ;nsufficiently soluble in an aqueous medium, usually with the formation of micelles. Non-ionic surface-active agents are used for this. The following compounds are suitable solubil;sing agents for the drop solutions accord;ng to the invention: sorbitan monolaurate, sor-l bitan monopalmitate, sorbitan monostearate, sorbitanmonooleate and sorbitan sesquioleate; polyethylene gly-col (20)-sorbitan monolaurate, polyethylene glycol (4)-sorbitan monolaurate, polyethylene glycol ~20)-sorbitan monopalmit3te, polyethylene glycol (Z0)-sorbitan tri-stearate, polyethylene glycol (20)-sorbitan monooleate and polyethylene glycol (20)-sorb;tan trioleate, but especially glycerol polyethylene glycol oxystearate oxyethylated with about 35 mols of ethylene oxide, glycerol polyethylene glycol oxystearate oxyethylated with about 45 mols of ethylene ox;de and glycerol poly-ethylene glycol oxystearate oxyethylated with about 60 mols of ethylene oxide.
D;luents which can be used in combination with the solubil;sing agents are water and all the solvents which are m;scible with water or the solub;l;s;ng agents an are suitable for oral purposes. Examples ox suitable - solvents are: ethanol, glycerol, 1,2-propylene glycol, polyethylene glycol 20n, polyethylene glycol 4~0 and polyethylene glycol 600.
The drops can also be aromatised. Examples of su;table aromas are: pepperm;nt o;l, contramarum aroma, cinnamon aroma, boonekamp aroma, orange aroma or lemon aroma Sweeteners, such as, for example, sacchar;n or the sod;um salt of saccharin can also be added.
Since the d;hydropyr;dine derivatives are very 3Z~
sensitive to light, it may prove to be necessary or cer-tain dyestuffs to be added to the drop solutions to pro-tect them from light and for the purpose of stabil;sation.
Suitable dyestuffs can be, for example, apocarotenal, canthaxanthine, tartrazine (E 102), amaranth YE 123) and erythrosine YE 127), but in particular Yellow Orange S
tE 110). The concentration ox the particular dyestuff is 0.01-0.5Y~ by we;ght, preferably 0.1-0.4X by weight, based on the liquid formulation.
The liquid formulations can be prepared by warming the solubilising agents, for exampLe to temperatures of 30 to 70C, d;ssolving the dihydropyridine therein, for example with stirring, adding the diluent and, if appro-pr;ate, add;ng the rema;n;ng const;tuents.
Example 1 Nimodip;ne 4û.000 9 Glycerol polyethylene glycol oxystearate oxyethylated w;th about 45 mols of ethylene ox;de 400.000 9 Ethanol 500.600 9 Example 2 N;modip;ne 40.000 9 6lycerol polyethylene glycol oxystearate oxyethylated w;th about ~5 mols of ethylene ox;de 400.000 9 Contramarum aroma 0.750 9 Ethanol 500.600 9 Example 3 N;modipine 40.000 9 Glycerol polyethylene glycol oxystearate oxyethylated w;th about 35 mols ox ethylene oxide 435.000 9 DemineraL;sed water 50.000 9 the sod;um salt of sacchar;n 9.000 9 3S Cinnamon aroma 0.500 9 Ethanol 529.200 9 3~
. - 8 -Example 4 Nisold;p;ne 20.000 g GLycerol polyethylene glycol oxystearate oxyethylated with about 60 mols of ethylene ox;de 300.000 9 Demineralised water 100.000 9 Ethanol 533.700 9 Example 5 N;sold;p;ne 25.000 9 Polyethylene glycol (20)~sorbitan monolaurate 360-000 9 Sacchar;n 5.000 9 Ethanol 700.000 9 Example 6 Nifedipine 40.000 9 Glycerol polyethylene glycol oxystearate oxyethylated w;th about 45 mols of ethylene ox;de 450.000 9 Polyethylene glycol 400 80.000 9 Dem;neralised water 80.00û 9 Boonekamp aroma 0.~00 9 Ethanol 530.600 g Example 7 Nifedipine 4Q.000 9 Glycerol polyethylene glycol oxystearate oxyethylated w;th about 45 mols of ethylene oxide 420.000 9 OranQe aroma 20.000 9 Sacchar;n 9.000 9 Ethanol 600.200 9 Example 8 M;mod;p;ne 20.000 9 Polyethylene glycol t20)-sorbitan monolaurate 380.000 9 Polyethylene glycol 400 80.000 9 Ethanol 6C7.300 9 _ 9 _ Example 9 3~Methyl 5-trifluoroethyl diester of
4-(2-chlorophenyl)-2,6-dimethyl-1,4-dihydropyridine 30.000 9 Glycerol polyethylene glycol oxystearate oxyethylated with about 35 mols of ethylene oxide 400.û00 9 Lemon aroma 10.0û0 9 Ethanol 619.600 g Example 10 3-methyl 5-tr;fluoromethyl d;ester of 4-(2-chlorophenyl)-2,6-dimethyl-1,4-dihydropyridine 40.000 9 Polyethylene glycol t2Q)-sorbitan monopalmitate 500.000 9 1,2 Propylene glycol Z00.000 9 Peppermint oil 1.000 9 Ethanol 518.000 9 Example 11 Nifedipine 20.000 g glycerol polyethylene glycol oxys~earate oxyethylated with about 45 mols of ethylene oxide 400.000 g Orange aroma 20.000 9 25 Yellow Orange S 4.000 9 Demineralised water 100.000 g Ethanol 509.700 9 Example 12 Nisoldipine 20.000 g Glycerol polyethylene glycol oxystearate oxyethylated with about 45 mols of ethylene oxide 420.000 9 Yellow Orange S 4.000 9 Demineralised water 110.000 9 - 35 Ethanol 513.300 9 Because of its properties, the liqu;d formulation I' ~Z~3~6 is suitabLe for the prophylax;s of acute and chronis ;schaem;c heart d;sease ;n the broadest sense, for the therapy of high blood pressure and for the treatment of disorders in cerebral and peripheral blood flow.
In general, ;t has proved advantageous, in the case of ;ntravenous administration, to adm;n;ster amounts of about 0.001 to ~0 mg/kg of body we;ght, preferably about 0.05 to 5 mg/kg of body we;ght, of d;hydropyr;dine per day to ach;eve effect;ve results, and in the case of oral adm;n;stration the dosage is about 0.05 to 20 mg/~g of body weight, preferably 0.5 to 5 mg/kg of body weight, per day.
~!evertheless, it may at times be necessary to dev;ate from the amounts mentioned, and in particular to do so as a function of the body we;sht or the type of administration route but also because of the an;mal spec;es and ;ts individual behaviour towards the medica-ment or the time or ;nterval at which adm;n;strat;on takes place. Thus, ;n some cases it may be sufficient to manage with less than the abovementioned min;mum amount, whilst in other cases the upper limit mentioned must be exceeded. Where relatively large amounts are administered, ;t may be advisable to d;v;de these into several ;nd;
v;dual administrat;ons throughout the day. The same dosage range ;s env;saged for administration in human medicine. The above statements also apply ;n the general sense.
Admin;strat;on of a drop solution gives a more rapid absorption of active compound and surprisingly 3n h;gher blood level values in compar;son w;th a capsule.
Such drop formulations can also be easily administered by stomach tube, without corpl;cat;ons, to unconsc;ous patients suffering from a vasospasm following subarach-noidal haemorrhage.
The more rapid absorption of active compound and the higher blood level value may be illustrated by the 3~
example of nimodipine with the aid of the follow;ng experiments:
6 volunteer test subjects each take 60 mg of n;mod;p;ne orally w;th 200 ml sf water. After certa;n periods of time after taking the active compound, the blood level values are determined by gas liqu;d chroma-tography.
After the formulat;on, according to the invention, ;n Examole 1 has been taken, the highest blood plasma 10 concentrat;on ;s 115.5 + 78.3 ~g/litre after 15 minutes.
After 24 hoursO the corresponding value ;s below the detection limit of 2 ~g/l;treO The mean area under curve 1 ~AUC~ is 107.6 51.4 hours. ygll;tre~ The mean value for the b;oava;lab;l;ty ;s calculated as 8.6 1 4.6%.
Figure 1 shows the exact course of the curve for the solut;on (-+-) and, as a comparison, that of the cap-sule (-0-).
- The nimodipine capsule taken for comparison gives, as a value for the highest blood plasma concen-20 tration, 60.8 + 48.0 yg/litre after 3û m;nutes. After 24 hours, the corresponding value is again below the detec-t;on limit. The mean value of the bioavailability is calculated as 8.8 1 4.4X. The mean area under curve 1 ~Al1C) ;s 91.6 35.8 hours. ~g/litre.
The d;fference in act;on between the l;quid formu-lation according to the invention and the corresponding capsule can eas;ly be seen from the curve and from the ; tabular values. After 15 ~;nutes, the bLood concentration is 16.6 12.4 ~g/litre when the capsule is taken, whilst the corresponding value for the liqu;d formulation is 115.5 + 78.3 ~g/litre.
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In general, ;t has proved advantageous, in the case of ;ntravenous administration, to adm;n;ster amounts of about 0.001 to ~0 mg/kg of body we;ght, preferably about 0.05 to 5 mg/kg of body we;ght, of d;hydropyr;dine per day to ach;eve effect;ve results, and in the case of oral adm;n;stration the dosage is about 0.05 to 20 mg/~g of body weight, preferably 0.5 to 5 mg/kg of body weight, per day.
~!evertheless, it may at times be necessary to dev;ate from the amounts mentioned, and in particular to do so as a function of the body we;sht or the type of administration route but also because of the an;mal spec;es and ;ts individual behaviour towards the medica-ment or the time or ;nterval at which adm;n;strat;on takes place. Thus, ;n some cases it may be sufficient to manage with less than the abovementioned min;mum amount, whilst in other cases the upper limit mentioned must be exceeded. Where relatively large amounts are administered, ;t may be advisable to d;v;de these into several ;nd;
v;dual administrat;ons throughout the day. The same dosage range ;s env;saged for administration in human medicine. The above statements also apply ;n the general sense.
Admin;strat;on of a drop solution gives a more rapid absorption of active compound and surprisingly 3n h;gher blood level values in compar;son w;th a capsule.
Such drop formulations can also be easily administered by stomach tube, without corpl;cat;ons, to unconsc;ous patients suffering from a vasospasm following subarach-noidal haemorrhage.
The more rapid absorption of active compound and the higher blood level value may be illustrated by the 3~
example of nimodipine with the aid of the follow;ng experiments:
6 volunteer test subjects each take 60 mg of n;mod;p;ne orally w;th 200 ml sf water. After certa;n periods of time after taking the active compound, the blood level values are determined by gas liqu;d chroma-tography.
After the formulat;on, according to the invention, ;n Examole 1 has been taken, the highest blood plasma 10 concentrat;on ;s 115.5 + 78.3 ~g/litre after 15 minutes.
After 24 hoursO the corresponding value ;s below the detection limit of 2 ~g/l;treO The mean area under curve 1 ~AUC~ is 107.6 51.4 hours. ygll;tre~ The mean value for the b;oava;lab;l;ty ;s calculated as 8.6 1 4.6%.
Figure 1 shows the exact course of the curve for the solut;on (-+-) and, as a comparison, that of the cap-sule (-0-).
- The nimodipine capsule taken for comparison gives, as a value for the highest blood plasma concen-20 tration, 60.8 + 48.0 yg/litre after 3û m;nutes. After 24 hours, the corresponding value is again below the detec-t;on limit. The mean value of the bioavailability is calculated as 8.8 1 4.4X. The mean area under curve 1 ~Al1C) ;s 91.6 35.8 hours. ~g/litre.
The d;fference in act;on between the l;quid formu-lation according to the invention and the corresponding capsule can eas;ly be seen from the curve and from the ; tabular values. After 15 ~;nutes, the bLood concentration is 16.6 12.4 ~g/litre when the capsule is taken, whilst the corresponding value for the liqu;d formulation is 115.5 + 78.3 ~g/litre.
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Claims (30)
PROPERTY OR PRIVILEGE IS CLAIMED ARE DEFINED AS FOLLOWS:
1. A liquid formulation containing one or more dihydropyri-dines of the formula I
I
in which R1 denotes C1-C4-alkyl, optionally substituted by C2-C3-alkoxy, R2 denotes C1-C10-alkyl, optionally substituted by C1-C3-alkoxy,trifluoromethyl or N-methyl-N-benzylamino, R3 denotes C1-C4-alkyl, cyano or hydroxymethyl and X denotes 2- or 3-nitro, 2-chloro, 2,3-dicloro or a 2,3-ring member consisting of =N-O-N=, characterised in that the dihydropyridine is present in an amount of 0.5-10% by weight, based on 100 parts by weight of a solution consisting of 20 to 60% by weight of a solubilising agent and 80 to 40% by weight of a diluent.
I
in which R1 denotes C1-C4-alkyl, optionally substituted by C2-C3-alkoxy, R2 denotes C1-C10-alkyl, optionally substituted by C1-C3-alkoxy,trifluoromethyl or N-methyl-N-benzylamino, R3 denotes C1-C4-alkyl, cyano or hydroxymethyl and X denotes 2- or 3-nitro, 2-chloro, 2,3-dicloro or a 2,3-ring member consisting of =N-O-N=, characterised in that the dihydropyridine is present in an amount of 0.5-10% by weight, based on 100 parts by weight of a solution consisting of 20 to 60% by weight of a solubilising agent and 80 to 40% by weight of a diluent.
2. A liquid formulation according to Claim 1 which contains 1-5% by weight of the dihydropyridine.
3. A liquid formulation according to Claim 1 wherein the solution consists of 30-50% by weight of a solubilising agent and 70-50% by weight of a diluent.
4. A liquid formulation according to Claim 1, 2 or 3 which contains, as the solubilising agent sorbitan monolaurate, sorbitan monopalmitate, sorbitan monostearate, sorbitan monooleate, sorbitan sesquioleate, polyethylene glycol (20)-sorbitan mono-laurate, polyethylene glycol (4)-sorbitan monolaurate, polyethylene glycol (20)-sorbitan monopalmitate, polyethylene glycol (20)-sorbitan tristearate, polyethylene glycol (20)-sorbitan monooleate or polyethylene glycol (20)-sorbitan trioleate.
5. A liquid formulation according to Claim 1, 2 or 3 which contains, as the solubilising agent, glycerol polyethylene glycol oxystearate oxyethylated with about 35 mols of ethylene oxide, glycerol polyethylene glycol oxystearate oxyethylated with about 45 mols of ethylene oxide or glycerol polyethylene glycol oxystearate oxyethylated with about 60 mols of ethylene oxide.
6. A liquid formulation according to Claim 1, 2 or 3, which contains, as the diluent, water, ethanol, glycerol, 1,2-propylene glycol, polyethylene glycol 200, polyethylene glycol 400 or polyethylene glycol 600.
7. A liquid formulation according to Claim 1, 2 or 3 containing a dihydropyridine of the formula I in which X represents 2- or 3-nitro or 2-chloro, R1 represents methyl, ethyl, propoxyethyl or iso-propyl, R2 represents methyl, trifluoroethyl, propoxyethyl, isobutyl or methoxyethyl and R3 represents methyl.
8. A process for the preparation of a liquid formulation according to Claim 1, wherein the solubilising agent is warmed, the dihydropyridine is dissolved therein and the diluent is added.
9. A process according to claim 8 wherein any remaining constituents are added with the diluent.
10. A process according to claim 8 wherein the solubilising agent composes 20 to 60% by weight of the solubilising agent plus diluent, the diluent composes 80 to 40% by weight of the solubilising agent plus diluent and the dihydropyridine is present in an amount of 0.5 to 10% by weight, based on 100 parts by weight of solubilis-ing agent plus diluent.
11. A liquid formulation according to claim 1,2 or 3 wherein the dihydropyridine comprises dimethyl 2,6-dimethyl-4-(2-nitrophenyl)-dihydropyridine-3,5-dicarboxylate of the formula
12. A liquid formulation according to claim 1,2 or 3 wherein the dihydropyridine comprises di-n-propoxyethyl 2,6-dimethyl-4-(3-nitrophenyl)-dihydropyridine-3,5-dicarboxylate of the formula
13. A liquid formulation according to claim 1,2 or 3 wherein the dihydropyridine comprises ethyl methyl 2,6-dimethyl-4-(3-nitrophenyl)-dihydropyridine-3,5-dicarboxylate of the formula
14. A liquid formulation according to claim 1,2 or 3 wherein the dihydropyridine comprises isobutyl methyl 2,6-dimethyl-4-(2-nitrophenyl)-dihydropyridine-3,5-dicarboxylate of the formula
15. A liquid formulation according to claim 1,2 or 3 wherein the dihydropyridine comprises isopropyl methoxy-ethyl 2,6-dimethyl-4-(3-nitrophenyl)-dihydropyridine-3,5-dicarboxylate of the formula
16. A liquid formulation according to claim 1,2 or 3 wherein the dihydropyridine comprises n-decyl ethyl 2,6-dimethyl-4-(3-nitrophenyl)-dihydropyridine-3,5-dicarboxylate of the formula
17. A liquid formulation according to claim 1, 2 or 3 wherein the dihydropyridine comprises methyl 2,2,2-tri-fluoroethyl 2,6-dimethyl-4-(2-chlorophenyl)-dihydro-pyridine-3,5-dicarboxylate of the formula
18. A liquid formulation according to claim 1,2 or 3 wherein the dihydropyridine comprises ethyl 2,2,2-tri-fluoroethyl 2,6-dimethyl-4-(2-chlorophenyl)-dihydropyridine-3,5-dicarboxylate of the formula
19. A liquid formulation according to claim 1,2 or 3 wherein the dihydropyridine comprises isopropyl n-propoxy-ethyl 2,6-dimethyl-4-(3-nitrophenyl) dihydropyridine-3,5-dicarboxylate of the formula
20. A liquid formulation according to claim 1, 2 or 3 wherein the dihydropyridine comprises methyl N-methylbenzylamino-ethyl 2,6-dimethyl-4-(3-nitrophenyl)-dihydropyridine-3,5-dicarboxylate of the formula
21. A process according to claim 8, 9 or 10 wherein the dihydro-pyridine is dimethyl 2,6-dimethyl-4-(2-nitrophenyl)-dihydropyridine-3,5-dicarboxylate.
22. A process according to claim 8, 9 or 10 wherein the dihydro-pyridine is di-n-propoxyethyl 2,6-dimethyl-4-(3-nitrophenyl)-dihydropyridine-3,5-dicarboxylate.
23. A process according to claim 8, 9 or 10 wherein the dihydro-pyridine is ethyl methyl 2,6-dimethyl-4-(3-nitrophenyl)-dihydropyridine-3,5-dicarboxylate.
24. A process according to claim 8, 9 or 10 wherein the dihydro-pyridine is isobutyl methyl 2,6-dimethyl-4-(2-nitrophenyl)-dihydropyridine-3,5-dicarboxylate.
25. A process according to claim 8, 9 or 10 wherein the dihydro-pyridine is isopropyl methoxyethyl 2,6-dimethyl-4-(3-nitrophenyl)-dihydro-pyridine-3,5-dicarboxylate.
26. A process according to claim 8, 9 or 10 wherein the dihydro-pyridine is n-decyl ethyl 2,6-dimethyl-4-(3-nitrophenyl)-dihydropyridine-3,5-dicarboxylate.
27. A process according to claim 8, 9 or 10 wherein the dihydro-pyridine is methyl 2,2,2-trifluoroethyl 2,6-dimethyl-4-(2-chlorophenyl)-dihydropyridine-3,5-dicarboxylate.
28. A process according to claim 8, 9 or 10 wherein the dihydro-pyridine is ethyl 2,2,2-trifluoroethyl, 2,6-dimethyl-4-(2-chlorophenyl)-di-hydropyridine-3,5-dicarboxylate.
29. A process according to claim 8, 9 or 10 wherein the dihydro-pyridine is isopropyl n-propoxyethyl 2,6-dimethyl-4-(3-nitrophenyl)-dihydro-pyridine-3,5-dicarboxylate.
30. A process according to claim 8, 9 or 10 wherein the dihydro-pyridine is methyl N-methylbenzylamino-ethyl 2,6-dimethyl-4-(3-nitrophenyl)-dihydropyridine-3,5-dicarboxylate.
Applications Claiming Priority (2)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| DEP3307422.4 | 1983-03-03 | ||
| DE19833307422 DE3307422A1 (en) | 1983-03-03 | 1983-03-03 | LIQUID PREPARATIONS OF DIHYDROPYRIDINES, A METHOD FOR THE PRODUCTION THEREOF AND THEIR USE IN THE FIGHT AGAINST DISEASES |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| CA1212326A true CA1212326A (en) | 1986-10-07 |
Family
ID=6192336
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CA000448601A Expired CA1212326A (en) | 1983-03-03 | 1984-03-01 | Liquid formulations of dihydropyridines, a process for their preparation, and their use in combating diseases |
Country Status (20)
| Country | Link |
|---|---|
| US (1) | US4537898A (en) |
| EP (1) | EP0117888B2 (en) |
| JP (1) | JPS59167512A (en) |
| KR (1) | KR900004091B1 (en) |
| AT (1) | ATE29665T1 (en) |
| AU (1) | AU566408B2 (en) |
| CA (1) | CA1212326A (en) |
| DE (2) | DE3307422A1 (en) |
| DK (1) | DK163961C (en) |
| ES (1) | ES8503948A1 (en) |
| GR (1) | GR79546B (en) |
| HK (1) | HK41290A (en) |
| HU (1) | HU194048B (en) |
| IE (1) | IE57158B1 (en) |
| IL (1) | IL71097A (en) |
| IT (1) | IT1212724B (en) |
| NO (1) | NO840770L (en) |
| PH (1) | PH21000A (en) |
| PT (1) | PT78149B (en) |
| ZA (1) | ZA841584B (en) |
Families Citing this family (32)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| JPS59222474A (en) * | 1983-06-02 | 1984-12-14 | Teijin Ltd | 1,4-dihydropyridine-3,5-dicarboxylic acid diester derivative, its preparation and drug containing said derivative as active component |
| JPS6038322A (en) * | 1983-08-11 | 1985-02-27 | Fujisawa Pharmaceut Co Ltd | Easily soluble solid preparation containing dihydropyridine-a substance |
| US4637930A (en) * | 1984-02-08 | 1987-01-20 | Yamanouchi Pharmaceutical Co, Ltd. | Transdermal formulation of nicardipine hydrochloride |
| JPS60246313A (en) * | 1984-05-22 | 1985-12-06 | Yamanouchi Pharmaceut Co Ltd | Injection of nicardipine hydrochloride and its preparation |
| FR2568773B1 (en) * | 1984-08-10 | 1989-03-03 | Sandoz Lab | NEW NASAL ADMINISTRATIVE PHARMACEUTICAL COMPOSITIONS |
| EP0175671A1 (en) † | 1984-08-23 | 1986-03-26 | Kuhlemann & Co. | Pharmaceutical preparation and method for the administration of this pharmaceutical preparation |
| DE3433239A1 (en) * | 1984-09-11 | 1986-03-20 | Bayer Ag, 5090 Leverkusen | SOLID PHARMACEUTICAL PREPARATION CONTAINING NITRENDIPINE AND METHOD FOR THE PRODUCTION THEREOF |
| DE3581987D1 (en) * | 1984-09-21 | 1991-04-11 | Univ Iowa Res Found | IMMUNOGENIC CONJUGATES AND THEIR USE IN A DIHYDROPYRIDINE SAMPLE. |
| US5260321A (en) * | 1984-11-12 | 1993-11-09 | Sandoz Ltd. | Use of 1,4-dihydropyridine derivatives and combinations thereof with calcitonins |
| GB8428552D0 (en) * | 1984-11-12 | 1984-12-19 | Sandoz Ltd | Organic compounds |
| GB8431119D0 (en) * | 1984-12-10 | 1985-01-16 | Fujisawa Pharmaceutical Co | Anti-arteriosclerotic composition |
| 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 |
| EP0188311A3 (en) * | 1985-01-07 | 1988-07-20 | Syntex (U.S.A.) Inc. | Pharmaceutical formulation of nicardipine and 1,2-dioxy-omega-trialkylammonium compounds |
| GB2180532B (en) * | 1985-09-17 | 1989-08-23 | Inst Organicheskogo Sinteza Ak | Alkoxy-and phenoxy-alkyl-esters of 2,6-dimethyl-4-(2-difluoromethoxyphenyl)-1,4-dihydropyridine-3,5-dicarboxylic acid |
| DE3544692A1 (en) * | 1985-12-18 | 1987-06-19 | Bayer Ag | DIHYDROPYRIDINE SPRAY, METHOD FOR THE PRODUCTION THEREOF AND ITS PHARMACEUTICAL USE |
| AT387518B (en) * | 1985-12-18 | 1989-02-10 | Bayer Ag | Process for the production of liquid dihydropyridine spray products |
| EP0240484B1 (en) * | 1986-03-10 | 1992-01-15 | Kurt Dr. Burghart | Pharmaceutical composition and its preparation |
| US4782070A (en) * | 1986-07-01 | 1988-11-01 | Fujisawa Pharmaceutical Co., Ltd. | Cerebral dysfunction therapeutic agent, which comprises a dihydropyridine compound |
| GB8629761D0 (en) * | 1986-12-12 | 1987-01-21 | Harris Pharma Ltd | Capsules |
| US5001139A (en) * | 1987-06-12 | 1991-03-19 | American Cyanamid Company | Enchancers for the transdermal flux of nivadipine |
| SE8703881D0 (en) * | 1987-10-08 | 1987-10-08 | Haessle Ab | NEW PHARMACEUTICAL PREPARATION |
| DE3738236A1 (en) * | 1987-11-11 | 1989-05-24 | Euro Celtique Sa | BIT CAPSULE |
| US5160734A (en) * | 1987-11-25 | 1992-11-03 | American Cyanamid Company | Sustained release delivery system for substituted dihydropyridine calcium channel blockers |
| ZA89552B (en) * | 1988-01-29 | 1989-10-25 | Merrell Dow Pharma | Pharmaceutical composition for 4-aroylimidazol-2-ones |
| US5478848A (en) * | 1994-01-26 | 1995-12-26 | Bayer Corporation | Inhibition of arthritis by L-type calcium channel antagonists nimodipine, nisoldipine and nifedipine |
| HU214582B (en) | 1994-07-26 | 1998-04-28 | EGIS Gyógyszergyár Rt. | Spayable antihypertensive composition and process for it`s production |
| ES2133052B1 (en) * | 1996-04-29 | 2000-05-01 | Almirall Prodesfarma Sa | NEW LIQUID PHARMACEUTICAL FORMULATIONS FOR THE ORAL WAY. |
| DE10142416A1 (en) * | 2001-08-31 | 2003-03-20 | Molecular And Clinical Drug Re | Process for the preparation of solutions |
| DE10142417A1 (en) * | 2001-08-31 | 2003-03-20 | Molecular And Clinical Drug Re | drug |
| JP2009511594A (en) * | 2005-10-14 | 2009-03-19 | トランスフオーム・フアーマシユーチカルズ・インコーポレーテツド | Liquid pharmaceutical composition of nimodipine |
| WO2011080246A1 (en) | 2009-12-28 | 2011-07-07 | Laboratorio Reig Jofré, S.A. | Oral liquid pharmaceutical composition of nifedipine |
| CN105168175A (en) * | 2015-08-25 | 2015-12-23 | 瑞阳制药有限公司 | Nisoldipine capsule and preparation method thereof |
Family Cites Families (10)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| DE1670827C3 (en) * | 1967-03-20 | 1974-10-24 | Bayer Ag, 5090 Leverkusen | 4- (2'-nitrophenyl) -2,6-dimethyl-3,5-dicarbmethoxy-1,4-dihydropyridine |
| SU432703A3 (en) * | 1971-08-24 | 1974-06-15 | Фридрих Боссерт, Вульф Фатер, Курт Бауер | |
| DE2400819C2 (en) * | 1974-01-09 | 1982-04-22 | Bayer Ag, 5090 Leverkusen | Process for the production of solid preparations of poorly soluble active pharmaceutical ingredients in extremely fine distribution |
| JPS5335124A (en) * | 1976-09-10 | 1978-04-01 | Nippon Denso Co Ltd | Converter |
| EP0001247A1 (en) * | 1977-09-14 | 1979-04-04 | Kanebo, Ltd. | Pharmaceutical preparation containing nifedipine and a method for producing the same. |
| DE2815578C2 (en) * | 1978-04-11 | 1986-01-16 | Bayer Ag, 5090 Leverkusen | New pharmaceutical use of nimodipine |
| SE429652B (en) * | 1978-06-30 | 1983-09-19 | Haessle Ab | 2,6-dimethyl-4- (2,3-dichlorophenyl) -1,4-dihydropyridine-3,5-dicarboxylic acid 3-methyl 5-ethyl ester |
| JPS56115726A (en) * | 1980-02-20 | 1981-09-11 | Kaken Pharmaceut Co Ltd | Pharmaceutical containing nifedipine |
| GB2084017B (en) * | 1980-09-18 | 1984-08-22 | Sandoz Ltd | Pharmaceutical compositions effective against coronary heat disease and hypertension |
| JPS57167911A (en) * | 1981-04-09 | 1982-10-16 | Kyoto Yakuhin Kogyo Kk | Liquid pharmaceutical of nifedipine |
-
1983
- 1983-03-03 DE DE19833307422 patent/DE3307422A1/en not_active Withdrawn
- 1983-03-14 EP EP83102475A patent/EP0117888B2/en not_active Expired - Lifetime
- 1983-03-14 AT AT83102475T patent/ATE29665T1/en not_active IP Right Cessation
- 1983-03-14 DE DE8383102475T patent/DE3373625D1/en not_active Expired
- 1983-03-25 IT IT8320301A patent/IT1212724B/en active
-
1984
- 1984-02-13 US US06/579,833 patent/US4537898A/en not_active Expired - Lifetime
- 1984-02-23 PT PT78149A patent/PT78149B/en not_active IP Right Cessation
- 1984-02-27 DK DK108684A patent/DK163961C/en not_active IP Right Cessation
- 1984-02-28 IL IL71097A patent/IL71097A/en not_active IP Right Cessation
- 1984-02-28 ES ES530115A patent/ES8503948A1/en not_active Expired
- 1984-02-29 NO NO840770A patent/NO840770L/en unknown
- 1984-02-29 PH PH30312A patent/PH21000A/en unknown
- 1984-02-29 JP JP59036370A patent/JPS59167512A/en active Granted
- 1984-03-01 AU AU25205/84A patent/AU566408B2/en not_active Ceased
- 1984-03-01 GR GR73969A patent/GR79546B/el unknown
- 1984-03-01 CA CA000448601A patent/CA1212326A/en not_active Expired
- 1984-03-02 IE IE517/84A patent/IE57158B1/en not_active IP Right Cessation
- 1984-03-02 HU HU84855A patent/HU194048B/en not_active IP Right Cessation
- 1984-03-02 ZA ZA841584A patent/ZA841584B/en unknown
- 1984-03-03 KR KR1019840001081A patent/KR900004091B1/en not_active IP Right Cessation
-
1990
- 1990-05-31 HK HK412/90A patent/HK41290A/en not_active IP Right Cessation
Also Published As
| Publication number | Publication date |
|---|---|
| DK108684D0 (en) | 1984-02-27 |
| EP0117888B1 (en) | 1987-09-16 |
| HK41290A (en) | 1990-06-08 |
| EP0117888A1 (en) | 1984-09-12 |
| NO840770L (en) | 1984-09-04 |
| ATE29665T1 (en) | 1987-10-15 |
| KR840008278A (en) | 1984-12-14 |
| DK163961C (en) | 1992-09-21 |
| IL71097A (en) | 1987-09-16 |
| GR79546B (en) | 1984-10-30 |
| IL71097A0 (en) | 1984-05-31 |
| DE3373625D1 (en) | 1987-10-22 |
| US4537898A (en) | 1985-08-27 |
| AU566408B2 (en) | 1987-10-22 |
| IE840517L (en) | 1984-09-03 |
| AU2520584A (en) | 1984-09-06 |
| IT1212724B (en) | 1989-11-30 |
| PT78149A (en) | 1984-03-01 |
| JPS59167512A (en) | 1984-09-21 |
| DE3307422A1 (en) | 1984-09-06 |
| HU194048B (en) | 1988-01-28 |
| IE57158B1 (en) | 1992-05-20 |
| EP0117888B2 (en) | 1992-08-26 |
| PT78149B (en) | 1986-05-19 |
| IT8320301A0 (en) | 1983-03-25 |
| DK108684A (en) | 1984-09-04 |
| DK163961B (en) | 1992-04-27 |
| PH21000A (en) | 1987-06-22 |
| ES530115A0 (en) | 1985-04-16 |
| ES8503948A1 (en) | 1985-04-16 |
| JPH0460092B2 (en) | 1992-09-25 |
| KR900004091B1 (en) | 1990-06-15 |
| ZA841584B (en) | 1985-06-26 |
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