CA1059914A - Pharmaceutical preparation for the treatment of circulatory disorders - Google Patents
Pharmaceutical preparation for the treatment of circulatory disordersInfo
- Publication number
- CA1059914A CA1059914A CA242,910A CA242910A CA1059914A CA 1059914 A CA1059914 A CA 1059914A CA 242910 A CA242910 A CA 242910A CA 1059914 A CA1059914 A CA 1059914A
- Authority
- CA
- Canada
- Prior art keywords
- active compound
- acid
- pharmaceutical preparation
- slow
- release
- 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
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/60—Salicylic acid; Derivatives thereof
- A61K31/618—Salicylic acid; Derivatives thereof having the carboxyl group in position 1 esterified, e.g. salsalate
- A61K31/621—Salicylic acid; Derivatives thereof having the carboxyl group in position 1 esterified, e.g. salsalate having the hydroxy group in position 2 esterified, e.g. benorylate
-
- 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
- A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
- A61K31/415—1,2-Diazoles
-
- 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
- A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
- A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
-
- 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
- A61K31/60—Salicylic acid; 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
- A61K31/60—Salicylic acid; Derivatives thereof
- A61K31/625—Salicylic acid; Derivatives thereof having heterocyclic substituents, e.g. 4-salicycloylmorpholine
-
- 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
- A61K9/20—Pills, tablets, discs, rods
- A61K9/2004—Excipients; Inactive ingredients
- A61K9/2013—Organic compounds, e.g. phospholipids, fats
Abstract
Pharmaceutical Preparation for the Treatment of Circulatory Disorders Abstract of the Disclosure Pharmaceutical preparations in the solid form, which can be used orally and which give slow and continuous release, that is to say so-called retard or slow release preparations, containing phentolamine, or a pharmaceutically usuable salt thereof, as the pharmacological active compound cause a long-lasting dilatation of the veins and arteries, which render the new preparations suitable, above all, for the treatment of chronic cardiac insufficiency (myocardial insufficiency) and of angina pectoris.
Description
It is kno~n that phentolamine, that is to say 2-[N-(3-hydroxyphenyl)-N-(4-methyl-phenyl)-aminomethyl]-imidazoline of the formula H3C ~ \ ~ N
CH2 C~
~ / H
HO
and its pharmaceutically usable sal-ts exhibit an antagonistic effect against the active compounds of the adrenergic system, that is to say act as alpha-receptor-blocking agents, there being, in addition, a vasodilating and beta-receptor-stimulating active component. Because of -their pharmacological properties, the compound and its salts effect a peripheral vasodilatation and an increase in the heart rate and augment the myocardial contractility, there being no undesirable de-~eases in the blood pressure. The field of application for the compound has, however, remained extremely restricted, namely to the test for suspected phaeochromocytoma, to the treat-ment of blood pressure crises when phaeochromocytoma is confirmed and to prophylaxis before and during the operation, as well as to the treatment of peripheral arterial perfusion disorders. As is stated in Helwig, Moderne Arzneimittel (Modern Medicaments), page 935 (4th edition 1972; Wissen-schaftliche Verlagsgesellschaft, Stuttgart, Germany), the preparation cannot be used for other indications.
It has now been found that when phentolamine, or a pharmaceutically usable salt thereof, is administered in a suitable pharmaceutical form the range of indications for these compounds can be extended in a surprising manner.
This extension of the range of indications is a result of the use of phentol-amine, or a pharmaceutically usable salt thereof, in the form of an oral phar-maceutical preparation which is suitable for the slow and continuous release of the active compoundO
It has been found that pharmaceutical preparations in the solid form, which can be used orally and which give slow and continuous release, that is to say so-called retard or slow release preparations, containing phentolamine, or a pharmaceutically usable salt thereof, as the pharmacological active compound cause a long-lasting dilatation of the veins and arteries, which, on the one hand, effects a reduction in the regurgitation of venous blood to the heart ~reduction in the "pre-load") and, on the other hand, reduces the peripheral arterial resistance (reduction in the "after-load"). This results in a sub-stantial relief of the heart with consecutive reduction in the myocardial oxygen consumption. Accordingly, the new preparations are suitable, above all, for the treatment of chronic cardiac insufficiency (myocardial insufficiency) and of angina pectoris.
The invention therefore relates to an oral pharmaceutical pre-paration of the slow-release type containing from about 25 mg to about 250 mg of phentolamine or a pharmaceutically usable salt thereof as the pharmaceutical active compound together with an auxiliary, excipient and/or coating material which effects the slow and continuous release of the active compound.
B~ _3 Pharlr.aceutically usable salts of phentolamine which can be employed are corresponding acid addition salts, such as those with suitable inorganic acids, such as hydrogen halide acids, for example hydrochloric acid or hydrobromic acid, and also nitric acid, sulphuric acid or phosphoric acid, or with suit-able organic acids, such as organic carboxylic acids, inter alia lower alkanecarboxylic acids or lower alkenecarboxylic acids, which optionally contain hydroxyl, for example acetic acid, propionic acid, glycollic acid, succinic acid, maleic acid, hydroxymaleic acid, methylmaleic acid, fumaric acid, malic acid, tartaric acid or citric acid, or arylcarboxylic acids, aryl-lower alkanecarboxylic acids, aryl-lower alkene-carboxylic acids or heterocyclylcarboxylic acids, for example benzoic acid, cinnamic acid, mandelic acid, salicylic acid, 4-amino-salicylic acid, 2-phenoxybenzoic acid, 2-ace-toxy-benzoic acid, embonic acid, nicotinic acid or isonicotinic acid, or organic sulphonic acids, such as lower alkanesulphonic acids which optionally contain hydroxyl, for example methane-sulphonic acid, ethanesulphonic acid, 2-hydroxyethanesulphonic acid or ethane-1,2-disulphonic acid, or arylsulphonic acids, for example benzenesulphonic acid, 4-methyl-benzenesulphonic acid or naphthalené-2-sulphonic acid.
Pharmaceutical preparations which can be used orally and which are able to release phentolamine, or a pharmaceuti-cally usable salt thereof,slowly and continuously over a pro-longed period are, above all, corresponding tablets, as well as dragées and also capsules with these properties. mey contain, per dosage uni~t, from about 25 mg to about 250 mg, preferably from about 50 mg to about 200 mg and above all about 100 mg of the active compound, which is used in -the form of the free base or, preferably, of a pharmaceutically usable salt.
In principle, the new preparations contain the active compound or an active compound/auxiliary mixture, together with an auxiliary, excipient and/or coating material which effects the slow and continuous release of the active compound.
Corresponding granules, which are sui-table for pro-cessing to give tablets, dragées or capsules, are an example of an active compound/auxiliary mixture. In addition to the active compound, granules of this type contain, inter alia, diluents or fillers, such as sugars, for example lactose or sucrose, or sugar alcohols, for example mannitol or sorbitol, cellulose preparations and/or calcium phosphates, for example tricalcium phosphate or calcium hydrogen phosphate, and also flow-regulating agents, such as talc or colloidal silica, slip agents, lubricants or non-stick agents, such as stearic acid or salts thereof, for example magnesium stearate or calcium stearate, and/or polyethylene glycol, and also glycerides, such as hydrogenated cottonseed oil or hydrogenated castor oil.
Such granules can be produced in a manner which is in itself known, optionally using moistening agents, such as water or organic solvents, for example ethanol, or mixtures.
In order that the release of the active compound is slowed down whilst still remaining con-tinuous, the rate of 11~59914 release of the acti~e compound must be reduced by the addition of, and/or by treatment wit~ suitable auxiliaries, excipients and/or coating substances. Such substances are, above all, film-forming agents for encapsula-tions or coatings, swelling agents with gel-forming properties for delaying diffusion and substances which provide a base structure for embedding, especially lipids and also plastics with thermoplastic proper-ties, or ion exchangers, it being possible to use only one type of auxiliaries or a combination thereof in order to achieve the delayed and continuous release of the active compound.
Usually, the film-forming agents used are above all water-insoluble auxiliaries, for example water-insoluble cel-lulose ethers or cellulose esters, such as corresponding cellulose lower alkyl ethers, for example water-insoluble èthyl cellulose, or water-insoluble cellulose esters with lower alkanecarboxylic acids, optionally with additional hyd-roxyl groups esterified by other carboxylic acids, such as dicarboxylic acids, for example water-insoluble cellulose acetate or cellu].ose acetate-phthalate, polymers or copolymers of unsaturated aliphatic esters of carboxylic acids with alco-hols, such as polymers or copolymers of esters of lower alkane-carboxylic acids with lower alkenols, for example polyvinyl acetate, or polymers or copolymers of esters of lower alkene-carboxylic acids with lower alkanols, for example a copolymer of acrylic acid ethyl ester and methacrylic acid methyl ester (for example in a ratio of about 70 parts of acrylic acid ethyl es-ter to about 30 parts of methacrylic acid methyl ester), ..... ... .. . . . . .. ... ... ... . . . . ..
and also shellac The film-forming agents, which make up from about 1%
to about 10~, preferably from abou-t 2% to about 6%, of the total weight of the preparation form, are used3 above all, for encapsulating active compound particles or, preferably, gran-ules, or as an additive to granules, which optionally can be pressed to give tablets. They can be applied or admixed in a dissolved form with the aid of organic solven-ts, for example alcohols, such as ethanol, or optionally chlorinated aliphatic hydrocarbons, such as methylene chloride, or ketones, for example acetone, or mixtures thereof, or in the form of dis~
persions, such as aqueous dispersions which can be coagulated.
Swelling agents which can be used are, above all, ethers of cellulose which have a high viscosity, such as corresponding lower alkylcelluloses and, in particular, methylcellulose with an average degree of substitution of about 1.8, and which are preferably added in the pulverulent form to the active compound or, in particular, to granules thereof. The mixtures which can be obtained in this way are then processed, for example to give tablets. This gives the pharmaceutical preparations which, on coming into contact with water, swell with the formation of a gel, a diffusion barrier which is independent of the pH thus being formed.
Lipids, which are suitable as water-insoluble substances which provide a base structure, are, inter alia, fatty alcohols, especially higher alkanols with more than 13, especially with 16 to 20, carbon atoms, for example cetyl alcohol or stearyl .... . . . . . . . . . .. ..
alcohol, as well as mixtures thereof; these lipids can be used to effec-t pEI-independent release of the active compound.
Further suitable lipid substances are fatty acids which effect a pH-dependent release of the active compound, especially higher alkanecarboxylic acids with more ~han 13, especially with 16 to 20, carbon atoms, for example stearic acid, and these lipids can be used as a powder or in a molten form.
Suitable glycerides, especially hydrogenated vegetable oils, such as hydrogenated cottonseed oil or hydrogenated castor oil, and also mono-, di- or tri-esters of glycerol with palmitic acid or stearic acid, or preferably mixtures thereof, can also be used as lipids, these are usually ernployed in pulverulent form and, as has been mentioned above, can be used at the same time as lubricants.
Plastics with thermoplastic properties, which can be used as water-insoluble substances which provide a base struc-ture, are, in particular, polymers or copolymers of unsaturated aliphatic halides, such as of lower alkenyl chlorides, for example polyvinyl chloride, or of unsaturated aliphatic esters, such as esters of lower alkanecarboxylic acids with lower alkenols, for example polyvinyl aceta-te.
The swelling agents and substances which provide a base structure, which are used in amounts of from about 5% to about 70%, preferably from about 10% to about 40%, of the total weight of the preparation, are usuaily mixed with the active compound, or preferably with an active compound/auxiliary mix-ture, such as an optionally granulated mixture, and, optionally ,, . . . . .. . . . ~ ... . , , ~
after adding further auxiliaries, such as slip agents and lubricants, pressed to give -tablets or processed -to give capsules.
Ion exchangers, which effect a pH-controlled slow and continuous release of the active compound, are acid resins, preferably crosslinked cation exchange resins which have a degree of crosslinking o~ about 1% to about 10%, preferably of about 2% to about 6%, and a particle size in the range from about 1 to about 150, especially from abou-t 5 to about 80, microns. Corresponding resins with sulphonic acid groups, such as highly acid aromatic sulphonic acid resins, ~or example polystyrenesulphonic acid, or with carboxylic acid groups, such as slightly acid aliphatic carboxylic acid resins, for example polymethacrylic acid, are particularly suitable.
Usually, the active compound, in the form of the free base, is adsorbed on the ion exchanger by treating the latter with a suitable solution of the active compound base, for example in an inert organic solvent, and the preparation which can thus be obtained is preferably used to produce capsules which, in this form, are suitable for the slow and continuous administration of the active compound.
The pharmaceutical prepara-tions of the present inven-tion are manufactured in a manner which is in itself known, for example by means of conventional mixing, granulating and dragee-making processes. Thus, dragee cores can be provided with suitable coatings, which, if desired, are resistant to gastric juices, and for this purpose, inter alia, concentrated _ g _ sugar solutions, ~hich optionally contain gum arabic, talc, polyvinylpyrrolidone, polye-thylene glycol and/or titanium dioxide, lacquer solu-tions in sui-table organic solvents or sol-vent mixtures or, in order to produce coatings resistant to gastric juices, solutions of suitable cellulose preparations, such as acetylcellulose phthalate or hydroxypropylmethylcel-lulose phthalate, are used. Dyestuffs or pigments can be added to the tablets or dragée coa-tings, for example for identifica-tion or in order to characterise different combinations of active compound doses.
As mentioned above, the pharmaceutical preparations, which can be administered ,orally, for the slow and continuous release of the active compound are manufactured in a manrler which is in itself known; the manufacture is explained in more detail in the examples which follow.
Example_l:
Tablets for the slow and con-tinuous release of 50 mg of 2-[N-(3-hydroxy-phenyl)-N-(4-methyl-phenyl)-amlno-methyl]-
CH2 C~
~ / H
HO
and its pharmaceutically usable sal-ts exhibit an antagonistic effect against the active compounds of the adrenergic system, that is to say act as alpha-receptor-blocking agents, there being, in addition, a vasodilating and beta-receptor-stimulating active component. Because of -their pharmacological properties, the compound and its salts effect a peripheral vasodilatation and an increase in the heart rate and augment the myocardial contractility, there being no undesirable de-~eases in the blood pressure. The field of application for the compound has, however, remained extremely restricted, namely to the test for suspected phaeochromocytoma, to the treat-ment of blood pressure crises when phaeochromocytoma is confirmed and to prophylaxis before and during the operation, as well as to the treatment of peripheral arterial perfusion disorders. As is stated in Helwig, Moderne Arzneimittel (Modern Medicaments), page 935 (4th edition 1972; Wissen-schaftliche Verlagsgesellschaft, Stuttgart, Germany), the preparation cannot be used for other indications.
It has now been found that when phentolamine, or a pharmaceutically usable salt thereof, is administered in a suitable pharmaceutical form the range of indications for these compounds can be extended in a surprising manner.
This extension of the range of indications is a result of the use of phentol-amine, or a pharmaceutically usable salt thereof, in the form of an oral phar-maceutical preparation which is suitable for the slow and continuous release of the active compoundO
It has been found that pharmaceutical preparations in the solid form, which can be used orally and which give slow and continuous release, that is to say so-called retard or slow release preparations, containing phentolamine, or a pharmaceutically usable salt thereof, as the pharmacological active compound cause a long-lasting dilatation of the veins and arteries, which, on the one hand, effects a reduction in the regurgitation of venous blood to the heart ~reduction in the "pre-load") and, on the other hand, reduces the peripheral arterial resistance (reduction in the "after-load"). This results in a sub-stantial relief of the heart with consecutive reduction in the myocardial oxygen consumption. Accordingly, the new preparations are suitable, above all, for the treatment of chronic cardiac insufficiency (myocardial insufficiency) and of angina pectoris.
The invention therefore relates to an oral pharmaceutical pre-paration of the slow-release type containing from about 25 mg to about 250 mg of phentolamine or a pharmaceutically usable salt thereof as the pharmaceutical active compound together with an auxiliary, excipient and/or coating material which effects the slow and continuous release of the active compound.
B~ _3 Pharlr.aceutically usable salts of phentolamine which can be employed are corresponding acid addition salts, such as those with suitable inorganic acids, such as hydrogen halide acids, for example hydrochloric acid or hydrobromic acid, and also nitric acid, sulphuric acid or phosphoric acid, or with suit-able organic acids, such as organic carboxylic acids, inter alia lower alkanecarboxylic acids or lower alkenecarboxylic acids, which optionally contain hydroxyl, for example acetic acid, propionic acid, glycollic acid, succinic acid, maleic acid, hydroxymaleic acid, methylmaleic acid, fumaric acid, malic acid, tartaric acid or citric acid, or arylcarboxylic acids, aryl-lower alkanecarboxylic acids, aryl-lower alkene-carboxylic acids or heterocyclylcarboxylic acids, for example benzoic acid, cinnamic acid, mandelic acid, salicylic acid, 4-amino-salicylic acid, 2-phenoxybenzoic acid, 2-ace-toxy-benzoic acid, embonic acid, nicotinic acid or isonicotinic acid, or organic sulphonic acids, such as lower alkanesulphonic acids which optionally contain hydroxyl, for example methane-sulphonic acid, ethanesulphonic acid, 2-hydroxyethanesulphonic acid or ethane-1,2-disulphonic acid, or arylsulphonic acids, for example benzenesulphonic acid, 4-methyl-benzenesulphonic acid or naphthalené-2-sulphonic acid.
Pharmaceutical preparations which can be used orally and which are able to release phentolamine, or a pharmaceuti-cally usable salt thereof,slowly and continuously over a pro-longed period are, above all, corresponding tablets, as well as dragées and also capsules with these properties. mey contain, per dosage uni~t, from about 25 mg to about 250 mg, preferably from about 50 mg to about 200 mg and above all about 100 mg of the active compound, which is used in -the form of the free base or, preferably, of a pharmaceutically usable salt.
In principle, the new preparations contain the active compound or an active compound/auxiliary mixture, together with an auxiliary, excipient and/or coating material which effects the slow and continuous release of the active compound.
Corresponding granules, which are sui-table for pro-cessing to give tablets, dragées or capsules, are an example of an active compound/auxiliary mixture. In addition to the active compound, granules of this type contain, inter alia, diluents or fillers, such as sugars, for example lactose or sucrose, or sugar alcohols, for example mannitol or sorbitol, cellulose preparations and/or calcium phosphates, for example tricalcium phosphate or calcium hydrogen phosphate, and also flow-regulating agents, such as talc or colloidal silica, slip agents, lubricants or non-stick agents, such as stearic acid or salts thereof, for example magnesium stearate or calcium stearate, and/or polyethylene glycol, and also glycerides, such as hydrogenated cottonseed oil or hydrogenated castor oil.
Such granules can be produced in a manner which is in itself known, optionally using moistening agents, such as water or organic solvents, for example ethanol, or mixtures.
In order that the release of the active compound is slowed down whilst still remaining con-tinuous, the rate of 11~59914 release of the acti~e compound must be reduced by the addition of, and/or by treatment wit~ suitable auxiliaries, excipients and/or coating substances. Such substances are, above all, film-forming agents for encapsula-tions or coatings, swelling agents with gel-forming properties for delaying diffusion and substances which provide a base structure for embedding, especially lipids and also plastics with thermoplastic proper-ties, or ion exchangers, it being possible to use only one type of auxiliaries or a combination thereof in order to achieve the delayed and continuous release of the active compound.
Usually, the film-forming agents used are above all water-insoluble auxiliaries, for example water-insoluble cel-lulose ethers or cellulose esters, such as corresponding cellulose lower alkyl ethers, for example water-insoluble èthyl cellulose, or water-insoluble cellulose esters with lower alkanecarboxylic acids, optionally with additional hyd-roxyl groups esterified by other carboxylic acids, such as dicarboxylic acids, for example water-insoluble cellulose acetate or cellu].ose acetate-phthalate, polymers or copolymers of unsaturated aliphatic esters of carboxylic acids with alco-hols, such as polymers or copolymers of esters of lower alkane-carboxylic acids with lower alkenols, for example polyvinyl acetate, or polymers or copolymers of esters of lower alkene-carboxylic acids with lower alkanols, for example a copolymer of acrylic acid ethyl ester and methacrylic acid methyl ester (for example in a ratio of about 70 parts of acrylic acid ethyl es-ter to about 30 parts of methacrylic acid methyl ester), ..... ... .. . . . . .. ... ... ... . . . . ..
and also shellac The film-forming agents, which make up from about 1%
to about 10~, preferably from abou-t 2% to about 6%, of the total weight of the preparation form, are used3 above all, for encapsulating active compound particles or, preferably, gran-ules, or as an additive to granules, which optionally can be pressed to give tablets. They can be applied or admixed in a dissolved form with the aid of organic solven-ts, for example alcohols, such as ethanol, or optionally chlorinated aliphatic hydrocarbons, such as methylene chloride, or ketones, for example acetone, or mixtures thereof, or in the form of dis~
persions, such as aqueous dispersions which can be coagulated.
Swelling agents which can be used are, above all, ethers of cellulose which have a high viscosity, such as corresponding lower alkylcelluloses and, in particular, methylcellulose with an average degree of substitution of about 1.8, and which are preferably added in the pulverulent form to the active compound or, in particular, to granules thereof. The mixtures which can be obtained in this way are then processed, for example to give tablets. This gives the pharmaceutical preparations which, on coming into contact with water, swell with the formation of a gel, a diffusion barrier which is independent of the pH thus being formed.
Lipids, which are suitable as water-insoluble substances which provide a base structure, are, inter alia, fatty alcohols, especially higher alkanols with more than 13, especially with 16 to 20, carbon atoms, for example cetyl alcohol or stearyl .... . . . . . . . . . .. ..
alcohol, as well as mixtures thereof; these lipids can be used to effec-t pEI-independent release of the active compound.
Further suitable lipid substances are fatty acids which effect a pH-dependent release of the active compound, especially higher alkanecarboxylic acids with more ~han 13, especially with 16 to 20, carbon atoms, for example stearic acid, and these lipids can be used as a powder or in a molten form.
Suitable glycerides, especially hydrogenated vegetable oils, such as hydrogenated cottonseed oil or hydrogenated castor oil, and also mono-, di- or tri-esters of glycerol with palmitic acid or stearic acid, or preferably mixtures thereof, can also be used as lipids, these are usually ernployed in pulverulent form and, as has been mentioned above, can be used at the same time as lubricants.
Plastics with thermoplastic properties, which can be used as water-insoluble substances which provide a base struc-ture, are, in particular, polymers or copolymers of unsaturated aliphatic halides, such as of lower alkenyl chlorides, for example polyvinyl chloride, or of unsaturated aliphatic esters, such as esters of lower alkanecarboxylic acids with lower alkenols, for example polyvinyl aceta-te.
The swelling agents and substances which provide a base structure, which are used in amounts of from about 5% to about 70%, preferably from about 10% to about 40%, of the total weight of the preparation, are usuaily mixed with the active compound, or preferably with an active compound/auxiliary mix-ture, such as an optionally granulated mixture, and, optionally ,, . . . . .. . . . ~ ... . , , ~
after adding further auxiliaries, such as slip agents and lubricants, pressed to give -tablets or processed -to give capsules.
Ion exchangers, which effect a pH-controlled slow and continuous release of the active compound, are acid resins, preferably crosslinked cation exchange resins which have a degree of crosslinking o~ about 1% to about 10%, preferably of about 2% to about 6%, and a particle size in the range from about 1 to about 150, especially from abou-t 5 to about 80, microns. Corresponding resins with sulphonic acid groups, such as highly acid aromatic sulphonic acid resins, ~or example polystyrenesulphonic acid, or with carboxylic acid groups, such as slightly acid aliphatic carboxylic acid resins, for example polymethacrylic acid, are particularly suitable.
Usually, the active compound, in the form of the free base, is adsorbed on the ion exchanger by treating the latter with a suitable solution of the active compound base, for example in an inert organic solvent, and the preparation which can thus be obtained is preferably used to produce capsules which, in this form, are suitable for the slow and continuous administration of the active compound.
The pharmaceutical prepara-tions of the present inven-tion are manufactured in a manner which is in itself known, for example by means of conventional mixing, granulating and dragee-making processes. Thus, dragee cores can be provided with suitable coatings, which, if desired, are resistant to gastric juices, and for this purpose, inter alia, concentrated _ g _ sugar solutions, ~hich optionally contain gum arabic, talc, polyvinylpyrrolidone, polye-thylene glycol and/or titanium dioxide, lacquer solu-tions in sui-table organic solvents or sol-vent mixtures or, in order to produce coatings resistant to gastric juices, solutions of suitable cellulose preparations, such as acetylcellulose phthalate or hydroxypropylmethylcel-lulose phthalate, are used. Dyestuffs or pigments can be added to the tablets or dragée coa-tings, for example for identifica-tion or in order to characterise different combinations of active compound doses.
As mentioned above, the pharmaceutical preparations, which can be administered ,orally, for the slow and continuous release of the active compound are manufactured in a manrler which is in itself known; the manufacture is explained in more detail in the examples which follow.
Example_l:
Tablets for the slow and con-tinuous release of 50 mg of 2-[N-(3-hydroxy-phenyl)-N-(4-methyl-phenyl)-amlno-methyl]-
2-imidazoline hydrochloride are mamlfactured as follows:
Composition (for 1 tablet):
2-[N-(3-Hydroxy-phenyl)-N-(4-methyl-phenyl)-amino-methyl~-2-imidazoline hydrochloride 50 mg Hydroxypropylmethylcellulose (low viscosity) 1.5 mg Hydrogenated cottonseed oil 5 mg Magnesium stearate 0,5 mg The tablets are manufactured as follows (for 10,000 tablets):
A mixture of 500 g o~ 2-[N-(3-hydroxy-phenyl)-N-(4-., ... , . . . . . ... .... . , .. . . .. . .. . . . . . .. ~ . . ~ .. . .
~059914 methyl-phen~ aminome-thyl~-2-imidazoline hydrochloride and 15 g of hydroxypropylmethylcellulose is worked up wi-th 150 g of demineralised water to give a moist mass and this is granu-lated through a sieve of 3 l~n mesh width, the granules are dried for 30 minutes at 45 and comminuted through a o.6-0.~ mm sieve. After admixing 50 g of hydrogenated cottonseed oil in the pulverulent form and 5 g of magnesium stearate, slightly domed tablets 6 mm in diameter are pressed.
Example 2:
Dragées for the slow and continuous release of 50 mg of 2-[N-(~-hydroxy-phenyl)-N~(4-methyl-phenyl)-aminomethyl]-2-imidazoline hydrochloride are manufactured as fol]ows:
5,000 g of the tablets obtainable according to the pro-cess described in Example 1 are placed in a dragee-coating kettle 45 cm in diameter and provided with a protective lacquer consisting of a dispersion of 350 g of a copolymer of acrylic acid ethyl ester and methacrylic acid methyl ester (70:30) in demineralised water containing 105 g of lactose and 105 g of talc. For this purpose, this protective lacquer is sprayed on continuously for 30 minutes and, at the same time, dried with warm air at 60. The cores lacquer-coated in this way are further coated with a sugar solution. For this pur-pose, first a sugar syrup consisting of two parts of sugar and one part of water, -to which talc (18%), polyvinylpyrrolidone (1.5%) and polyethylene glyco] 6,ooo (1%) have been added, and then a pure sugar syrup are used.
.... . . . . . . . . . . . . .. . ..
10599:14 Tablets for the slow and continuous release of 100 mg of 2-[N-(3-hydroxy-phenyl)-N-(4-methyl-phenyl)-aminomethyl~-2-imidazoline hydrochloride are manufactured as follows: -Composition (for 1 tablet):
2-~N-(3-Hydroxy-phenyl)-N-(4-methyl-phenyl)-amino-methyl~-2-imidazoline hydrochloride 100 mg Lactose 160 mg Aqueous dispersion of a 70:30 copolymer of lC~ acrylic acid ethyl ester and methacrylic acid methyl ester (Eudragit E 30 D) 25 mg Magnesium stearate 1 mg Mixture of mono-, di- and tri-esters of glycerol with palmitic acid and stearic acid (Precirol) 12 mg Colloidal silica (Aerosil 200) 2 mg 20,000 tablets can be manufactured as follows:
A mixture of 2,000 g of 2-[N-(3-hydroxy-phenyl)~N-(4-methyl-phenyl)-aminomethyl~-2-imidazoline hydrochloride and ; 3,200 g of lactose is spray-granulated with 500 g of an aqueous dispersion of the 70:30 copolymer of acrylic acid ethyl ester and methacrylic acid methyl ester (Eudragit E 30 D) and the granules are then dried at about 30C. The dry gran-ules are forced through a sieve, in order to obtain a uniform particle size, and mixed with 20 g of magnesium stearate, 240 g of the mixture of mono-, di- and tri-esters of glycerol with palmitic acid and stearic acid (Precirol) and 40 g of the colloidal silica (Aerosil 200) and the resulting mixture is pressed to give tablets which weigh 0.3 g.
.. ...
Composition (for 1 tablet):
2-[N-(3-Hydroxy-phenyl)-N-(4-methyl-phenyl)-amino-methyl~-2-imidazoline hydrochloride 50 mg Hydroxypropylmethylcellulose (low viscosity) 1.5 mg Hydrogenated cottonseed oil 5 mg Magnesium stearate 0,5 mg The tablets are manufactured as follows (for 10,000 tablets):
A mixture of 500 g o~ 2-[N-(3-hydroxy-phenyl)-N-(4-., ... , . . . . . ... .... . , .. . . .. . .. . . . . . .. ~ . . ~ .. . .
~059914 methyl-phen~ aminome-thyl~-2-imidazoline hydrochloride and 15 g of hydroxypropylmethylcellulose is worked up wi-th 150 g of demineralised water to give a moist mass and this is granu-lated through a sieve of 3 l~n mesh width, the granules are dried for 30 minutes at 45 and comminuted through a o.6-0.~ mm sieve. After admixing 50 g of hydrogenated cottonseed oil in the pulverulent form and 5 g of magnesium stearate, slightly domed tablets 6 mm in diameter are pressed.
Example 2:
Dragées for the slow and continuous release of 50 mg of 2-[N-(~-hydroxy-phenyl)-N~(4-methyl-phenyl)-aminomethyl]-2-imidazoline hydrochloride are manufactured as fol]ows:
5,000 g of the tablets obtainable according to the pro-cess described in Example 1 are placed in a dragee-coating kettle 45 cm in diameter and provided with a protective lacquer consisting of a dispersion of 350 g of a copolymer of acrylic acid ethyl ester and methacrylic acid methyl ester (70:30) in demineralised water containing 105 g of lactose and 105 g of talc. For this purpose, this protective lacquer is sprayed on continuously for 30 minutes and, at the same time, dried with warm air at 60. The cores lacquer-coated in this way are further coated with a sugar solution. For this pur-pose, first a sugar syrup consisting of two parts of sugar and one part of water, -to which talc (18%), polyvinylpyrrolidone (1.5%) and polyethylene glyco] 6,ooo (1%) have been added, and then a pure sugar syrup are used.
.... . . . . . . . . . . . . .. . ..
10599:14 Tablets for the slow and continuous release of 100 mg of 2-[N-(3-hydroxy-phenyl)-N-(4-methyl-phenyl)-aminomethyl~-2-imidazoline hydrochloride are manufactured as follows: -Composition (for 1 tablet):
2-~N-(3-Hydroxy-phenyl)-N-(4-methyl-phenyl)-amino-methyl~-2-imidazoline hydrochloride 100 mg Lactose 160 mg Aqueous dispersion of a 70:30 copolymer of lC~ acrylic acid ethyl ester and methacrylic acid methyl ester (Eudragit E 30 D) 25 mg Magnesium stearate 1 mg Mixture of mono-, di- and tri-esters of glycerol with palmitic acid and stearic acid (Precirol) 12 mg Colloidal silica (Aerosil 200) 2 mg 20,000 tablets can be manufactured as follows:
A mixture of 2,000 g of 2-[N-(3-hydroxy-phenyl)~N-(4-methyl-phenyl)-aminomethyl~-2-imidazoline hydrochloride and ; 3,200 g of lactose is spray-granulated with 500 g of an aqueous dispersion of the 70:30 copolymer of acrylic acid ethyl ester and methacrylic acid methyl ester (Eudragit E 30 D) and the granules are then dried at about 30C. The dry gran-ules are forced through a sieve, in order to obtain a uniform particle size, and mixed with 20 g of magnesium stearate, 240 g of the mixture of mono-, di- and tri-esters of glycerol with palmitic acid and stearic acid (Precirol) and 40 g of the colloidal silica (Aerosil 200) and the resulting mixture is pressed to give tablets which weigh 0.3 g.
.. ...
Claims (4)
PROPERTY OR PRIVILEGE IS CLAIMED ARE DEFINED AS FOLLOWS:
1. An oral pharmaceutical preparation of the slow-release type contain-ing from about 25 mg to about 250 mg of phentolamine or a pharmaceutically usable salt thereof as the pharmaceutical active compound together with an auxiliary, excipient and/or coating material which effects the slow and con-tinuous release of the active compound.
2. A solid oral pharmaceutical preparation according to claim 1 contain-ing from about 50 mg to about 200 mg of the pharmaceutical active compound per dosage unit.
3. A solid pharmaceutical preparation according to claim 1 containing about 100 mg of the pharmaceutical active compound per dosage unit.
4. A solid pharmaceutical preparation according to one of claim 1 to 3 wherein auxiliaries, excipients and/or coating agents are film-forming agents for encapsulations or coatings, swelling agents with gel-forming properties for delaying diffusion and substances which provide a base structure for embedding; especially lipids, and also plastics with thermoplastic properties or ion exchangers, it being possible to use only one type of auxiliaries or a combination thereof in order to achieve the delayed and continuous release of the active compound.
Applications Claiming Priority (2)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CH7175 | 1975-01-06 | ||
| CH1474775 | 1975-11-13 |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| CA1059914A true CA1059914A (en) | 1979-08-07 |
Family
ID=25683420
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CA242,910A Expired CA1059914A (en) | 1975-01-06 | 1976-01-02 | Pharmaceutical preparation for the treatment of circulatory disorders |
Country Status (10)
| Country | Link |
|---|---|
| JP (1) | JPS5191314A (en) |
| AU (1) | AU499139B2 (en) |
| BE (1) | BE837294A (en) |
| CA (1) | CA1059914A (en) |
| DE (1) | DE2600021A1 (en) |
| FR (1) | FR2296415A1 (en) |
| GB (1) | GB1500300A (en) |
| IE (1) | IE42765B1 (en) |
| IL (1) | IL48787A (en) |
| NL (1) | NL7600047A (en) |
Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US5981563A (en) * | 1995-04-28 | 1999-11-09 | Zonagen, Inc. | Methods and formulations for modulating the human sexual response |
Families Citing this family (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| FI63335B (en) * | 1979-02-02 | 1983-02-28 | Orion Yhtymae Oy | FARING REFERENCE FOR A TABLETTER WITH A LIGHT LIGHT OF AN EFFECTIVE |
| IN151913B (en) * | 1980-01-11 | 1983-09-03 | Boots Co Ltd | |
| FI20060501L (en) * | 2006-05-22 | 2007-11-23 | Biohit Oyj | Composition and method for binding acetaldehyde in the stomach |
| WO2008013084A1 (en) * | 2006-07-25 | 2008-01-31 | Kowa Company, Ltd. | Sugar-coated preparation and process for producing the same |
Family Cites Families (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| NL51480C (en) * | ||||
| FR1013681A (en) * | 1947-01-31 | 1952-08-01 | Ciba Geigy | New imidazolines and process for their manufacture |
-
1975
- 1975-12-31 GB GB53294/75A patent/GB1500300A/en not_active Expired
-
1976
- 1976-01-02 FR FR7600014A patent/FR2296415A1/en active Granted
- 1976-01-02 DE DE19762600021 patent/DE2600021A1/en not_active Withdrawn
- 1976-01-02 CA CA242,910A patent/CA1059914A/en not_active Expired
- 1976-01-05 IE IE10/76A patent/IE42765B1/en unknown
- 1976-01-05 AU AU10001/76A patent/AU499139B2/en not_active Expired
- 1976-01-05 NL NL7600047A patent/NL7600047A/en unknown
- 1976-01-05 BE BE163296A patent/BE837294A/en unknown
- 1976-01-05 IL IL48787A patent/IL48787A/en unknown
- 1976-01-06 JP JP51000126A patent/JPS5191314A/ja active Pending
Cited By (5)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US5981563A (en) * | 1995-04-28 | 1999-11-09 | Zonagen, Inc. | Methods and formulations for modulating the human sexual response |
| US6051594A (en) * | 1995-04-28 | 2000-04-18 | Zonagen, Inc. | Methods and formulations for modulating the human sexual response |
| US6100286A (en) * | 1995-04-28 | 2000-08-08 | Zonagen, Inc. | Methods and formulations for modulating the human sexual response |
| US6124337A (en) * | 1995-04-28 | 2000-09-26 | Zonagen, Inc. | Methods and formulations for modulating the human sexual response |
| US6166061A (en) * | 1995-04-28 | 2000-12-26 | Zonagen, Inc. | Methods and formulations for modulating the human sexual response |
Also Published As
| Publication number | Publication date |
|---|---|
| GB1500300A (en) | 1978-02-08 |
| NL7600047A (en) | 1976-07-08 |
| BE837294A (en) | 1976-07-05 |
| IE42765B1 (en) | 1980-10-08 |
| IL48787A0 (en) | 1976-03-31 |
| FR2296415A1 (en) | 1976-07-30 |
| AU1000176A (en) | 1977-07-14 |
| JPS5191314A (en) | 1976-08-10 |
| FR2296415B1 (en) | 1978-08-18 |
| DE2600021A1 (en) | 1976-07-15 |
| AU499139B2 (en) | 1979-04-05 |
| IE42765L (en) | 1976-07-06 |
| IL48787A (en) | 1978-09-29 |
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