Note: Descriptions are shown in the official language in which they were submitted.
1059914
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.
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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.
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1059914
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
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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),
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1059914
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
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1059914
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
,, . . . . .. . . . ~ ... . , , ~
1059914
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
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1059914
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-
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.,
... , . . . . . ... .... . , .. . . .. . .. . . . . . .. ~ . . ~ .. . .
~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.
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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
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pressed to give tablets which weigh 0.3 g.
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