IE42765B1 - Pharmaceutical preparation for the treatment of circulatory disorders - Google Patents

Abstract

1500300 Compositions containing phentolamine CIBA - GEIGY AG 31 Dec 1975 [6 Jan 1975 13 Nov 1975] 53294/75 Heading A5B Pharmaceutical preparations which can be used orally are characterised by a slow and continuous release of phentolamine or a pharmaceutically usable salt thereof.

Description

It is known that phentolamine, that is to say 2-[N-(3hydroxyphenyl)-N-(4-methyl-phenyl)-aminomethyl]-imidazoline of the formula and its pharmaceutically usable salts 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-receptorstimulating 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 decreases 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 treatment of blood pressure crises when phaeochromocytoma is cohfirmed 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; Wissenschaftliche Verlagsgesellschaft, Stuttgart, Germany), the preparation cannot he used for other indications. - 2 42765 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 phentolamine, or a pharmaceutically usable salt thereof, in the form of an oral pharmaceutical preparation which is suitable for the slow and continuous release of the active compound.

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 substantial 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 pharmaceutical preparations which can be used orally and which are characterised by a slow and continuous release of phentolamine or, preferably, of a pharmaceutically usable salt thereof. - 3 42765 Pharmaceutically 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 suitable 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 LO acid, hydroxymaleic acid, methylmaleic acid, fumaric acid, malic acid, tartaric acid or citric acid, or arylcarboxylic acids, aryl-lower alkanecarboxylic acids, aryl-lower alkenecarboxylic acids or heterocyclylcarboxylic acids, for example benzoic acid, cinnamic acid, mandelic acid, salicylic aoid, .5 4-amino-salicylic acid, 2-phenoxybenzoic acid, 2-acetoxybenzoic acid, embonic acid, nicotinic acid or isonicotinic acid, or organic sulphonic acid, such as lower alkanesulphonic acids which optionally contain hydroxyl, for example methanesulphonic acid, ethanesulphonic acid, 2-hydroxyethanesulphonic iO acid or ethane-1,2-disulphonic acid, or arylsulphonic acids, for example benzenesulphonic acid, 4-methyl-benzenesulphonic acid or naphthalene-2-sulphonic acid.

Pharmaceutical preparations which can be used orally and which are able to release phentolamine, or a pharmaceuti5 cally usable salt thereof, slowly and continuously over a prolonged period are, above all, corresponding tablets, as well as dragees and also capsules with these properties. They - 4 4276S contain, per dosage unit, 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 suitable for processing to give tablets, dragees 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 ox- 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 continuous, the rate of - 5 42765 release of the active compound, must be reduced by the addition of, and/or by treatment with, suitable auxiliaries, excipients and/or coating substances. Such substances orc, above all, 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 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 cellulose ethers or cellulose esters, such as corresponding cellulose lower alkyl ethers, for example water-insoluble ethyl cellulose, or water-insoluble cellulose esters with lower alkanecarboxylic acids, optionally with additional hydroxyl groups esterified by other carboxylic acids, such as ‘ dicarboxylic acids, for example water-insoluble cellulose acetate or cellulose acetate-phthalate, polymers or copolymers of unsaturated aliphatic esters of carboxylic acids with alcohols, such as polymers or copolymers of esters of lower alkanecarboxylic acids with lower alkenols,. for example polyvinyl acetate, or polymers or copolymers of esters of lower alkenecarboxylic 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 ester to about 30 parts of methacrylic acid methyl ester), - 6 42765 and also shellac.

The film-forming agents, which make up from 1% to 10%, preferably from 2% to 6%, of the total weight of the preparation form, are used, above all, for encapsulating active compound particles or, preferably, granules, or as an additive to granules, which optionally can bo pressed to give tablets. They can be applied or admixed in a dissolved form with the aid of organic solvents, 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 dispersions, 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, methyHcellulose 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 whioh can be obtained in this way are then processed, for example to give tablets. This gives the pharmaceutical preparations vzhich, on coming into contact with water, svzell 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 substance: 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 - 7 43765 alcohol, as well as mixtures thereof; these lipids can be used to effect pH-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 than 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 employed in pulverulent form and, as has been mentioned above, can be used at the same time as lubricants.

L5 Plastics with thermoplastic properties, which can be used as water-insoluble substances which provide a base structure, are, in particular, polymers or copolymers of unsaturated 1' I 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 acetate.

The swelling agents and substances which provide a base structure, which are used in amounts of from 5% to 70%, preferably from 10% to 40%, of the total weight of the preparation, are usually mixed with the active compound, or preferably with an active compound/auxiliary mixture, such as an optionally granulated mixture, and, optionally - 8 4276S 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 of 1% to 10%, preferably of 2% to 6%, and a particle size in the range from about 1 to about 150, especially fi’om 5 to 80, microns. Corresponding resins with sulphonic acid groups, such as highly acid aromatic sulphonic acid resins, for 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 preparations of the present invention 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 - 9 42765 sugar solutions, which optionally contain gum arahic, talc, polyvinylpyrrolidone, polyethylene glycol and/or titanium dioxide, lacquer solutions in suitable organic solvents or solvent mixtures or, in order to produce coatings resistant to gastric juices, solutions of suitable cellulose preparations, such as acetylcellulose phthalate or hydroxypropylmethylcellulose phthalate, are used. Dyestuffs or pigments can be added to the tablets or dragee coatings, for example for identification 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 manner which is in itself known; the manufacture is explained in more detail in the examples which follow.

Example 1: Tablets for the slow and continuous release of 50 mg of 2-[N-(3-hydroxy-phenyl)-N-(4-methyl-pheny1)-amino-methyl]2-imidazoline hydrochloride are manufactured as follows: Composition (for 1 tablet): 2-[N-(3-Hydroxy-phenyl)-N-(^-methyl-phenyl)-amino- methyl]-2-imidazoline hydrochloride 50 mg Hydroxypropylmethylcellulose (low viscosity) 1.5 mg Hydrogenated cottonseed oil 5 mg 25 Magnesium stearate 0.5 mg The tablets are manufactured as follows (for 10,000 tablets): A mixture of 500 g of 2-[N-(3-hydroxy-phenyl)-N-(4~ - 10 42765 methyl-phenyl)-aminomethyl]-2-imidazoline hydrochloride and 15 g of hydroxypropylmethylcellulose is worked up with 150 g of demineralised water to give a moist mass and this is granulated through a sieve of 3 mm mesh width, the granules are dried for 30 minutes at 45° and comminuted through a 0.60.8 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: Dragees for the slow and continuous release of 50 mg of 2-[N-(3-hydrcxy-phenyl)-N-(4-methy1-pheny1)-aminomethyl]2-imidazoline hydrochloride are manufactured as follows: ,000 g of the tablets obtainable according to the pro cess described in Example 1 are placed in a drage'e-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. Por 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. Por this purpose, first a sugar syrup consisting of two parts of sugar and one part of water, to which talc (18%), polyvinylpyrrolidone (1.5%) and polyethylene glycol 6,000 (l%) have been added, and then a pure sugar syrup are used. - 11 43765 Example 3: Tablets for the slow and continuous release of 100 mg of 2-[N-(3-hydroxy-phenyl)-N-(4-methyl-pheny1)-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 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) (Registered Trade Mark) 2 mg 20,000 tablets can be manufactured as follows: A mixture of 2,000 g of 2-[N-(3-hydroxy-phenyl)-N-(4methyl-phenyl)-aminomethyl]-2-imidazoiine 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 30°C. The dry granules are forced through a sieve, in order to obtain a uniform particle size, ahd 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 43765 pressed to give tablets which weigh 0.3 g.

Claims (7)

1. CLAIMS:1. Pharmaceutical preparations which can be used orally and which are characterised by a slow and continuous release of phentolamine or, preferably, of a pharmaceutically usable 5 salt thereof.

2. Pharmaceutical preparations according to Claim 1, characterised in that they contain from 25 mg to 250 mg of the active compound per dosage unit.

3. Pharmaceutical preparations according to Claim 1, 10 characterised in that they contain from 50 mg to 200 mg of the active compound per dosage unit.

4. Pharmaceutical preparations according to Claim 1, characterised in that they contain about 100 mg of the active compound per dosage unit. 15

5. Pharmaceutical preparations according to Claims 1-4, characterised in that they contain the active compound, or an active compound/auxiliary mixture, together with an auxiliary, excipient and/or coating material which effects the aim; and continuous release, of the active compound. 20

6. Pharmaceutical preparations according to Claim 5, characterised in that tiie auxiliaries, excipients and/or coating agents which are used are film-forming agents for encapsulations or coatings, swelling agents with gel-forming properties for delaying diffusion and substances which provide a base 25 structure for embedding, especially lipids, and also plastics with thermoplastic properties cr ion exchangers, it being possible to use only one type of auxiliaries or a combination - 14 43765 thereof in order to achieve the delayed and continuous release of the active compound.

7. Pharmaceutical preparations according to Claims 1-6 substantially as described in Examples 1-3.