Note: Descriptions are shown in the official language in which they were submitted.
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Pharmaceutical dosa2e form which can be administered orally and has modified
release
The present invention relates to orally administrable modified-release
pharmaceutical dosage
forms comprising sodium (3S)-3-(4-chloro-3-{[(2S,3R)-2-(4-chloropheny1)-4,4,4-
trifluoro-3-
methylbutanoyllaminolpheny1)-3-cyclopropylpropanoate and to processes for
preparing the
dosage forms and to their use for the treatment and/or prevention of diseases,
in particular for
the treatment and/or prevention of cardiac, renal, pulmonary and ophthalmic
disorders,
disorders of the central nervous system, fibrotic and inflammatory disorders
and metabolic
disorders.
WO 2012/139888 discloses the compound (3S)-3-(4-chloro-3- { [(2S,3R)-2-(4-
chloropheny1)-
4,4,4-trifluoro-3-methy lbutanoyllaminolpheny1)-3-cyclopropylpropanoic acid of
the formula
(I)
0
HO
CI
H
FF CI
F
(I),
and its preparation in Example 22. The compound of the formula (I) acts as
activator of soluble
guanylate cyclase. The document also discloses that the chemical compounds
described can
generally be converted into tablets, orally administrable suspensions and
orally administrable
solutions. These pharmaceutical dosage forms represent exclusively rapid-
release
pharmaceutical compositions.
In cases of diseases which require treatment over a lengthy period, or for the
long-term
prophylaxis of diseases, it is desirable to keep the frequency of intake of
medicaments as low as
possible. This is not only more convenient for the patient, it also increases
the reliability of
treatment by reducing the disadvantages of irregular intake. The desired
reduction in the
frequency of intake, for example from administration twice a day to once a
day, can be
achieved by prolonging the therapeutically effective plasma levels by modified
release of active
ingredients from the dosage forms.
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Moreover, following intake of dosage forms having a modified release of active
ingredient it is
possible to prevent side-effects by smoothing the plasma level time curve. By
minimizing the
peak-trough ratio, i.e. by avoiding high plasma active ingredient
concentrations which are
frequently observed after administration of rapid-release pharmaceutical
forms, the occurrence
.. of unwanted side effects correlating with the concentration peaks can be
reduced. Accordingly,
such a modified-release drug form should be developed. Here, an osmotic
release system was
chosen to ensure the required profile of a uniform, long-lasting and complete
release of active
ingredient over a variable, pre-defined time period. Compared to other delayed-
release
administration systems, osmotic release systems are characterized, for
example, in that the
release profiles can be adjusted flexibly by adjusting the thickness of the
shell (Kaushal, A.M.,
Garg, S. An Update on Osmotic Drug Delivery Patents. Pharmaceutical
Technology.
2003.13(1):8-97).
Osmotic release systems are also referred to as gastrointestinal therapeutic
systems (GITS) or
oral osmotic systems (OROS). The long-lasting and uniform release of an active
ingredient is
controlled by the osmotic pressure.
Osmotic release systems can be differentiated into single-chamber systems
(elementary osmotic
pump) and two-chamber systems (push-pull systems).
In single-chamber systems, one or more osmotically active substances are mixed
with the active
ingredient and compressed. These cores are surrounded by a semipermeable
membrane which
has at least one orifice. This semi-permeable membrane, referred to as shell
below, is
impermeable for components of the core, but allows entry of water from outside
by osmosis.
The water which has penetrated in then releases, via the resulting osmotic
pressure, the active
ingredient in dissolved or suspended form from one or more orifices in the
shell. Overall active
ingredient release and release rate can be controlled substantially via the
thickness and porosity
of the shell, the composition of the core and the number and size of the
orifices.
In two-chamber systems, one chamber comprises the active ingredient, the other
chamber
comprises the osmotically active substance. The two chambers can be separated
by a flexible
separating wall. This core is likewise surrounded by a shell which has at
least one orifice on the
side of the chamber containing the active ingredient.
Advantages, formulation aspects, use forms and information on production
processes of
osmotic release systems are described inter alia in the following
publications:
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= Kaushal, A.M., Garg, S.: "An Update on Osmotic Drug Delivery Patents",
Pharmaceutical Technology 2003, 13, 8-97.
= Kumar, P. and Mishra, B.: "An Overview of Recent Patents on Oral Osmotic
Drug
Delivery Systems", Recent Patents on Drug Delivery & Formulation 2007, 1, 236-
255.
= Verma, R.K., Mishra, B., Garg, S.: "Osmotically controlled oral drug
delivery", Drug
Development and Industrial Pharmacy 2000, 26, 695-708.
= Verma, R.K., Krishna, D.M., Garg, S.: "Formulation aspects in the
development of
osmotically controlled oral drug delivery systems", Journal of Controlled
Release 2002,
79, 7-27.
= Sareen. R., Jain, N., Kumar, D.: "An Insight to Osmotic Drug Delivery",
Current Drug
Delivery 2012, 9, 285-296.
= Malaterre, V., Ogorka, J., Loggia, N., Gurny, R.: "Oral osmotically
driven systems: 30
years of development and clinical use", European Journal of Pharmaceutics and
Biopharmaceutics 2009, 73, 311-323.
= US 4,327,725
= US 4,765,989
= US 20030161882
= EP-A 1024793
In the context of the present invention, the compound of the formula (I)
should be formulated in
the form of an osmotic release system to achieve long-lasting and uniform
release.
The hydrophilic swellable polymer usually employed is, in particular in the
case of two-
chamber systems, polyethylene oxide (WO 2006/072367). Unexpectedly, the
compound of the
formula (I) cannot be formulated in the customary manner in the form of an
osmotic release
system with polyethylene oxide as hydrophilic swellable polymer. During the
preparation
process of the osmotic release system comprising the compound of the formula
(I), melt
phenomena were encountered during granulation. The resulting inefficient
preparation process
yielded dosage forms which did not meet the requirements and the specification
of a
pharmaceutical product.
When using the compound of the formula (I) and polyethylene oxide as
hydrophilic swellable
polymer, during dry granulation using a roller changes in the consistency of
part of the granules
obtained were observed. The components of the granules fused to one another
giving a hard
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plastic-like material similar to a solidified melt, which was not suitable for
further processing.
The planned production process had to be abandoned. Comminution of the
solidified melt by
grating and sieving was possible only with high expenditure of force, material
and time, which
rendered the production process inefficient and unreliable with respect to a
reproducible
pharmaceutical quality of the product.
During further processing of the active-ingredient-comprising roller granules,
which had been
sieved with high expenditure, there were further disadvantageous effects
during compression of
the tablets. As early as in the feed funnel, -bridge formation" was observed,
which means that
the grains were getting caught on each other owing to the rough surface of the
grains. Thus, the
mixture ready for compression was not flowable without additional agitation.
Continuous
tabletting of the granules as a mixture ready for compression was therefore
not possible. Here,
too, the preparation process had to be abandoned. The machine parts of the
tabletting machine
such as punch, template and rotary table showed significant attachment of the
active-ingredient-
comprising mixture for compression. The few tablets obtained showed capping
tendency where
the upper or the lower part of the tablet, on ejection from the tabletting
press or during
processing, detached partially or fully horizontally from the main part and
formed a cap. Such
tablets do not meet the requirements of an acceptable pharmaceutical quality
and are no longer
suitable for use.
When various samples of the active-ingredient-comprising powder mixture prior
to granulation,
of the plastic-like material prior to sieving, of the plastic-like material
after comminution and
sieving and of the residue on the grinding sieve were taken and analysed,
significant variations
in the content of the compound of the formula (I) were found. Starting with
100% of the
declared active ingredient content in the active-ingredient-comprising powder
mixture prior to
granulation, the samples showed content values of from 107% to 120%, based on
the declared
active ingredient content. The consistently elevated content values are
probably due to the fact
that during the preparation only some of the roller granules melt and the
compound of the
formula (I) is present in heterogeneous form. A pharmaceutical dosage form
having such
deviations in the active ingredient content is unacceptable and cannot be used
for further
development. It has to be assumed that the measured content variations of the
powder mixture
also lead to content variations of a tablet prepared therefrom, and that these
tablets therefore do
not correspond to the requirements of the pharmacopeia, for example uniformity
of content (Ph.
Eur. Edition 9; 2.9.40 -Uniformity of Dosage Units").
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Surprisingly, by replacing the compound of the formula (I) with the sodium
salt of this
compound, i.e. sodium (3S)-3-(4-chloro-3-{[(2S,3R)-2-(4-chloropheny1)-4,4,4-
trifluoro-3-
methy lbutanoyl] amino 1 phenyl)-3-cyclopropy 1propano ate of the formula (II)
0
0
N a + CI
H N 0
H3 C 4,. "=,õ IS
F F CI
F
(II),
it was possible to obtain an osmotic release system which has neither the
described
disadvantageous properties of the osmotic release system comprising the
compound of the
formula (I) nor the disadvantages encountered during the described production
of the osmotic
release system comprising the compound of the formula (I). When the compound
of the
formula (II) was used, there were no melt phenomena or other disadvantageous
observations
made during the individual process steps. The production process could be
completed without
any unplanned interruptions. Content determination gave results conforming
with the
specifications with respect to the declared active ingredient content.
The different behaviour of a mixture of the compound of the formula (I) and
polyethylene oxide
compared to a mixture of the compound of the formula (II) and polyethylene
oxide can
additionally be demonstrated by measuring the DSC (differential scanning
calorimetry)
thermograms of the substances in question on their own and in trituration in a
ratio of 1:1
(binary mixtures). The changes which can be observed in the thermograms are
indicative for the
processability of the powder mixture. A trituration comprising equal amounts
of the compound
of the formula (I) and polyethylene oxide shows no melting peak which can be
assigned to the
compound of the formula (I) (Figure 1). Disappearance of the melting peak of
the active
compound, broadening of the melting peak of the hydrophilic swellable polymer
and earlier
onset of melting correlate with the processability deficits mentioned. Thus,
the melting process
starts even at a temperature between 50 C and 60 C. These temperatures may
occur during the
preparation of the osmotic release systems and cause the melting phenomena
described. A
trituration comprising equal amounts of the compound of the formula (II) and
polyethylene
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oxide shows, in addition to the melting peak of polyethylene oxide, an
additional melting peak
which can be assigned to the compound of the formula (II) (Figure 2). The
melting range of the
compound of the formula (II) is reduced in trituration; however, it is in a
temperature range
which is not reached during the preparation of the osmotic release systems. In
addition, in
contrast to the compound of the formula (I), the compound of the formula (II)
does not lower
the melting temperature of polyethylene oxide. In this combination, the
melting phenomena are
therefore not observed. Trituration in a ratio of 1:1 of the compound of the
formula (II) with
xanthan, vinylpyrrolidone/vinyl acetate copolymer (Kollidon VA 64),
polyvinylpyrrolidone
(PVP 25), hydroxypropylcellulose (HPC LM), anionic copolymers of methacrylic
acid and
methyl methacrylates (Eudragit L100, Eudragit RL PO) likewise show a melting
peak of the
compound of the formula (II) located in a higher temperature range (Figure 3
to Figure 8).
Since these polymers are amorphous, no melting peak which can be assigned to
the polymers is
seen in the measured range. The thermogram of a trituration of the compound of
the
formula (II) and polyacrylic acid shows no melting peak which can be assigned
to the
compound of the formula (II) (Figure 9). It suggests itself that, after the
glass transition
temperature of polyacrylic acid has been reached, the compound of the formula
(II) dissolves
with increasing temperature. Since the glass transition temperature is about
106 C, melting
phenomena during the preparation of the osmotic release system with
polyacrylic acid as
hydrophilic swellable polymer are not to be expected.
There have been efforts to produce a large number of other pharmaceutically
acceptable salts of
the compound of the formula (I). These included potassium, choline,
bicarbonate, sodium
carbonate, (diethylamino)ethanol, L-lysine, tris, N-methyl-D-glucamine, L-
arginine, sodium
bicarbonate and potassium bicarbonate salts of the compound of the formula
(I). When
developing a drug form, it is an important requirement that the active
ingredient can be isolated
reproducibly in a defined crystalline form. The amorphous forms are unsuitable
for the
preparation of pharmaceutical dosage forms since, frequently, they have a
lower
thermodynamic stability and disadvantageous properties for the formulation of
pharmaceutical
dosage forms, for example poor micronizability, adhesiveness or poor
tabletability.
Additionally, the crystalline form of the active ingredient should have
reproducible
bioavailability and remain stable during the micronization process so that no
conversion and
recrystallization takes place.
Surprisingly, it has been found that only the sodium salt of the compound of
the formula (I)
could be obtained in crystalline form and that the crystalline form of the
sodium salt of the
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compound of the formula (II) has the advantageous properties described.
Hereinbelow, this
crystalline form is referred to as compound of the formula (II) in crystalline
form of
modification 1.
All other salts of the compound of the formula (I) tested could not be
obtained in crystalline
form, and consequently the compound of the formula (II) was preferably used
for preparing an
osmotic release system.
The present invention provides a solid orally administrable modified-release
pharmaceutical
dosage form comprising sodium (3S)-3-(4-chloro-3- {[(2S,3R)-2-(4-chloropheny1)-
4,4,4-
tri fluoro-3-methy lbutanoyl] ami nolpheny1)-3 -cyclopropy 1propano ate of the
formula (II),
characterized in that 80% of the compound of the formula (II) are released
over a period of 2 to
24, preferably 4 to 20, hours, measured according to USP release method (USP
39; Chapter
<711> Dissolution) using apparatus 2 (paddle) and the statements in the
chapter -Release
properties".
Suitable for formulating the compounds of the formula (II) in the form of an
osmotic release
system are both two-chamber systems (push-pull systems) and single-chamber
systems
(elementary osmotic pump). Both the two-chamber system and the single-chamber
system
consist of a core coated with a shell and optionally a coating. In the osmotic
release systems,
the compound of the formula (II) can be present either in crystalline or else
in amorphous form
or as a mixture comprising crystalline and amorphous portions. In the osmotic
release system,
the compound of the formula (II) is preferably present in crystalline form. In
the osmotic
release system, the compound of the formula (II) is preferably present in
micronized form.
The present invention furthermore provides a solid, orally administrable
modified-release
pharmaceutical dosage form comprising sodium (3S)-3-(4-chloro-3-{[(25,3R)-2-(4-
chloropheny1)-4,4,4-trifluoro-3-methylbutanoyll aminolpheny1)-3-cyclopropy
1propano ate of the
formula (II),
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0
0
Na + CI
H N 0
H q C
,., 4,.../......õ40
F F F CI
(II),
characterized in that the pharmaceutical dosage form is based on an osmotic
release system.
The present invention provides a solid, orally administrable modified-release
pharmaceutical
dosage form comprising the compound of the formula (II), characterized in that
the
pharmaceutical dosage form is based on an osmotic single-chamber system.
The present invention provides a solid, orally administrable modified-release
pharmaceutical
dosage form comprising the compound of the formula (II), characterized in that
the
pharmaceutical dosage form is based on an osmotic two-chamber system.
In one embodiment, the osmotic release system consists of a core and a shell,
where the shell
consists of a water-permeable material impermeable for the components of the
core and has at
least one orifice, and where the core comprises the compound of the formula
(II) and at least
one hydrophilic swellable polymer.
In a further embodiment, the osmotic release system consists of a core and a
shell, where the
shell consists of a water-permeable material impermeable for the components of
the core and
has at least one orifice, and where the core comprises the compound of the
formula (II) and at
least one hydrophilic swellable polymer, preferably selected from a list
consisting of
polyethylene oxide, xanthan, cellulose derivatives, for example
hydroxypropylcellulose,
hydroxypropylmethylcellulose or sodium carboxymethylcellulose, starch
derivatives, for
example sodium carboxymethyl starch, vinylpyrrolidone/vinyl acetate copolymer,
polyvinylpyrrolidone, methacrylic acid copolymers, for example methacrylic
acid/methyl
methacrylate copolymer and polyacrylic acids, or preferably selected from a
list consisting of
polyethylene oxide, xanthan, hydroxypropylcellulose,
hydroxypropylmethylcellulose, sodium
carboxymethylcellulose, sodium carboxymethyl starch, vinylpyrrolidone/vinyl
acetate
copolymer and polyacrylic acids.
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In a further embodiment, the osmotic release system consists of a core and a
shell, where the
shell consists of a water-permeable material impermeable for the components of
the core and
has at least one orifice, and where the core comprises the compound of the
formula (II), at least
one hydrophilic swellable polymer, preferably selected from a list consisting
of polyethylene
oxide, xanthan, cellulose derivatives, for example hydroxypropylcellulose,
hydroxypropylmethylcellulose or sodium carboxymethylcellulose, starch
derivatives, for
example sodium carboxymethyl starch, vinylpyrrolidone/vinyl acetate copolymer,
polyvinylpyrrolidone, methacrylic acid copolymers, for example methacrylic
acid/methyl
methacrylate copolymer and polyacrylic acids, or preferably selected from a
list consisting of
polyethylene oxide, xanthan, hydroxypropylcellulose,
hydroxypropylmethylcellulose, sodium
carboxymethylcellulose, sodium carboxymethyl starch, vinylpyrrolidone/vinyl
acetate
copolymer and polyacrylic acids, optionally at least one pharmaceutically
customary auxiliary
and optionally an osmotically active additive.
In a further embodiment, the osmotic release system consists of a core and a
shell, where the
shell consists of a water-permeable material impermeable for the components of
the core and
has at least one orifice, and where the core comprises the compound of the
formula (II), at least
one hydrophilic swellable polymer selected from a list consisting of
polyethylene oxide,
xanthan and vinylpyrrolidone/vinyl acetate copolymer or selected from a list
consisting of
polyethylene oxide and xanthan, optionally at least one further hydrophilic
swellable polymer,
optionally at least one pharmaceutically customary auxiliary and optionally an
osmotically
active additive.
In a further embodiment, the osmotic release system consists of a core and a
shell, where the
shell consists of a water-permeable material impermeable for the components of
the core and
has at least one orifice, and where the core comprises the compound of the
formula (II), the
hydrophilic swellable polymer polyethylene oxide, optionally at least one
further hydrophilic
swellable polymer, optionally at least one pharmaceutically customary
auxiliary and optionally
an osmotically active additive.
In a further embodiment, the osmotic release system consists of a core and a
shell, where the
shell consists of a water-permeable material impermeable for the components of
the core and
has at least one orifice, and where the core comprises 0.5% by weight to 50%
by weight of the
compound of the formula (II), 40% by weight to 99.5% by weight of at least one
hydrophilic
swellable polymer, preferably selected from a list consisting of polyethylene
oxide, xanthan,
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cellulose derivatives, for example hydroxypropylcellulose,
hydroxypropylmethylcellulose or
sodium carboxymethylcellulose, starch derivatives, for example sodium
carboxymethyl starch,
vinylpyrrolidone/vinyl acetate copolymer, polyvinylpyrrolidone, methacrylic
acid copolymers,
for example methacrylic acid/methyl methacrylate copolymer and polyacrylic
acids, or selected
from a list consisting of polyethylene oxide, xanthan, hydroxypropylcellulose,
hydroxypropylmethylcellulose, sodium carboxymethylcellulose, sodium
carboxymethyl starch,
vinylpyrrolidone/vinyl acetate copolymer and polyacrylic acids, particularly
preferably
polyethylene oxide, xanthan and vinylpyrrolidone/vinyl acetate copolymer, very
particularly
preferably polyethylene oxide, optionally at least one pharmaceutically
customary auxiliary and
optionally an osmotically active additive.
In a further embodiment, the osmotic release system consists of a core and a
shell, where the
shell consists of a water-permeable material impermeable for the components of
the core and
has at least one orifice, and where the core comprises 1% by weight to 40% by
weight of the
compound of the formula (II), 50% by weight to 99% by weight of at least one
hydrophilic
swellable polymer, preferably selected from a list consisting of polyethylene
oxide, xanthan,
cellulose derivatives, for example hydroxypropylcellulose,
hydroxypropylmethylcellulose or
sodium carboxymethylcellulose, starch derivatives, for example sodium
carboxymethyl starch,
vinylpyrrolidone/vinyl acetate copolymer, polyvinylpyrrolidone, methacrylic
acid copolymers,
for example methacrylic acid/methyl methacrylate copolymer and polyacrylic
acids, or selected
from a list consisting of polyethylene oxide, xanthan, hydroxypropylcellulose,
hydroxypropylmethylcellulose, sodium carboxymethylcellulose, sodium
carboxymethyl starch,
vinylpyrrolidone/vinyl acetate copolymer and polyacrylic acids, particularly
preferably
polyethylene oxide, xanthan and vinylpyrrolidone/vinyl acetate copolymer, very
particularly
preferably polyethylene oxide, optionally at least one pharmaceutically
customary auxiliary and
optionally an osmotically active additive.
In a further embodiment, the osmotic release system consists of a core and a
shell, where the
shell consists of a water-permeable material impermeable for the components of
the core and
has at least one orifice, and where the core comprises 2% by weight to 20% by
weight of the
compound of the formula (II), 60% by weight to 90% by weight of at least one
hydrophilic
swellable polymer, preferably selected from a list consisting of polyethylene
oxide, xanthan,
cellulose derivatives, for example hydroxypropylcellulose,
hydroxypropylmethylcellulose or
sodium carboxymethylcellulose, starch derivatives, for example sodium
carboxymethyl starch,
vinylpyrrolidone/vinyl acetate copolymer, polyvinylpyrrolidone, methacrylic
acid copolymers,
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for example methacrylic acid/methyl methacrylate copolymer and polyacrylic
acids, or selected
from a list consisting of polyethylene oxide, xanthan, hydroxypropylcellulose,
hydroxypropylmethylcellulose, sodium carboxymethylcellulose, sodium
carboxymethyl starch,
vinylpyrrolidone/vinyl acetate copolymer and polyacrylic acids, particularly
preferably
polyethylene oxide, xanthan and vinylpyrrolidone/vinyl acetate copolymer, very
particularly
preferably polyethylene oxide, optionally at least one pharmaceutically
customary auxiliary and
optionally an osmotically active additive.
In a further embodiment, the osmotic release system consists of a core and a
shell, where the
shell consists of a water-permeable material impermeable for the components of
the core and
has at least one orifice, and where the core comprises 2% by weight to 10% by
weight of the
compound of the formula (II), 70% by weight to 85% by weight of at least one
hydrophilic
swellable polymer, preferably selected from a list consisting of polyethylene
oxide, xanthan,
cellulose derivatives, for example hydroxypropylcellulose,
hydroxypropylmethylcellulose or
sodium carboxymethylcellulose, starch derivatives, for example sodium
carboxymethyl starch,
vinylpyrrolidone/vinyl acetate copolymer, polyvinylpyrrolidone, methacrylic
acid copolymers,
for example methacrylic acid/methyl methacrylate copolymer and polyacrylic
acids, or
preferably selected from a list consisting of polyethylene oxide, xanthan,
hydroxypropylcellulose, hydroxypropylmethylcellulose, sodium
carboxymethylcellulose,
sodium carboxymethyl starch, vinylpyrrolidone/vinyl acetate copolymer and
polyacrylic acids,
particularly preferably polyethylene oxide, xanthan and vinylpyrrolidone/vinyl
acetate
copolymer, very particularly preferably polyethylene oxide, optionally at
least one
pharmaceutically customary auxiliary and optionally an osmotically active
additive.
In a further embodiment, the osmotic release system consists of a core and a
shell, where the
shell consists of a water-permeable material impermeable for the components of
the core and
has at least one orifice, and where the core comprises
= 0.5% by weight to 50% by weight of the compound of the formula (II),
= 10% by weight to 50% by weight of xanthan,
= 5% by weight to 40% by weight of a vinylpyrrolidone/vinyl acetate
copolymer,
optionally at least one further hydrophilic swellable polymer, optionally at
least one further
pharmaceutically customary auxiliary and optionally an osmotically active
additive.
The percentages by weight are in each case based on the total mass of the
core.
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Preferably, the osmotic single-chamber system comprises, as one of the
essential components of
the core, the hydrophilic water-swellable polymer xanthan. This is an anionic
heteropolysaccharide which is obtainable commercially, for example under the
name
Rhodigel0 (produced by Rhodia) or -Xanthan FN Lebensminelqualitat normal"
(produced by
Jungbunzlauer Ladenburg GmbH). It is present in an amount of from 10 to 50% by
weight,
preferably from 25 to 40% by weight, based on the total mass of the core
components.
A further essential component of the core is the vinylpyrrolidone/vinyl
acetate copolymer. This
copolymer is known per se and can be produced in any desired monomer mixing
ratio. For
example, the commercially available Kollidon0 VA64 (produced by BASF), which
is
preferably used, is a 60:40 copolymer. It generally has a weight average
molecular weight,
determined by light-scattering measurements, of about 45 000 to about 70 000.
The amount of
the vinylpyrrolidone/vinyl acetate copolymer in the core is 5 to 40% by
weight, preferably 15 to
25% by weight, based on the total mass of the core components.
Hydrophilic swellable polymers which are additionally present where
appropriate in the core
are, for example, hy droxypropy lcellulose, hy droxypropylmethylcellulose,
sodium
carboxymethylcellulose, sodium carboxymethyl starch, polyacrylic acids or
salts thereof.
The present invention furthermore provides a process for preparing an osmotic
release system,
characterized in that the components of the core are mixed with one another,
granulated and
tabletted, the resulting core is coated with a shell and the shell is finally
provided with one or
.. more orifices suitable for the compound of the formula (II) exiting.
The present invention furthermore provides a process for preparing an osmotic
single-chamber
system according to the invention, where the components of the core are mixed
with one
another, optionally subjected to wet or dry granulation and then tabletted,
and the resulting core
is coated with the shell. At the active compound side, the shell is provided
with one or more
orifices. Alternatively, the introduction of the one or more orifices in this
process step may be
dispensed with and initially a coating, for example a light protection coating
and/or colour
coating, may be applied. In this case, only after the coating with one or more
further coatings
has been carried out, both sides of the tablet are provided with in each case
one orifice which in
each case reach from the outside to the inner core, i.e. traverse coating and
shell, and are
.. suitable for the compound of the formula (II) exiting.
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In a preferred embodiment of the present invention, when producing the osmotic
single-
chamber system the core components are subjected to wet granulation since this
process step
results in better wettability of the constituents of the tablet core, owing to
which there is better
core penetration of the ingressing gastrointestinal fluid, frequently
resulting in a more rapid and
more complete release of the active ingredient.
In a further embodiment, the core of the osmotic release system consists of
two layers, an active
ingredient layer and an osmosis layer. An osmotic two-chamber system of this
type is described
in detail, for example, in DE 3417113 C2, WO 2006/072367 or WO 2010/060564,
the
disclosures of which are incorporated herein by reference.
In a further embodiment, the osmotic release system consists of a core and a
shell, where the
shell consists of a water-permeable material impermeable for the components of
the core and
has at least one orifice, and where the core consists of an active ingredient
layer and an osmosis
layer.
In a further embodiment, the osmotic release system consists of a core and a
shell, where the
shell consists of a water-permeable material not permeable for the components
of the core, with
at least one orifice, and where the core consists of an active ingredient
layer and an osmosis
layer and the active ingredient layer is polyethylene oxide having a viscosity
of from 40 to
100 mPa.s (measured in a 5% strength aqueous solution, 25 C) and the at least
one hydrophilic
swellable polymer of the osmosis layer is polyethylene oxide having a
viscosity of 5000 to
8000 mPa.s (measured in a 1% strength aqueous solution, 25 C).
In a further embodiment, the osmotic release system consists of a core and a
shell, where the
shell consists of a water-permeable material impermeable for the components of
the core and
has at least one orifice, and where the core consists of an active ingredient
layer and an osmosis
layer and the active ingredient layer comprises 1% by weight to 50% by weight
of the
compound of the formula (II), 20% by weight to 99% by weight of at least one
hydrophilic
swellable polymer, preferably selected from a list consisting of polyethylene
oxide, xanthan,
cellulose derivatives, for example hydroxypropylcellulose,
hydroxypropylmethylcellulose or
sodium carboxymethylcellulose, starch derivatives, for example sodium
carboxymethyl starch,
vinylpyrrolidone/vinyl acetate copolymer, polyvinylpyrrolidone, methacrylic
acid copolymers,
for example methacrylic acid/methyl methacrylate copolymer and polyacrylic
acids, or selected
from a list consisting of polyethylene oxide, xanthan, hydroxypropylcellulose,
hydroxypropylmethylcellulose, sodium carboxymethylcellulose, sodium
carboxymethyl starch,
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vinylpyrrolidone/vinyl acetate copolymer and polyacrylic acids, particularly
preferably
polyethylene oxide, xanthan and vinylpyrrolidone/vinyl acetate copolymer, very
particularly
preferably polyethylene oxide, optionally at least one osmotically active
additive and optionally
at least one pharmaceutically customary auxiliary.
In a further embodiment, the active ingredient layer comprises 1% by weight to
45% by weight,
preferably 1% by weight to 30% by weight, particularly preferably 2% by weight
to 20% by
weight of the compound of the formula (II), 30% by weight to 99% by weight,
preferably 50%
by weight to 99% by weight, particularly preferably 60% by weight to 98% by
weight of at
least one hydrophilic swellable polymer, optionally at least one osmotically
active additive and
optionally at least one pharmaceutically customary auxiliary.
In a further embodiment, the osmotic release system consists of a core and a
shell, where the
shell consists of a water-permeable material impermeable for the components of
the core and
has at least one orifice, and where the core consists of an active ingredient
layer and an osmosis
layer and the active ingredient layer comprises 1% by weight to 50% by weight
of the
compound of the formula (II), 20% by weight to 99% by weight of polyethylene
oxide,
preferably polyethylene oxide having a viscosity of 40 to 100 mPa.s (measured
in a 5%
strength aqueous solution, 25 C), optionally at least one further hydrophilic
swellable polymer,
optionally at least one osmotically active additive and optionally at least
one pharmaceutically
customary auxiliary.
In a further embodiment, the osmotic release system consists of a core and a
shell, where the
shell consists of a water-permeable material impermeable for the components of
the core and
has at least one orifice, and where the core consists of an active ingredient
layer and an osmosis
layer and the active ingredient layer comprises 1% by weight to 45% by weight
of the
compound of the formula (II), 30% by weight to 99% by weight of polyethylene
oxide,
preferably polyethylene oxide having a viscosity of 40 to 100 mPa.s (measured
in a 5%
strength aqueous solution, 25 C), optionally at least one further hydrophilic
swellable polymer,
optionally at least one osmotically active additive and optionally at least
one pharmaceutically
customary auxiliary.
In a further embodiment, the osmotic release system consists of a core and a
shell, where the
shell consists of a water-permeable material impermeable for the components of
the core and
has at least one orifice, and where the core consists of an active ingredient
layer and an osmosis
layer and the active ingredient layer comprises 1% by weight to 30% by weight
of the
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compound of the formula (II), 50% by weight to 99% by weight of polyethylene
oxide,
preferably polyethylene oxide having a viscosity of 40 to 100 mPa.s (measured
in a 5%
strength aqueous solution, 25 C), optionally at least one further hydrophilic
swellable polymer,
optionally at least one osmotically active additive and optionally at least
one pharmaceutically
customary auxiliary.
In a further embodiment, the osmotic release system consists of a core and a
shell, where the
shell consists of a water-permeable material impermeable for the components of
the core and
has at least one orifice, and where the core consists of an active ingredient
layer and an osmosis
layer and the active ingredient layer comprises 2% by weight to 20% by weight
of the
compound of the formula (II), 60% by weight to 98% by weight of polyethylene
oxide,
preferably polyethylene oxide having a viscosity of 40 to 100 mPa.s (measured
in a 5%
strength aqueous solution, 25 C), optionally at least one further hydrophilic
swellable polymer,
optionally at least one osmotically active additive and optionally at least
one pharmaceutically
customary auxiliary.
The percentages by weight are in each case based on the total mass of the
active ingredient
layer.
The viscosity of polyethylene oxide having a viscosity of 40 to 100 mPa.s
(measured in a 5%
strength aqueous solution, 25 C) is preferably measured using a suitable
Brookfield
viscosimeter and a suitable spindle at a suitable speed of rotation; use is
made in particular of a
Brookfield viscosimeter Model RVT and a spindle No. 1 at a speed of rotation
of 50 rpm or
using a comparable model under corresponding conditions (spindle, speed of
rotation).
In a further embodiment, the osmotic release system consists of a core and a
shell, where the
shell consists of a water-permeable material impermeable for the components of
the core and
has at least one orifice, and where the core consists of one of the active
ingredient layers
described above and an osmosis layer, where the osmosis layer comprises 40% by
weight to
90% by weight, preferably 50% by weight to 80% by weight of at least one
hydrophilic
swellable polymer preferably selected from a list consisting of polyethylene
oxide, xanthan,
cellulose derivatives, for example hydroxypropylcellulose,
hydroxypropylmethylcellulose or
sodium carboxymethylcellulose, starch derivatives, for example sodium
carboxymethyl starch,
vinylpyrrolidone/vinyl acetate copolymer, polyvinylpyrrolidone, methacrylic
acid copolymers,
for example methacrylic acid/methyl methacrylate copolymer and polyacrylic
acids, or selected
from a list consisting of polyethylene oxide, xanthan, hydroxypropylcellulose,
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hydroxypropylmethylcellulose, sodium carboxymethylcellulose, sodium
carboxymethyl starch,
vinylpyrrolidone/vinyl acetate copolymer and polyacrylic acids, preferably
polyethylene oxide,
xanthan and vinylpyrrolidone/vinyl acetate copolymer, very particularly
preferably
polyethylene oxide, 10% by weight to 60% by weight, preferably 20% by weight
to 50% by
.. weight of at least one osmotically active additive and optionally at least
one pharmaceutically
customary auxiliary.
The hydrophilic swellable polymer used in the osmosis layer is preferably
polyethylene oxide.
Polyethylene oxide having a viscosity of 5000 to 8000 mPa.s (measured in a 1%
strength
aqueous solution, 25 C) is particularly preferred.
The viscosity of polyethylene oxide having a viscosity of 5000 to 8000 mPa.s
(measured in a
1% strength aqueous solution, 25 C) is preferably measured using a suitable
Brookfield
viscosimeter and a suitable spindle at a suitable speed of rotation, in
particular using a
Brookfield viscosimeter Model RVF and a spindle No. 2 at a speed of rotation
of 2 rpm or
using a comparable model under corresponding conditions (spindle, speed of
rotation).
.. In a further embodiment, the osmotic release system consists of a core and
a shell, where the
shell consists of a water-permeable material impermeable for the components of
the core and
has at least one orifice, and where the core consists of an active ingredient
layer and an osmosis
layer, where the active ingredient layer comprises 0.5% by weight to 65% by
weight of the
compound of the formula (II), 20% by weight to 99.5% by weight of at least one
hydrophilic
swellable polymer, preferably selected from a list consisting of polyethylene
oxide, xanthan,
cellulose derivatives, for example hydroxypropylcellulose,
hydroxypropylmethylcellulose or
sodium carboxymethylcellulose, starch derivatives, for example sodium
carboxymethyl starch,
vinylpyrrolidone/vinyl acetate copolymer, polyvinylpyrrolidone, methacrylic
acid copolymers,
for example methacrylic acid/methyl methacrylate copolymer and polyacrylic
acids, or selected
from a list consisting of polyethylene oxide, xanthan, hydroxypropylcellulose,
hydroxypropylmethylcellulose, sodium carboxymethylcellulose, sodium
carboxymethyl starch,
vinylpyrrolidone/vinyl acetate copolymer and polyacrylic acids, preferably
polyethylene oxide,
xanthan and vinylpyrrolidone/vinyl acetate copolymer, very particularly
preferably
polyethylene oxide, optionally at least one osmotically active additive and
optionally at least
one pharmaceutically customary auxiliary, and the osmosis layer comprises 40%
by weight to
90% by weight of at least one hydrophilic swellable polymer, preferably
selected from a list
consisting of polyethylene oxide, xanthan, cellulose derivatives, for example
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hydroxypropylcellulose, hydroxypropylmethylcellulose or sodium
carboxymethylcellulose,
starch derivatives, for example sodium carboxymethyl starch,
vinylpyrrolidone/vinyl acetate
copolymer, polyvinylpyrrolidone, methacrylic acid copolymers, for example
methacrylic
acid/methyl methacrylate copolymer and polyacrylic acids, or selected from a
list consisting of
polyethylene oxide, xanthan, hydroxypropylcellulose,
hydroxypropylmethylcellulose, sodium
carboxymethylcellulose, sodium carboxymethyl starch, vinylpyrrolidone/vinyl
acetate
copolymer and poly acrylic acids, preferably polyethylene oxide, xanthan and
vinylpyrrolidone/vinyl acetate copolymer, very particularly preferably
polyethylene oxide, 10%
by weight to 60% by weight of an osmotically active additive and optionally at
least one
pharmaceutically customary auxiliary.
In a further embodiment, the osmotic release system consists of a core and a
shell, where the
shell consists of a water-permeable material impermeable for the components of
the core and
has at least one orifice, and where the core consists of an active ingredient
layer and an osmosis
layer, where the active ingredient layer comprises 1% by weight to 50% by
weight of the
compound of the formula (II), 20% by weight to 99% by weight of polyethylene
oxide,
preferably polyethylene oxide having a viscosity of 40 to 100 mPa.s (measured
in a 5%
strength aqueous solution, 25 C), optionally at least one osmotically active
additive and
optionally at least one pharmaceutically customary auxiliary, and the osmosis
layer comprises
40% by weight to 90% by weight of polyethylene oxide, preferably polyethylene
oxide having
a viscosity of 5000 to 8000 mPa.s (measured in a 1% strength aqueous solution,
25 C), 10% by
weight to 60% by weight of an osmotically active additive and optionally at
least one
pharmaceutically customary auxiliary.
In a further embodiment, the active ingredient layer comprises 1% by weight to
45% by weight,
preferably 1% by weight to 30% by weight, particularly preferably 2% by weight
to 20% by
weight of the compound of the formula (II), 30% by weight to 99% by weight,
preferably 50%
by weight to 99% by weight, particularly preferably 60% by weight to 98% by
weight of
polyethylene oxide having a viscosity of 40 to 100 mPa.s (measured in a 5%
strength aqueous
solution, 25 C), optionally at least one osmotically active additive and
optionally at least one
pharmaceutically customary auxiliary, and the osmosis layer comprises 40% by
weight to 90%
by weight, preferably 50% by weight to 80% by weight of polyethylene oxide
having a
viscosity of 5000 to 8000 mPa.s (measured in a 1% strength aqueous solution,
25 C), 10% by
weight to 60% by weight, preferably 20% by weight to 50% by weight of at least
one
osmotically active additive and optionally at least one pharmaceutically
customary auxiliary.
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In a further embodiment, the osmotic release system consists of a core and a
shell, where the
shell consists of a water-permeable material impermeable for the components of
the core and
has at least one orifice, and where the core consists of an active ingredient
layer and an osmosis
layer, where the active ingredient layer comprises 2% by weight to 20% by
weight of the
compound of the formula (II), 60% by weight to 98% by weight of polyethylene
oxide having a
viscosity of 40 to 100 mPa.s (measured in a 5% strength aqueous solution, 25
C), optionally at
least one osmotically active additive and optionally at least one
pharmaceutically customary
auxiliary, and the osmosis layer comprises 50% by weight to 80% by weight of
polyethylene
oxide having a viscosity of 5000 to 8000 mPa.s (measured in a 1% strength
aqueous solution,
25 C), 20% by weight to 50% by weight of an osmotically active additive and
optionally at
least one pharmaceutically customary auxiliary.
In a further embodiment, the osmotic release system consists of one of the
osmotic release
systems described above, where the shell consists of cellulose acetate or a
mixture of cellulose
acetate and polyethylene glycol.
In a further embodiment, the osmotic release system is one of the osmotic
release systems
described above where 80% of the compound of the formula (II) are released
after 2 hours to
24 hours, preferably 4 hours to 20 hours, particularly preferably 5 hours to
16 hours (measured
according to USP release method (USP 39; Chapter <711> Dissolution) using
apparatus 2
(paddle) and the statements in the chapter -Release properties").
In a further embodiment, the osmotic release system is one of the osmotic
release systems
described above where the osmotic release system complies with the
requirements regarding
uniformity of content (Ph. Eur. Edition 9; 2.9.40 -Uniformity of Dosage
Units").
In a further embodiment, the osmotic release system is one of the osmotic
release systems
described above where the standard deviation in per cent of the compound of
formula (II)
within the osmotic release system is less than 7%, preferably less than 6%,
more preferably less
than 5%, most preferably less than 4%, calculated from n=10 individual
contents determined.
In the context of the present invention, hydrophilic swellable polymers are
all pharmaceutically
acceptable polymer compounds known to the person skilled in the art which
swell by taking up
water. Preference is given to using at least one hydrophilic swellable polymer
selected from a
list consisting of polyethylene oxide, xanthan, cellulose derivates, for
example
hydroxypropylcellulose, hydroxypropylmethylcellulose or sodium
carboxymethylcellulose,
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starch derivatives, for example sodium carboxymethyl starch,
vinylpyrrolidone/vinyl acetate
copolymer, polyvinylpyrrolidone, methacrylic acid copolymers, for example
methacrylic
acid/methyl methacrylate copolymer and polyacrylic acids, or selected from a
list consisting of
polyethylene oxide, xanthan, cellulose derivates, for example
hydroxypropylcellulose,
.. hydroxypropylmethylcellulose or sodium carboxymethylcellulose, starch
derivatives, for
example sodium carboxymethyl starch, vinylpyrrolidone/vinyl acetate copolymer,
polyvinylpyrrolidone and methacrylic acid copolymers, for example methacrylic
acid/methyl
methacry late copolymer.
Furthermore, preference is given to using at least one hydrophilic swellable
polymer selected
from a list consisting of polyethylene oxide, xanthan, hydroxypropylcellulose,
hydroxypropylmethylcellulose, sodium carboxymethylcellulose, sodium
carboxymethyl starch,
vinylpyrrolidone/vinyl acetate copolymer and polyacrylic acids, or selected
from a list
consisting of polyethylene oxide, xanthan,
hydroxypropylcellulose,
hydroxypropylmethylcellulose, sodium carboxymethylcellulose, sodium
carboxymethyl starch
and vinylpyrrolidone/vinyl acetate copolymer; particular preference is given
to using xanthan,
polyethylene oxide and vinylpyrrolidone/vinyl acetate copolymer or mixtures
thereof.
Furthermore, preference is given to using at least one hydrophilic swellable
polymer selected
from a list consisting of polyethylene oxide, xanthan, Kollidon VA 64, PVP 25,
Eudragit L100,
Eudragit RL PO, HPC LM and polyacrylic acid, or selected from a list
consisting of
polyethylene oxide, xanthan, Kollidon VA 64, PVP 25, Eudragit L100, Eudragit
RL PO and
HPC LM; particular preference is given to using polyethylene oxide.
Furthermore, particular preference is given to using at least one hydrophilic
swellable polymer
selected from a list consisting of polyethylene oxide (corresponding to Ph.
Eur. (Edition 9)
monograph -Macrogols, High Molecular Mass"; viscosity 5000 to 8000 mPa.s;
measured in a
1% strength aqueous solution, 25 C; POLYOXIm Water-Soluble Resin NF WSR N-80;
Dow)
and polyethylene oxide (corresponding to Ph. Eur. (Edition 9) monograph -
Macrogols, High
Molecular Mass"; viscosity 40 to 100 mPa.s; measured in a 5% strength aqueous
solution,
25 C; POLYOXIm Water-Soluble Resin NF WSR N-80; Dow).
In the context of the present invention, starch derivatives suitable as
hydrophilic swellable
.. polymers are maize, wheat, rice and potato starch, substituted starches
such as carboxymethyl
starch and its salt, hydroxyethyl starch or mixtures thereof.
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In the context of the present invention, cellulose derivatives suitable as
hydrophilic swellable
polymers are methylcellulose (MC), hydroxymethylpropylcellulose (HPMC),
hydroxypropylcellulose (HPC), carboxymethylcellulose-sodium
(Na-CMC),
hydroxyethylcellulose (HEC) or mixtures thereof.
The hydrophilic swellable polymers mentioned can be employed on their own or
in
combination with other hydrophilic swellable polymers.
Alternatively, some hydrophilic swellable polymers can be used as
pharmaceutically acceptable
auxiliaries in the core, for example as binders or disintegrants. If the
proportion of such a
substance in the core, based on the mass of the core, is 10 per cent or more,
such a substance is,
in the context of the present invention, a hydrophilic swellable polymer.
Osmotically active additives in the context of the present invention are, for
example, all water-
soluble substances acceptable for use in the pharmaceutical industry, such as,
for example, the
water-soluble auxiliaries mentioned in pharmacopeias, in 'Hager" and
'Remington
Pharmaceutical Science" or other literature (Sareen. R., Jain, N., Kumar, D.,
Current Drug
Delivery, 9, (2012), 285-296). It is possible in particular to use water-
soluble salts of inorganic
or organic acids or nonionic organic substances with high solubility in water,
such as, for
example, carbohydrates, especially sugars, sugar alcohols or amino acids. For
example, the
osmotically active additives can be selected from inorganic salts such as
chlorides, sulfates,
carbonates and bicarbonates of alkali metals or alkaline earth metals, such as
lithium, sodium,
potassium, magnesium, calcium, and phosphates, hydrogen phosphates or
dihydrogen
phosphates, acetates, succinates, benzoates, citrates or ascorbates thereof.
It is furthermore
possible to use pentoses such as arabinose, ribose or xylose, hexoses such as
glucose, fructose,
galactose or mannose, disaccharides such as sucrose, maltose or lactose or
trisaccharides such
as raffinose. The water-soluble amino acids include glycine, leucine, alanine
or methionine.
Preference is given to using sodium chloride.
Pharmaceutically customary auxiliaries in the context of the present invention
are, for example,
buffers such as sodium bicarbonate, binders such as hydroxypropylcellulose,
hydroxypropylmethylcellulose, po lyv iny 1pyrro li done or viny 1pyrro li
done/vinyl acetate
copolymers (Kollidon0 VA64), disintegrants such as sodium carboxymethyl
starch, lubricants
such as magnesium stearate, wetting agents such as sodium lauryl sulfate, flow
regulators such
as finely divided silica, protective colloids as described in EP-B-0277092
(p.5, lines 10-25),
plasticizers as described, for example, in EP-B-0277092 (p. 5, lines 29-32),
surfactants as
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described, for example, in EP-B-0277092 (p. 5, lines 33-44), carrier materials
as described, for
example in EP-B-0277092 (p. 5, lines 45-47), and also one or more colour
pigments such as, for
example, iron oxide in one of the two layers for differentiation between
active ingredient layer
and osmosis layer. Suitable protective colloids are, for example, methylated
cellulose
.. derivatives, e.g. methylcellulose having a methoxy content of about 27.0 to
32.0% and a degree
of substitution of about 1.75 to 2.1 or methylhydroxypropylcellulose having a
content of about
16.0 - 30.0% methoxy and 4.0 - 32.0% hydroxypropoxy groups. Suitable
plasticizers are, for
example, glycerol, methyl citrate, diethyl phthalate or diethyl sebacate.
Suitable surfactants are,
for example, anionic surfactants of the alkyl sulfate type, for example
sodium, potassium or
magnesium n-dodecyl sulfate, n-tetradecyl sulfate, n-hexadecyl sulfate or n-
octadecyl sulfate,
alkyl ether sulfate, for example sodium, potassium or magnesium n-
dodecyloxyethyl sulfate, n-
tetradecyloxyethyl sulfate, n-hexadecyloxyethyl sulfate or n-octadecyloxyethyl
sulfate or
alkanesulfonate, for example sodium, potassium or magnesium n-
dodecanesulfonate, n-
tetradecanesulfonate, n-hexadecanesulfonate or n-octadecanesulfonate. Suitable
surfactants are
furthermore nonionic surfactants of the fatty acid polyhydroxyalcohol ester
type, such as
sorbitan monolaurate, -oleate, -stearate or -palmitate, sorbitan tristearate
or trioleate,
polyoxyethylene adducts of fatty acid polyhydroxyalcohol esters such as
polyoxyethylene
sorbitan monolaurate, -oleate, -stearate, -palmitate, tristearate or
trioleate, polyethylene glycol
fatty esters such as polyoxyethyl stearate, polyethylene glycol 400 stearate,
polyethylene glycol
2000 stearate, in particular ethylene oxide propylene oxide block polymers of
the Pluronics0
(BWC) or Synperonic0 (ICI) type. Suitable carrier materials are, for example,
lactose, sucrose,
sorbitol, mannitol, starch, for example potato starch, corn starch or
amylopectin, or cellulose.
Both in the single-chamber system and in the two-chamber system, the shell of
the osmotic
active ingredient release system consists of a water-permeable film-forming
material which is
impermeable for the components of the core. Such shell materials are known in
principle and
are described, for example, in EP1024793. Suitable for use as shell materials
are, for example,
acylated cellulose derivatives.
Acylated cellulose derivatives (cellulose esters) are celluloses mono- to
trisubstituted by acetyl
groups or mono- to disubstituted by acetyl groups and substituted by a further
acyl radical
different from acetyl, e.g. cellulose acetate, cellulose tri acetate,
cellulose acetate
ethylcarbamate, cellulose acetate phthalate, cellulose acetate
methylcarbamate, cellulose acetate
succinate, cellulose acetate dimethylaminoacetate, cellulose acetate
ethylcarbonate, cellulose
acetate chloroacetate, cellulose acetate ethyloxalate, cellulose acetate
methylsulfonate, cellulose
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acetate butylsulfonate, cellulose acetate propionate, cellulose acetate
diethylaminoacetate,
cellulose acetatoacetate, cellulose acetate laurate, cellulose acetate p-
toluenesulfonate, cellulose
acetate butyrate, and shell materials from the group of the cellulose ethers
such as
ethylcellulose or other cellulose acetate derivatives and also agar acetate
and amylose acetate.
Suitable materials for the shell are also ethyl cellulose and polymeric
epoxides, copolymers of
alkylene oxide and alkylglycidyl ethers, polyglycols and polylactic acid
derivatives and other
derivatives thereof. Furthermore, it is also possible to use mixtures of
acrylates which are
water-insoluble per se (e.g. a copolymer of ethyl acrylate and methyl
methacrylate).
In the context of the present invention, preferred for use as shell materials
are cellulose acetate
or mixtures of cellulose acetate and polyethylene glycol.
The amounts and the constituents used for producing the shell of the osmotic
drug release
system influence the rate of entry of the gastrointestinal fluid in a known
manner. In principle,
the rate of entry of the gastrointestinal fluid decreases with an increasing
amount of shell
material.
.. If required, a coat, for example a light-protection and/or colour coat, can
be applied to the shell.
Particularly suitable materials are, for example, polymers such as polyvinyl
alcohol,
hydroxypropylcellulose and/or hydroxypropylmethylcellulose, where appropriate
in
combination with suitable plasticizers such as, for example, polyethylene
glycol or
polypropylene glycol, and pigments such as, for example, titanium dioxide or
iron oxides. By
way of example, mention may be made of coating with a film coat obtained by
initially
dissolving polyvinyl alcohol and polyethylene glycol 3350 in water at room
temperature and
mixing with stiffing. Gradually, talc, titanium dioxide and iron oxide are
added with stiffing.
Coating suspensions can be applied to the tablet cores using, for example, a
suitable coating
unit, for example a smooth coater. Alternatively, instead of coating there may
be sugar coating.
In general, such a coating is applied using an aqueous or organic coating
medium. In the
context of the present invention, the term coating additionally also comprises
coatings of the
shell applied by an alternative process, for example a solvent-free process.
The coatings used may also be finished coatings. They already comprise a
mixture of
auxiliaries and are dissolved in water and applied. An example which may be
mentioned is
Opadry II 85F230009 Orange (Colorcon PVA-based finished coating) which
comprises
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partially hydrolyzed polyvinyl alcohol, talc, polyethylene glycol (PEG 3350),
titanium dioxide,
red iron oxide, yellow iron oxide and polysorbate 80 (Tween 80).
The shell of the osmotic drug release system of the present invention has at
least one orifice or
passage through which the active ingredient together with the other core
constituents slowly
exits. The orifice is introduced into the shell by laser drilling, mechanical
drilling or, for
example, by punching. One or more orifices may be present in the shell. The
size of the orifice
(diameter) is preferably 0.2 to 1.6 mm, particularly preferably 0.3 to 1.2 mm.
The nature and
the methods for producing the orifice are knwon per se and described, for
example, in US
4063064, US 4088864, US 3916899 or EP-B-0277092. The coating optionally
present may
likewise have one or more orifices.
Preferred for use as osmotically active additive in the embodiments described
is at least one
water-soluble salt of inorganic or organic acids, particularly preferably
sodium chloride.
Preferred for use as pharmaceutically customary auxiliaries in the embodiments
described are
binders, for example hydroxypropylcellulose, lubricants, for example magnesium
stearate, flow
regulators, for example finely divided silica, and colour pigments, for
example iron oxide.
To prepare the osmotic two-chamber system, it is possible, for example, to mix
the components
of the active ingredient layer and to subject them to wet or dry, preferably
dry, granulation, to
mix and granulate the components of the osmosis layer and then to compress
both sets of
granules on a bilayer tablet press to give a bilayer tablet. The resulting
inner core is then coated
with a shell. The shell is, on the active ingredient side, provided with one
or more orifices.
Alternatively, the provision of the one or more orifices in this process step
may be dispensed
with. In this case, only after the coating with one or more coatings has been
carried out, both
sides of the tablet are each provided with an orifice extending in each case
from the outside to
the inner core, i.e. stretching across coating and shell.
Preferably, both the components of the active ingredient layer and the
components of the
osmosis layer are each subjected to granulation, in particular by means of
roller granulation, in
the production of the osmotic two-chamber system.
The present invention furthermore provides a process for preparing the osmotic
release systems
mentioned, characterized in that the components of the core are mixed with one
another,
granulated and tabletted, the resulting core is coated with a shell and the
shell is finally
provided with one or more orifices suitable for the compound of the formula
(II) exiting.
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The present invention furthermore provides a process for preparing the osmotic
release systems
mentioned, characterized in that the components of the active ingredient layer
are mixed and
granulated and the components of the osmosis layer are mixed and granulated,
both sets of
granules are subsequently compressed on a bilayer tablet press to give a
bilayer tablet, the
resulting core is then coated with the shell and the shell is, on the active
ingredient side,
provided with one or more orifices.
Preference is given according to the invention, because of the physicochemical
properties of the
active ingredient, to osmotic two-chamber systems (push-pull systems) in which
the active
ingredient layer and the osmosis layer are separated, by way of example and
with preference
formulated as a bilayer tablet. Here, the advantages compared to osmotic
single-chamber
systems are the more uniform release rate over a longer period of time, and
also the possibility
to reduce the systemically required excess of active ingredient.
The present invention furthermore provides the compound sodium (3S)-3-(4-
chloro-3-
{ [(2 S,3R)-2-(4-chloropheny1)-4,4,4-tri fluoro-3-methy lbutanoyl]
aminolpheny1)-3 -
cyclopropylpropanoate of the formula (II)
0
0
CI
Na +
H N o
\,
H
FF CI
F
(II).
Also provided is the compound of the formula (II) in crystalline form of
modification 1,
characterized in that the X-ray diffractogram of the compound has peak maxima
of the 2 theta
angle at 8.1, 22.3 and 22.6 .
Also provided is the compound of the formula (II) in crystalline form of
modification 1,
characterized in that the X-ray diffractogram of the compound has peak maxima
of the 2 theta
angle at 8.1, 17.2, 18.8, 22.3 and 22.6 .
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Also provided is the compound of the formula (II) in crystalline form of
modification 1,
characterized in that the X-ray diffractogram of the compound has peak maxima
of the 2 theta
angle at 6.5, 8.1, 17.2, 18.8, 22.3, 22.6 and 25.5 .
Also provided is the compound of the formula (II) in crystalline form of
modification 1,
characterized in that the X-ray diffractogram of the compound has peak maxima
of the 2 theta
angle at 6.5, 8.1, 16.4, 17.2, 18.0, 18.8, 19.4, 22.3, 22.6 and 25.5 .
Also provided is the compound of the formula (II) in crystalline form of
modification 1,
characterized in that the IR spectrum of the compound has band maxima at 3381,
1691 and
1565 cm-1.
Also provided is the compound of the formula (II) in crystalline form of
modification 1,
characterized in that the IR spectrum of the compound has band maxima at 3381,
1691, 1565,
1524 and 1419 cm-1.
Also provided is the compound of the formula (II) in crystalline form of
modification 1,
characterized in that the IR spectrum of the compound has band maxima at 3381,
3066, 1691,
1565, 1524, 1419 and 1101 cn11.
Also provided is the compound of the formula (II) in crystalline form of
modification 1,
characterized in that the IR spectrum of the compound has band maxima at 3381,
3066, 2975,
1691, 1565, 1524, 1419, 1135, 1101 and 817 cm-1.
The compound of the formula (II) in crystalline modification 1 can be prepared
from the
compound of the formula (I). The preparation of the compound of the formula
(I) in amorphous
form is disclosed in WO 2012/139888 as Example 22. The preparation of the
compound of the
formula (I) in crystalline form is disclosed in EP17204842.3 (published as WO
2019/105881).
Both the compound of the formula (I) in amorphous form and the compound of the
formula in
crystalline form are equally suitable for preparing the compound of the
formula (II) in
crystalline modification 1 in the processes described below.
When preparing the compound of the formula (II) from the compound of the
formula (I), there
is the risk that the compound of the formula (I) epimerizes to (3S)-3-(4-
chloro-3-{[(2R,3R)-2-
(4-chloropheny1)-4,4,4-trifluoro-3-methylbutanoyllaminolpheny1)-3-
cyclopropylpropanoic acid
of the formula (III),
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0 7
HO
. CI
H N 0
H 3.
F F CI
F
(III),
or that the compound of the formula (II) epimerizes to sodium (3S)-3-(4-chloro-
3-1[(2R,3R)-2-
(4-chloropheny1)-4,4,4-tri fluoro-3 -methy lbutanoyl] amino 1 phenyl)-3 -
cyclopropy 1propano ate of
the formula (IV),
0
0
N a + C I
H N 0
H 3 C
F F CI
F
(IV).
Thus, for example, there is significant epimerization during the preparation
of the compound of
the formula (II) with aqueous sodium hydroxide solution or when the solvent
used is methanol
or ethanol. As a consequence, relevant amounts of the compounds of the
formulae (III) and (IV)
are produced in such reactions, thus reducing the yield of the desired
compound of the formula
(II). Accordingly, epimerization should be avoided. Surprisingly, in the
preparation processes
described below, there was little of this side reaction.
To prepare the compound of the formula (II) in crystalline modification 1, the
compound of the
formula (I) is, preferably under protective gas atmosphere, for example under
nitrogen
atmosphere, dissolved in a polar aprotic solvent. Suitable for use as polar
aprotic solvent are,
for example, acetonitrile, toluene, methyl tert-butyl ether (MTBE) or
tetrahydrofuran (THF);
preference is given to using acetonitrile. Subsequently sodium hydroxide is
used, preferably in
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solid form. The mixture is stirred, preferably for several hours. After
filtration, the solid
obtained is washed with a polar aprotic solvent and dried.
In particular the choice of solvent, the amount of sodium hydroxide employed
and the use of
sodium hydroxide in solid form lead to a reduction of the unwanted
epimerization of the
.. compound of the formula (I) during the synthesis.
In particular for the production of relatively large amounts (kilogram scale)
of the compound of
the formula (II), there is the possibility that part of the solid sodium
hydroxide is not converted
during the reaction and, after filtration, remains in the solid obtained.
Accordingly, an
alternative preparation process (Preparation Process 2) was developed.
In an alternative preparation method, the compound of the formula (I) is,
preferably under
protective gas atmosphere, for example under nitrogen atmosphere, dissolved in
a polar aprotic
solvent and preferably filtered. Suitable for use as polar aprotic solvent
are, for example,
acetonitrile, toluene, methyl tert-butyl ether (MTBE) or tetrahydrofuran
(THF); preference is
given to using acetonitrile. The solution is cooled and, preferably at a
temperature of -20 C to
50 C, particularly preferably -10 C to 10 C, very particularly preferably 0 C,
a sterically
demanding sodium alkoxide, for example sodium tert-butoxide or sodium 2-
methylbut-2-oxide,
dissolved in a suitable polar aprotic solvent is added. The sterically
demanding sodium alkoxide
is preferably employed in an amount of 0.7 to 1.0 molar equivalents,
particularly preferably 0.9
to 1.0 molar equivalents and very particularly preferably 0.98 molar
equivalents, based on the
compound of the formula (I). Suitable for use as polar aprotic solvent are,
for example,
acetonitrile, toluene, methyl tert-butyl ether (MTBE), 2-methyltetrahydrofuran
or
tetrahydrofuran (THF); preference is given to using THF. During the addition
of the sterically
demanding sodium alkoxide, seed crystals of the compound of the formula (II)
in crystalline
modification 1 may be added. This results in a more efficient precipitation
and a higher yield.
The seed crystals can be prepared, for example, by Preparation Process 1. The
mixture is stirred
at -20 C to 20 C, preferably -5 C to 5 C, particularly preferably 0 C,
preferably for several
hours. After filtration, the solid obtained is washed with a polar aprotic
solvent and dried.
Surprisingly, the amount of base, in relation to the amount of the compound of
the formula (I)
employed, has a strong effect on the extent of epimerization. 0.7 to 1.0 molar
equivalents,
preferably 0.9 to 1.0 molar equivalents and particularly preferably 0.98 molar
equivalents of
base, relative to the compound of the formula (I), are advantageous.
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Alternatively, the compound of the formula (II) in crystalline modification 1
can be prepared by
dissolving the amorphous form of the compound of the formula (II) or another
modification of
the compound of the formula (II) in a polar solvent, for example
tetrahydrofuran, isopropanol or
methanol, and subsequent crystallization.
The present invention provides the preparation of the compound of the formula
(II) in
crystalline modification 1, characterized in that the compound of the formula
(I) is dissolved in
a polar aprotic solvent, a base selected from a list consisting of sodium
hydroxide or a sterically
demanding sodium alkoxide is added and the precipitated solid is, after
stirring, isolated and
dried.
The present invention provides the preparation of the compound of the formula
(II) in
crystalline modification 1, characterized in that the compound of the formula
(I), dissolved in
the present case in a polar aprotic solvent, has a base selected from a list
consisting of sodium
hydroxide or a sterically demanding sodium alkoxide added to it and the
precipitated solid is,
after stirring, isolated and dried.
The present invention provides the preparation of the compound of the formula
(II) in
crystalline modification 1, characterized in that the compound of the formula
(I), dissolved in
the present case in a polar aprotic solvent, preferably acetonitrile, toluene,
methyl tert-butyl
ether (MTBE) or tetrahydrofuran (THF), particularly preferably acetonitrile,
has a base selected
from a list consisting of sodium hydroxide or a sterically demanding sodium
alkoxide added to
it and the precipitated solid is, after stirring, isolated and dried.
If the base used is sodium hydroxide, preference is given to using sodium
hydroxide in solid
form.
The present invention provides the preparation of the compound of the formula
(II) in
crystalline modification 1, characterized in that the compound of the formula
(I), dissolved in
the present case in acetonitrile, has sodium hydroxide in solid form added to
it and the
precipitated solid is, after stirring, isolated and dried.
The base is preferably employed in an amount of 0.7 to 1.0 molar equivalents,
particularly
preferably 0.9 to 1.0 molar equivalents and very particularly preferably 0.98
molar equivalents,
based on the compound of the formula (I).
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Sterically demanding sodium alkoxides include all suitable sodium alkoxides
known to the
person skilled in the art whose chemical structure is more complex than that
of sodium
methoxide or sodium ethoxide. Preferred sterically demanding sodium alkoxides
are, for
example, sodium tert-butoxide or sodium 2-methylbut-2-oxide.
The present invention provides the preparation of the compound of the formula
(II) in
crystalline modification 1, characterized in that the sterically demanding
sodium alkoxide is
sodium tert-butoxide or sodium 2-methylbut-2-oxide.
The present invention provides the preparation of the compound of the formula
(II) in
crystalline modification 1, characterized in that the compound of the formula
(I), dissolved in
the present case in a polar aprotic solvent, preferably acetonitrile, toluene,
methyl tert-butyl
ether (MTBE) or tetrahydrofuran (THF), particularly preferably acetonitrile,
has a base selected
from a list consisting of sodium hydroxide, sodium tert-butoxide and sodium 2-
methylbut-2-
oxide added to it and the precipitated solid is, after stirring, isolated and
dried.
The present invention provides the preparation of the compound of the formula
(II) in
crystalline modification 1, characterized in that the compound of the formula
(I), dissolved in
the present case in acetonitrile, has sodium tert-butoxide added to it and the
precipitated solid
is, after stirring, isolated and dried.
The present invention provides the preparation of the compound of the formula
(II) in
crystalline modification 1, characterized in that the compound of the formula
(I), dissolved in
the present case in acetonitrile, has sodium 2-methylbut-2-oxide added to it
and the precipitated
solid is, after stirring, isolated and dried.
The base is preferably employed in an amount of 0.7 to 1.0 molar equivalents,
particularly
preferably 0.9 to 1.0 molar equivalents and very particularly preferably 0.98
molar equivalents,
based on the compound of the formula (I).
The present invention provides the preparation of the compound of the formula
(II) in
crystalline modification 1, characterized in that the compound of the formula
(I), dissolved in
the present case in acetonitrile, has sodium tert-butoxide added to it in an
amount of 0.7 to 1.0
molar equivalents, particularly preferably 0.9 to 1.0 molar equivalents and
very particularly
preferably 0.98 molar equivalents, based on the compound of the formula (I),
and the
precipitated solid is, after stirring, isolated and dried.
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The present invention provides the preparation of the compound of the formula
(II) in
crystalline modification 1, characterized in that the compound of the formula
(I), dissolved in
the present case in acetonitrile, has sodium 2-methylbut-2-oxide added to it
in an amount of 0.7
to 1.0 molar equivalents, particularly preferably 0.9 to 1.0 molar equivalents
and very
.. particularly preferably 0.98 molar equivalents, based on the compound of
the formula (I), and
the precipitated solid is, after stirring, isolated and dried.
Addition of the base and subsequent stirring are, independently of one
another, carried out at a
temperature of -20 C to 50 C, preferably -20 C to 20 C, particularly
preferably -10 C to 10 C,
very particularly preferably 0 C.
Optionally, seed crystals of the compound of the formula (II) in crystalline
modification 1 may
be added during the reaction.
The compound of the formula (II) according to the invention and the dosage
forms according to
the invention have valuable pharmacological properties and can be used for
treatment and/or
prevention of disorders in humans and animals.
In the context of the present invention, the wan "treatment" or "treating"
includes inhibition,
retardation, checking, alleviating, attenuating, restricting, reducing,
suppressing, repelling or
healing of a disease, a condition, a disorder, an injury or a health problem,
or the development,
the course or the progression of such states and/or the symptoms of such
states. The term
"therapy" is understood here to be synonymous with the term "treatment".
The terms "prevention", "prophylaxis" and "preclusion" are used synonymously
in the context
of the present invention and refer to the avoidance or reduction of the risk
of contracting,
experiencing, suffering from or having a disease, a condition, a disorder, an
injury or a health
problem, or a development or advancement of such states and/or the symptoms of
such states.
The treatment or prevention of a disease, a condition, a disorder, an injury
or a health problem
may be partial or complete.
The compound of the formula (II) according to the invention and the dosage
forms according to
the invention lead to vascular relaxation, inhibition of platelet aggregation
and lowering of
blood pressure, and they also increase coronary blood flow and
microcirculation. These effects
are mediated by a direct, haem-independent activation of soluble guanylate
cyclase and a rise of
intracellular cGMP levels.
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The compound of the formula (II) according to the invention and the dosage
forms according to
the invention are especially suitable for the treatment and/or prevention of
renal and cardiorenal
disorders, in particular chronic kidney disease (CKD) and diabetic kidney
disease (DKD),
cardiac and cardiovascular disorders, in particular heart failure (HFpEF and
HFrEF),
myocardial infarction, angina pectoris, cardiomyopathies, hypertension and
arteriosclerosis,
pulmonary and cardiopulmonary disorders, in particular pulmonary hypertension
(PH),
disorders of the central nervous system, in particular dementia, bone
disorders, in particular
osteogenesis imperfecta, thromboembolic disorders, muscular dystrophies,
ischaemias, vascular
disorders, impaired microcirculation, fibrotic disorders, in particular
systemic sclerosis, in
particular age-related macular degeneration, inflammatory disorders, and
metabolic disorders,
in particular metabolic syndrome, dyslipidaemia and diabetes.
The compound of the formula (II) according to the invention and the dosage
forms according to
the invention can be used for the treatment and/or prevention of cardiac,
cardiovascular and
cardiopulmonary disorders such as, for example high blood pressure
(hypertension), heart
failure, coronary heart disease, stable and unstable angina pectoris,
pulmonary arterial
hypertension (PAH) and secondary forms of pulmonary hypertension (PH), chronic
thromboembolic pulmonary hypertension (CTEPH), renal hypertension, disorders
of peripheral
and cardial vessels, arrhythmias, atrial and ventricular arrhythmias and
impaired conduction
such as, for example, grade I-III atrioventricular blocks, supraventricular
tachyarrhythmia, atrial
fibrillation, atrial flutter, ventricular fibrillation, ventricular flutter,
ventricular tachyarrhythmia,
Torsade de pointes tachycardia, atrial and ventricular extrasystoles, AV-
junctional
extrasystoles, sick sinus syndrome, syncopes, AV nodes reentry tachycardia,
Wolff-Parkinson-
White syndrome, acute coronary syndrome (ACS), autoimmune heart disorders
(pericarditis,
endocarditis, valvolitis, aortitis, cardiomyopathies), boxer cardiomyopathy,
aneurysms, shock
such as cardiogenic shock, septic shock and anaphylactic shock.
The compound of the formula (II) according to the invention and the dosage
forms according to
the invention can be used for the treatment and/or prevention of
thromboembolic disorders and
ischaemias such as myocardial ischaemia, myocardial infarction, stroke,
cardial hypei Li ophy,
transistory and ischaemic attacks, preeclampsia, inflammatory cardiovascular
disorders, spasms
of the coronary arteries and the peripheral arteries, formation of oedemas
such as, for example,
pulmonary oedema, brain oedema, renal oedema or heart failure-induced oedema,
impaired
peripheral perfusion, reperfusion damage, arterial and venous thromboses,
microalbuminuria,
heart failure, endothelial dysfunction, micro- and macrovascular damage
(vasculitis), and also
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for preventing restenoses for example after thrombolysis therapies,
percutaneous transluminal
angioplasties (PTA), percutaneous transluminal coronary angioplasties (PTCA),
heart
transplants, bypass operations and micro- and macrovascular damage
(vasculitis), increased
level of fibrinogen and of low-density LDL and increased concentrations of
plasminogen
activator inhibitor 1 (PAT-1), and for the treatment and/or prophylaxis of
erectile dysfunction
and female sexual dysfunction.
In the context of the present invention, the term "pulmonary hypertension"
includes both
primary and secondary sub-forms thereof as defined according to the Dana Point
classification
in accordance with their respective etiology [see D. Montana and G. Simonneau,
in: A.J.
.. Peacock et al. (Eds.), Pulmonary Circulation. Diseases and their treatment,
3rd edition, Hodder
Arnold Publ., 2011, pp. 197-206; M.M. Hoeper et al., J. Am. Coll. Cardiol.,
2009, 54 (1), p85-
p961. These include in particular in Group 1 pulmonary arterial hypertension
(PAH), which
includes inter alia the idiopathic and the familiar forms (IPAH and FPAH,
respectively), acute
pulmonary hypertension, in particular the acute respiratory distress syndrome
(ARDS), acute
lung injury (ALT) and infant respiratory distress syndrome (IRDS).
Furthermore, PAH also
embraces persistent pulmonary hypertension of the newborn and the associated
pulmonary
arterial hypertension (APAH) associated with collagenoses, congenital systemic
pulmonary
shunt lesions, portal hypertension, HIV infections, the intake of certain
drugs and medicaments
(for example of appetite suppressants), with disorders having a significant
venous/capillary
component such as pulmonary venoocclusive disorder and pulmonary capillary
haemangiomatosis, or with other disorders such as disorders of the thyroid,
glycogen storage
diseases, Gaucher disease, hereditary teleangiectasia, haemoglobinopathies,
myeloproliferative
disorders and splenectomy. Group 2 of the Dana Point classification comprises
PH patients
having a causative left heart disorder, such as ventricular, atrial or
valvular disorders. Group 3
comprises forms of pulmonary hypertension associated with a lung disorder, for
example with
chronic obstructive lung disease (COPD), interstitial lung disease (ILD),
pulmonary fibrosis
(IPF), and/or hypoxaemia, sleep apnoea syndrome, alveolar hypoventilation,
chronic high-
altitude sickness, hereditary deformities. Group 4 includes PH patients having
chronic
thrombotic and/or embolic disorders, for example in the case of thromboembolic
obstruction of
proximal and distal pulmonary arteries (CTEPH) or non-thrombotic embolisms
(e.g. as a result
of tumour disorders, parasites, foreign bodies). Less common forms of
pulmonary hypertension,
such as in patients suffering from sarcoidosis, histiocytosis X or
lymphangiomatosis, are
summarized in group 5.
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In the context of the present invention, the term "heart failure" encompasses
both acute and
chronic forms of heart failure, and also specific or related disease types
thereof, such as acute
decompensated heart failure, right heart failure, left heart failure, global
failure, ischaemic
cardiomyopathy, di latativ e cardiomyopathy, hypei ________________________ Ii
ophic cardiomyopathy, idiopathic
cardiomyopathy, congenital heart defects, heart valve defects, heart failure
associated with heart
valve defects, mitral valve stenosis, mitral valve insufficiency, aortic valve
stenosis, aortic
valve insufficiency, tricuspid valve stenosis, tricuspid valve insufficiency,
pulmonary valve
stenosis, pulmonary valve insufficiency, combined heart valve defects,
myocardial
inflammation (myocarditis), chronic myocarditis, acute myocarditis, viral
myocarditis, diabetic
heart failure, alcoholic cardiomyopathy, cardiac storage disorders and
diastolic and systolic
heart failure, heart failure with reduced ejection fraction (HFrEF), heart
failure with preserved
ejection fraction (HFpEF).
The compound of the formula (II) according to the invention and the dosage
forms according to
the invention are also suitable for the treatment and/or prevention of
metabolic disorders. In the
context of the present invention, metabolic disorders are, for example,
disorders of glucose
metabolism and disorders and complications associated with impaired glucose
metabolism.
Disorders of glucose metabolism are, for example, Diabetes mellitus (Type 1 or
Type 2),
insulin resistance, impaired glucose tolerance, hyperglycaemia, hypoglycaemia,
hyperinsulinaemia or hypoinsulinaemia. Disorders associated with impaired
glucose
metabolism are, for example, micro- and macroangiopathies, diabetic
retinopathies, diabetic
neuropathies, diabetic nephropathies, delayed/impaired wound healing, diabetic
foot, tissue
ischaemias, ulcers on the extremities, gangrene, metabolic acidosis, ketosis,
dyslipidaemias,
myocardial infarction, acute coronary syndrome, stable or unstable angina
pectoris,
cardiomyopathies, heart failure, cardiac arrhythmias, vascular restenosis,
peripheral arterial
occlusive disease, obesity, syndrome X, impaired fat metabolism,
arteriosclerosis or high blood
pressure. The compound of the formula (II) according to the invention and the
dosage forms
according to the invention are also suitable for maintaining, improving and
restoring the
functions of cells of the pancreas, in particular for maintaining, improving
and restoring the
number and size of the (3 cells of the pancreas.
In the context of the present invention, metabolic disorders also include
disorders of fat
metabolism such as, for example, impaired lipid metabolism,
hypolipoproteinaemias,
dyslipidaemias, hypertriglyceridaemias, hyperlipidaemias, combined
hyperlipidaemias,
hypercholesterolaemias, abetalipoproteinaemi a, sitosterolaemia,
xanthomatosis, Tangier
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disease, adiposity, obesity, arteriosclerosis and metabolic syndrome. The
compound of the
formula (II) according to the invention and the dosage forms according to the
invention are also
suitable for the treatment and/or prevention of cardiovascular disorders
associated with a
metabolic disorder.
The compound of the formula (II) according to the invention and the dosage
forms according to
the invention are also suitable for the treatment and/or prevention of
muscular or neuromuscular
disorders. The expression "muscular or neuromuscular disorders" relates to a
medical condition
affecting the muscles and/or their direct control of the nervous system. They
may be acquired or
of genetic origin. Muscular or neuromuscular disorders are in particular
Duchenne muscular
dystrophy (DMD), Becker muscular dystrophy (BMD), congenital muscular
dystrophy,
Miyoshi myopathy, Emery-Dreifuss muscular dystrophy, facioscapulohumeral
muscular
dystrophy, limb-girdle muscular dystrophy, myotonic muscular dystrophy,
oculopharyngeal
muscular dystrophy, myasthenia gravis, Lambert-Eaton myasthenic syndrome and
Charcot-
Marie-Tooth disease.
Furthermore, the compound of the formula (II) according to the invention and
the dosage forms
according to the invention may be employed for the treatment and/or prevention
of primary and
secondary Raynaud phenomena, microcirculation impairments, claudication,
hearing
difficulties, tinnitus, peripheral and autonomous neuropathies, diabetic
microangiopathies,
diabetic retinopathy, CREST syndrome, erythematosis, onychomycosis and
rheumatic
disorders.
The compound of the formula (II) according to the invention and the dosage
forms according to
the invention can additionally be employed for the treatment and/or prevention
of ischaemia-
and/or reperfusion-related damage to organs or tissues and as additive for
perfusion and
preservation solutions for organs, organ parts, tissues or tissue parts of
human or animal origin,
in particular for surgical interventions or in the field of transplantation
medicine.
The compound of the formula (II) according to the invention and the dosage
forms according to
the invention are also suitable for treatment and/or prevention of renal
disorders, in particular
renal insufficiency and kidney failure. In the context of the present
invention, the terms "renal
insufficiency" and "kidney failure" encompass both acute and chronic
manifestations thereof
(chronic kidney disease; CKD) and also underlying or related renal disorders
such as renal
hypoperfusion, intradialytic hypotension, obstructive uropathy,
glomerulopathies,
glomerulonephritis, acute glomerulonephritis, glomerulosclerosis,
tubulointerstitial diseases,
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nephropathic disorders such as primary and congenital kidney disease,
nephritis, immunological
kidney disorders such as kidney transplant rejection and immunocomplex-induced
kidney
disorders, nephropathy induced by toxic substances, nephropathy induced by
contrast agents,
diabetic and non-diabetic nephropathy, diabetic kidney disease (DKD),
pyelonephritis, renal
cysts, nephrosclerosis, hypertensive nephrosclerosis and nephrotic syndrome
which can be
characterized diagnostically, for example by abnormally reduced creatinine
and/or water
excretion, abnormally elevated blood concentrations of urea, nitrogen,
potassium and/or
creatinine, altered activity of renal enzymes, for example glutamyl
synthetase, altered urine
osmolarity or urine volume, elevated microalbuminuria, macroalbuminuria,
lesions on
glomerulae and arterioles, tubular dilatation, hyperphosphataemia and/or need
for dialysis. The
present invention also encompasses the use of the dosage forms according to
the invention for
treatment and/or prevention of sequelae of renal insufficiency, for example
hypertension,
pulmonary oedema, heart failure, uraemia, anaemia, electrolyte disturbances
(for example
hyperkalaemia, hyponatraemia) and disturbances in bone and carbohydrate
metabolism.
In addition, the compound of the formula (II) according to the invention and
the dosage forms
according to the invention are suitable for the treatment and/or prevention of
disorders of the
urogenital system, for example benign prostate syndrome (BPS), benign prostate
hyperplasia
(BPH), benign prostate enlargement (BPE), bladder outlet obstruction (BOO),
lower urinary
tract syndromes (LUTS), interstitial cystitis, neurogenic overactive bladder
(OAB),
incontinence, for example mixed urinary incontinence, urge urinary
incontinence, stress urinary
incontinence or overflow urinary incontinence (MUI, UUI, SUI, OUT), pelvic
pain, erectile
dysfunction, female sexual dysfunction, vaginal atrophy, dyspareunia or
atrophic vaginitis.
The compound of the formula (II) according to the invention and the dosage
forms according to
the invention are also suitable for treatment and/or prevention of asthmatic
disorders, chronic-
obstructive pulmonary diseases (COPD), acute respiratory distress syndrome
(ARDS) and acute
lung injury (ALT), alpha-I antitrypsin deficiency (AATD), pulmonary fibrosis,
pulmonary
emphysema (for example pulmonary emphysema induced by cigarette smoke),
pulmonary
venous hypertension, interstitial lung disorder, sleep apnoea, alveolar
hypoventilation
impairments, chronic exposition to high altitudes, neonatal lung disorder,
alveolar capillary
dysplasia, sickle cell anaemia, impaired coagulation, chronic thromboembolism,
tumour-
associated pulmonary embolism, disorders of the connective tissue, lupus,
schistosomiasis,
sarcoidosis, chronic bronchitis, capillary pulmonary haemangiomatosis;
histiocytosis X,
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lymphangiomatosis and compressed lung vessels owing to adenopathy, fibrosing
mediastinitis
and cystic fibrosis (CF).
The compound of the formula (II) according to the invention described in the
present invention
and the dosage forms according to the invention are also active compounds and
dosage forms
for the control of diseases in the central nervous system which are
characterized by disturbances
of the NO/cGMP system. They are suitable in particular for improving
perception,
concentration, learning or memory after cognitive impairments like those
occurring in particular
in association with situations/diseases/syndromes such as mild cognitive
impairment, age-
associated learning and memory impairments, age-associated memory losses,
dementia,
vascular dementia, mixed forms of dementia, dementia occurring after strokes
(post stroke
dementia), post-traumatic craniocerebral trauma, general concentration
impairments,
concentration impairments in children with learning and memory problems,
Alzheimer's
disease, Lewy body dementia, dementia with degeneration of the frontal lobes
including Pick's
syndrome, Parkinson's disease, progressive nuclear palsy, dementia with
corticobasal
degeneration, amyolateral sclerosis (ALS), Huntington's disease,
demyelination, multiple
sclerosis, thalamic degeneration, Creutzfeld-Jacob dementia, HIV dementia,
schizophrenia with
dementia or Korsakoffs psychosis, Binswanger dementia (subcortical
arteriosclerotic
encephalopathy), cerebral autosomal-dominant arteriopathy with subcortical
infarcts and
leukoencephalopathy (iCADASIL or CADASIL syndrome), asymptomatic
neurocognitive
impairment (ANT), multiple sclerosis (MS) (including the clinically isolated
syndrome (CIS),
relapsing-remitting MS (RRMS), primary progressive MS (PPMS) and secondary
progressive
MS (SPMS), multisystem atrophy (MSA), Parkinson's disease, Parkinson plus,
progressive
supranuclear palsy (PSP, Steele-Richardson-Olszewski syndrome), attention
deficit syndrome
(ADS) and attention deficit hyperactivity disorder (ADHS). They are also
suitable for treatment
and/or prevention of central nervous system disorders such as states of
anxiety, tension and
depression, CNS-related sexual dysfunctions and sleep disturbances, and for
controlling
pathological disturbances of the intake of food, stimulants and addictive
substances. They are
also suitable for the treatment and/or prevention of injuries, for example
traumatic brain injury
(TBI) including, for example, concussion and traumatic encephalopathies (CTE),
or non-
traumatic strokes (including ischaemic strokes, aneurysms or hypoxias), brain
damage,
cognitive impairments, brain injuries, neurodegenerative disorders or
neuropathic pain. They
are also suitable for the treatment and/or prevention of dystonias, for
example general, focal,
segmental, vegetative, acute dystonic reactions and genetic/primary dystonias
and dyskinesias,
including acute, chronic/tardive and non-motoric and levodopa-induced
dyskinesias (LID).
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They are also suitable for the treatment and/or prevention of disorders
characterized by reduced
synaptic plasticity and synaptic processes, for example fragile X syndrome,
Rett syndrome,
Williams syndrome, Renpenning syndrome, disorders of the autism spectrum
including autism,
Asperger syndrome or far-reaching development disorders. They are also
suitable for the
treatment and/or prevention of mental, affective or psychological disorders,
for example bipolar
disorder, schizophrenia, general psychosis, drug-induced psychosis, paranoia,
schizoaffective
disorder, obsessive-compulsive disorder (OCD), depressive disorders, anxiety
disorders, panic
disorders or posttraumatic stress disorder (PTSD).
Furthermore, the compound of the formula (II) according to the invention and
the dosage forms
according to the invention are also suitable for controlling cerebral blood
flow and are thus
effective agents for controlling migraines. They are also suitable for the
prophylaxis and control
of sequelae of cerebral infarct (Apoplexia cerebri) such as stroke, cerebral
ischaemias and
craniocerebral trauma. The dosage forms according to the invention can
likewise be employed
for controlling states of pain.
In addition, the compound of the formula (II) according to the invention and
the dosage forms
according to the invention have anti-inflammatory action and can therefore be
used as anti-
inflammatory agents for treatment and/or prevention of sepsis (SIRS), multiple
organ failure
(MODS, MOF), inflammatory disorders of the kidney, chronic intestinal
inflammations (IBD,
Crohn's disease, UC), pancreatitis, peritonitis, rheumatoid disorders and
inflammatory skin
disorders.
The compound of the formula (II) according to the invention and the dosage
forms according to
the invention are furthermore suitable for the treatment and/or prevention of
acute pain, central
pain syndrome, chemotherapy-induced neuropathy and neuropathic pain, diabetic
neuropathy,
fibromyalgia, inflammatory pain, neuropathic pain, postoperative pain, tonic
pain or visceral
pain.
The compound of the formula (II) according to the invention and the dosage
forms according to
the invention are furthermore suitable for the treatment and/or prevention of
fibrotic disorders
of the internal organs, for example the lung, the heart, the kidneys, the bone
marrow and in
particular the liver, and also dermatological fibroses and fibrotic eye
disorders. In the context of
the present invention, the term "fibrotic disorders" includes in particular
disorders such as
hepatic fibrosis, cirrhosis of the liver, pulmonary fibrosis, endomyocardial
fibrosis,
nephropathy, glomerulonephritis, interstitial renal fibrosis, fibrotic damage
resulting from
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diabetes, bone marrow fibrosis and similar fibrotic disorders, scleroderma,
systemic sclerosis,
morphea, keloids, hypei __ Li ophic scarring, naevi, diabetic retinopathy,
proliferative
vitroretinopathy and disorders of the connective tissue (for example
sarkoidosis). The dosage
forms according to the invention can likewise be used for treating
steatohepatitis, in particular
non-alcoholic steatohepatitis (NASH), for promotion of wound healing, for
controlling
postoperative scarring, for example following glaucoma operations and
cosmetically for ageing
and keratinized skin.
The compound of the formula (II) according to the invention and the dosage
forms according to
the invention are furthermore suitable for the treatment and/or prevention of
bone disorders, by
way of example and preferably osteogenesis imperfecta (CH), bone fractures,
impared bone
healing, rickets, osteomalacia, avascular bone necrosis, Paget disease,
osteodystrophy,
osteopenia, osteolytic lesions caused by bone metastases, radiation therapy or
chemotherapy,
parodontitis, hypercalcaemia, osteonecrosis, osteosarcoma, osteolytic
metastases, familiar
expansive osteolysis, expansive skeletal and idiopathic hyperplasia, juvenile
Paget disease,
Camurati-Engelmann disease, loosening of prostheses, periprostetic osteolysis,
cleidocranial
dysplasia (CCD), multiple myeloma, alveolar bone loss, bone loss owing to
immobilization or
sexual hormone deficiency, bone loss associated with a disease selected from
the group
consisting of cachexia, anorexia, alopecia and inflammatory disorders selected
from the group
consisting of rheumatoid arthritis, psoriatic arthritis, psoriasis,
spondyloarthritis, SLE, systemic
sclerosis, metastasizing cancer and inflammatory bowel disease,
osteoarthritis, impaired bone
healing after osteotomy, idiopathic bone loss in infancy, deformed spine,
osteoporosis, primary
osteoporosis, secondary osteoporosis and in particular osteoporosis, primary
osteoporosis or
secondary osteoporosis not caused by sexual hormone deficiency.
The compound of the formula (II) according to the invention and the dosage
forms according to
.. the invention are furthermore suitable for the treatment and/or prevention
of dysfunctions of
gastrointestinal sphincters, such as achalasia, sphincter spasms and
hypertensive sphincter, in
particular lower oesophagus sphincter (LES) achalasia, oesophagus achalasia,
spastic LES,
hypertensive LES (HTNLES), pylorus sphincter (pylorus) achalasia, pylorus
spasm
(pylorospasm), hypertensive pylorus, ileocaecal sphincter or valve (ICY)
achalasia,
hypertensive ICY, spastic ICY or ICY spasm, sphincter of Oddi dysfunction
(SOD), sphincter
of Oddi achalasia, spastic sphincter of Oddi, hypertensive sphincter of Oddi,
internal anal
sphincter (IAS) achalasia, hypertensive IAS, spastic IAS or IAS cramp. In a
further
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embodiment, the gastrointestinal sphincter dysfunctions mentioned are caused
by a
neurological, metabolic, endocrine or neurodegenerative disorder.
Furthermore, the compound of the formula (II) according to the invention and
the dosage forms
according to the invention are suitable for the treatment and/or prevention of
ophthalmic
disorders which, in the context of the invention, include, for example, the
following disorders:
age-related macular degeneration (AMD) including dry (non-exudative) and wet
(exudative,
neovascular) AMD, choroidal neovascularization (CNV), choroidal neovascular
membranes
(CNVM), cystoid macular oedema (CME), epiretinal membranes (ERM) and macular
perforations, myopia-associated choroidal neovascularization, angioid and
vascular streaks,
retina detachment, diabetic retinopathy, non-proliferative diabetic
retinopathy (NPDR), diabetic
macular oedema (DME), atrophic and hypethophic changes of the retinal pigment
epithelium,
retinal vein occlusion, choroidal retinal vein occlusion, macular oedema,
macular oedema
associated with retinal vein occlusion, retinitis pigmentosa. Stargardt's
disease, retinopathy of
prematurity, glaucoma, inflammatory eye disorders, for example uveitis,
scleritis or
endophthalmitis, cataract, refraction abnormalities, for example myopia,
hyperopia,
astigmatism and keratoconus, corneal angiogenesis as a consequence of hypoxia
(for example
by extensive use of contact lenses), pterygium conjunctivae, subcomeal oedema
and
intracomeal oedema.
By virtue of their activity profile, the compound of the formula (II)
according to the invention
and the dosage forms according to the invention are suitable in particular for
the treatment
and/or prevention of cardiovascular and cardiopulmonary disorders such as
primary and
secondary forms of pulmonary hypertension, heart failure, angina pectoris and
hypertension and
also of thromboembolic disorders, ischaemias, vascular disorders, impaired
microcirculation,
renal insufficiency, fibrotic disorders and arteriosclerosis.
Preferably, the compound of the formula (II) according to the invention and
the dosage forms
according to the invention are suitable for the treatment and/or prevention of
renal and
cardiorenal disorders, in particular chronic kidney disease (CKD) and diabetic
kidney disease
(DKD), cardiac and cardiovascular disorders, in particular heart failure
(HFpEF and HFrEF),
myocardial infarction, angina pectoris, cardiomyopathies, hypertension and
arteriosclerosis,
pulmonary and cardiopulmonary disorders, in particular pulmonary hypertension
(PH),
ophthalmic disorders, in particular non-proliferative diabetic retinopathy
(NPDR) and diabetic
macular oedema (DME), disorders of the central nervous system, in particular
dementia, bone
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disorders, in particular osteogenesis imperfecta, thromboembolic disorders,
muscular
dystrophies, ischaemias, vascular disorders, impaired microcirculation,
fibrotic disorders, in
particular systemic sclerosis, inflammatory disorders, and metabolic
disorders, in particular
metabolic syndrome, dyslipidaemia and diabetes.
Preferably, the compound of the formula (II) according to the invention and
the dosage forms
according to the invention are suitable for the treatment and/or prevention of
renal and
cardiorenal disorders, in particular chronic kidney disease (CKD).
Preferably, the compound of the formula (II) according to the invention and
the dosage forms
according to the invention are suitable for the treatment and/or prevention of
ophthalmic
disorders, in particular non-proliferative diabetic retinopathy (NPDR) and
diabetic macular
oedema (DME).
Preferably, the compound of the formula (II) according to the invention and
the dosage forms
according to the invention are suitable for the treatment and/or prevention of
cardiovascular
disorders, in particular heart failure including heart failure with reduced
ejection fraction
(HFrEF) and heart failure with preserved ejection fraction (HFpEF).
Preferably, the compound of the formula (II) according to the invention and
the dosage forms
according to the invention are suitable for the treatment and/or prevention of
cardiopulmonary
disorders, in particular pulmonary hypertension.
Preferably, the compound of the formula (II) according to the invention and
the dosage forms
according to the invention are suitable for the treatment and/or prevention of
disorders of the
central nervous system, in particular dementia including vascular dementia and
mixed forms of
dementia.
Preferably, the compound of the formula (II) according to the invention and
the dosage forms
according to the invention are suitable for the treatment and/or prevention of
"muscular or
neuromuscular disorders", in particular Duchenne muscular dystrophy (DMD) and
Becker
muscular dystrophy (BMD).
The present invention furthermore provides the use of the compound of the
formula (II)
according to the invention and the dosage forms according to the invention for
the treatment
and/or prevention of sickle cell anaemia, where traumatized patients receive a
synthetic blood
substitute, and for preservation of blood substitutes.
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The present invention furthermore provides the use of the compound of the
formula (II)
according to the invention and the dosage forms according to the invention for
the treatment
and/or prevention of polycystic ovary syndrome (PCOS).
The present invention furthermore provides the use of the compound of the
formula (II)
according to the invention and the dosage forms according to the invention for
the treatment
and/or prevention of preeclampsia.
The present invention furthermore provides the use of the compound of the
formula (II)
according to the invention and the dosage forms according to the invention for
the treatment
and/or prevention of disorders, especially of the aforementioned disorders.
The present invention furthermore provides the use of the compound of the
formula (II)
according to the invention and the dosage forms according to the invention in
a method for
treatment and/or prevention of disorders, especially of the aforementioned
disorders.
The present invention further provides a process for treatment and/or
prevention of disorders,
especially of the aforementioned disorders, using an effective amount of the
compound of the
formula (II) according to the invention or at least one of the dosage forms
according to the
invention.
The compound of the formula (II) according to the invention or the dosage
forms according to
the invention can be used alone or, if required, in combination with other
active compounds.
The present invention further provides medicaments comprising at least one of
the dosage
forms according to the invention and one or more further active compounds,
especially for the
treatment and/or prophylaxis of the aforementioned disorders. Preferred
examples of active
compounds suitable for combinations include:
= organic nitrates and NO donors, for example sodium nitroprusside,
nitroglycerin,
isosorbide mononitrate, isosorbide dinitrate, molsidomine or SIN-1, and
inhaled NO;
= further substances which increase the cGMP concentration, for example
protoporphyrine IX, arachidonic acid or phenylhydrazine derivatives;
= NO synthase substrates, for example N-hydroxyguanidine derivatives, L-
arginine
derivatives, N-alkyl-N'-hydroxyguanidine derivatives, N-aryl-N'-
hydroxyguanidine
derivatives or guanidine derivatives;
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= compounds which inhibit the degradation of cyclic guanosine monophosphate
(cGMP)
and/or cyclic adenosine monophosphate (cAMP), for example inhibitors of
phosphodiesterases (PDE) 1, 2, 3, 4, 5, 9 and/or 10, especially PDE 4
inhibitors such as
roflumilast or revamilast and PDE 5 inhibitors such as sildenafil, vardenafil,
tadalafil,
udenafil, dasantafil, avanafil, mirodenafil or lodenafil;
= NO-independent but haem-dependent stimulators of guanylate cyclase,
especially
riociguat, nelociguat, vericiguat, praliciguat (IW-1973), olinciguat (IW-1701)
and the in
WO 00/06568, WO 00/06569, WO 02/42301, WO 03/095451, WO 2011/147809, WO
2012/004258, WO 2012/028647 and WO 2012/059549;
= prostacyclin analogues and IP receptor agonists, by way of example and with
preference
iloprost, beraprost, treprostinil, epoprostenol, NS-304, selexipag or
ralinepag;
= endothelin receptor antagonists, by way of example and with preference
bosentan,
darusentan, ambrisentan, macicentan or sitaxsentan;
= inhibitors of human neutrophil elastase (HNE), by way of example and with
preference
sivelestat or DX-890 (Reltran);
= compounds which inhibit the signal transduction cascade, in particular
from the group of
the tyrosine kinase inhibitors, by way of example and with preference
dasatinib,
nilotinib, bosutinib, regorafenib, sorafenib, sunitinib, cediranib, axitinib,
telatinib,
imatinib, brivanib, pazopanib, vatalanib, gefitinib, erlotinib, lapatinib,
canertinib,
lestaurtinib, pelitinib, semaxanib, masitinib or tandutinib;
= Rho kinase inhibitors, by way of example and with preference fasudil, Y-
27632, SLx-
2119, BF-66851, BF-66852, BF-66853, KI-23095 or BA-1049;
= anti-obstructive agents as used, for example, for the therapy of chronic
obstructive
pulmonary disease (COPD) or bronchial asthma, by way of example and with
preference, inhalatively or systemically administered beta-receptor mimetics
(e.g.
bedoradrine) or inhalatively administered anti-muscarinergic substances;
= anti-inflammatory and/or immunosuppressive agents as used, for example,
for the
therapy of chronic obstructive pulmonary disease (COPD), bronchial asthma or
pulmonary fibrosis, such as, by way of example and with preference,
systemically or
inhalatively administered corticosteroids, flutiform, pirfenidone,
acetylcysteine,
azathioprine or BIBF-1120;
= chemotherapeutics like those employed, for example, for the therapy of
neoplasms in
the lung or other organs;
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= active compounds used for the systemic and/or inhalative treatment of
pulmonary
disorders, for example for cystic fibrosis (alpha- 1-antitrypsin, azti ____
eonam, ivacaftor,
lumacaftor, ataluren, amikacin, levofloxacin), chronic obstructive pulmonary
disease
(COPD) (LAS40464, PT003, SUN-101), acute respiratory distress syndrome (ARDS)
and acute lung injury (ALT) (interferon-beta-la, traumakines), obstructive
sleep apnoea
(VI-0521), bronchiectasis (mannitol, ciprofloxacin), bronchiolitis obliterans
(cyclosporin, aztreonam) and sepsis (pagibaximab, Voluven, ART-123);
= active compounds used for the treatment of muscular dystrophy, for
example idebenone;
= antithrombotic agents, by way of example and with preference from the
group of the
platelet aggregation inhibitors, the anticoagulants or the profibrinolytic
substances;
= active compounds altering lipid metabolism, for example and with
preference from the
group of the thyroid receptor agonists, cholesterol synthesis inhibitors, by
way of
example and preferably HMG-CoA reductase inhibitors or squalene synthesis
inhibitors,
ACAT inhibitors, CETP inhibitors, MTP inhibitors, PPAR-alpha, PPAR-gamma
and/or
PPAR-delta agonists, cholesterol absorption inhibitors, lipase inhibitors,
polymeric bile
acid adsorbents, bile acid reabsorption inhibitors and lipoprotein(a)
antagonists;
= active compounds which inhibit neoangiogenesis, by way of example and
with
preference inhibitors of the VEGF and/or PDGF signalling pathways, inhibitors
of the
integrin signalling pathways, inhibitors of the angiopoietin-Tie signalling
pathways,
inhibitors of the PI3K-Akt-mTor signalling pathways, inhibitors of the Ras-Raf-
Mek-
Erk signalling pathway, inhibitors of the MAPK signalling pathways, inhibitors
of the
FGF
signalling pathways, inhibitors of the sphingosine- 1-phosphate signalling
pathways, inhibitors of endothelial cell proliferation or apoptosis-inducing
active
ingredients;
= active compounds which reduce vascular wall permeability (oedema formation),
by way
of example and with preference corticosteroids, inhibitors of the ALK1-Smad1/5
signalling pathway, inhibitors of the VEGF and/or PDGF signalling pathways,
cyclooxygenase inhibitors, inhibitors of the kallikrein-kinin system or
inhibitors of the
sphingosine- 1-phosphate signalling pathways;
= active compounds which reduce damage to the retina under oxidative stress,
by way of
example and with preference inhibitors of the complement system, especially
antagonists of the complement C5a receptor, or agonists of the 5-HT1A
receptor;
= antioxidants and free-radical scavengers;
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= active hypotensive compounds, by way of example and with preference from
the group
of the calcium antagonists, angiotensin All antagonists, ACE inhibitors, beta-
receptor
blockers, alpha-receptor blockers, diuretics, phosphodiesterase inhibitors,
sGC
stimulators, cGMP elevators, ECE inhibitors, vasopeptidase inhibitors and/or
mineralocorticoid receptor antagonists;
= antiarrhythmic agents, for example sodium channel blockers, beta-receptor
blockers,
potassium channel blockers or calcium channel blockers;
= alpha-l-adrenoceptor antagonists;
= centrally acting alpha-2-adrenoceptor agonists;
= imidazoline I-1 receptor agonists;
= dopamine D1 receptor agonists;
= 5-HT2 antagonists;
= vasopressin antagonists;
= calcium channel sensitizers;
= bronchodilators, for example beta-2-adrenoceptor agonists, anticholinergics,
theopylline
or PDE inhibitors;
= corticosteroids, for example prednisolone;
= PGD2 receptor antagonists;
= non-steroidal antiasthmatics, for example beta-2-adrenoceptor agonists or
combinations
of beta-2-adrenoceptor agonists and corticosteroids;
= non-steroidal anti-inflammatory drugs (NSAIDs) and selective
cyclooxigenase-2 (COX-
2) inhibitors;
= medicaments for excess weight and obesity, for example methamphetamine,
amfepramon, phentermine, benzphetamine, phendimetrazine, mazindol, orlistat,
sibutramine or rimonabant and combinations such as, for example,
phentermine/topiramate, bupropion/naltrexone, sibutramine/metformin, bupropion
SR/zonisami de SR, salmeterol, xinafoate/fluticasone;
lorcaserin,
phentermine/topiramate, cetilistat, exenatide, liraglutide, metformin, CORT-
108297,
canagliflozin, chromium picolinate, GSK-1521498, LY-377604, metreleptin,
obinepitide, P-S7AS3, PSN-821, salmeterol xinafoate/fluticasone, somatropin
(recombinant), tesamorelin, tesofensine, velneperit, zonisamide, beloranib,
resveratrol,
sobetirome, tetrahydrocannabivarin and beta-lapachone;
= adenylate cyclase inhibitors, for example colforsin dapropate;
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= positive inotropic substances, for example digoxin;
= medicaments for the treatment of erectile dysfunction, for example
alprostadil;
= drugs for dementia such as acetylcholinesterase inhibitors, for example
donepezil,
galantamine and rivastigmine; or NMDA receptor antagonists, for example
memantine;
= medicaments
for the treatment of mental disorders, for example dopamine D4 receptor
antagonists such as clozapine, dopamine D2 receptor antagonists, such as
nemonaprid,
mixed dopamine Dl/D2 receptor antagonists such as zuclopenthixol, GABA A
receptor
modulators such as carbamazepine, sodium channel inhibitors such as
lamotrigine,
monoamine oxidase inhibitors such as moclobemide, tricyclic antidepressants
such as
amitriptyline, desipramine, imipramine, amoxapine, nortriptyline or
clomipramine,
selective serotonin reuptake inhibitors (SSR1s) such as paroxetine, fluoxetine
or
citralopram, doxepine, trazodonc or agomelatine, selective noradrenaline
reuptake
inhibitors (SNR1s) such as venlafaxine or dopaminergic antidepressants such as
bupropion;
= inhibitors of neural endopeptidase (NEP inhibitors) such as sacubitril,
omapatrilate or
methylene blue, AVE-7688, or in dual combination (`ARNIs') with angiotensin
receptor
blockers (e.g. valsartan), e.g. LCZ696;
= natriuretic peptides, for example atrial natriuretic peptide (ANP,
anaritide), B-type
natriuretic peptide or brain natriuretic peptide (BNP, nesiritide), C-type
natriuretic
peptide (CNP) and urodilatin;
= antidiabetics, by way of example and with preference from the group of
the insulins and
insulin derivatives, sulphonylureas, biguanides, meglitinide derivatives,
glucosidase
inhibitors, PPAR-gamma agonists, GLP 1 receptor agonists, glucagon
antagonists,
insulin sensitizers, CCK1 receptor agonists, inhibitors of dipeptidylpeptidase
4
(gliptins), SGLT 2 inhibitors, leptin receptor agonists, potassium channel
antagonists
and the inhibitors of hepatic enzymes that are involved in the stimulation of
gluconeogenesis and/or glycogenolysis;
= anti-infectives, by way of example and with preference from the group of
the
antibacterial, antifungal and/or antiviral active substances; and/or
= substances for treatment of glaucoma, by way of example and with preference
from the
group of the adrenergics, beta-receptor blockers, carbonic anhydrase
inhibitors,
parasympathomimetics and prostaglandins; and/or
= substances for the treatment of bone disorders, by way of example and
with preference
bisphosphonates, vitamin D or its metabolites, strontium ranelate, selective
oestrogen
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receptor modulators (SERM), parathyroid hormone or analogues thereof and/or
RANKL
(receptor activator of nuclear factor kappa-B ligand) modulators.
Antithrombotic agents are preferably understood to mean compounds from the
group of the
platelet aggregation inhibitors, the anticoagulants or the profibrinolytic
substances.
In a preferred embodiment of the invention, the compound of the formula (II)
according to the
invention or the dosage forms according to the invention are administered in
combination with
a platelet aggregation inhibitor, by way of example and with preference
aspirin, clopidogrel,
ticlopidine or dipyridamole.
In a preferred embodiment of the invention, the compound of the formula (II)
according to the
invention or the dosage forms according to the invention are administered in
combination with
a thrombin inhibitor, by way of example and with preference ximelagatran,
melagatran,
dabigatran, bivalirudin or clexane.
In a preferred embodiment of the invention, the compound of the formula (II)
according to the
invention or the dosage forms according to the invention are administered in
combination with
a GPIIb/IIIa antagonist, by way of example and with preference tirofiban or
abciximab.
In a preferred embodiment of the invention, the compound of the formula (II)
according to the
invention or the dosage forms according to the invention are administered in
combination with
a factor Xa inhibitor, by way of example and with preference rivaroxaban,
apixaban, fidexaban,
razaxaban, fondaparinux, idraparinux, DU-176b, PMD-3112, YM-150, KFA-1982, EMD-
503982, MCM-17, MLN-1021, DX 9065a, DPC 906, JTV 803, SSR-126512 or SSR-
128428.
In a preferred embodiment of the invention, the compound of the formula (II)
according to the
invention or the dosage forms according to the invention are administered in
combination with
heparin or a low molecular weight (LMW) heparin derivative.
.. In a preferred embodiment of the invention, the compound of the formula
(II) according to the
invention or the dosage foam according to the invention are administered in
combination with
a vitamin K antagonist, by way of example and with preference coumarin,
phenprocumon or
warfarin.
Hypotensive agents are preferably understood to mean compounds from the group
of the
calcium antagonists, angiotensin All antagonists, ACE inhibitors, endothelin
antagonists, renin
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inhibitors, alpha-receptor blockers, beta-receptor blockers, mineralocorticoid
receptor
antagonists, and the diuretics.
In a preferred embodiment of the invention, the compound of the formula (II)
according to the
invention or the dosage forms according to the invention are administered in
combination with
a calcium antagonist, by way of example and with preference nifedipine,
amlodipine, verapamil
or di ltiazem.
In a preferred embodiment of the invention, the compound of the formula (II)
according to the
invention or the dosage forms according to the invention are administered in
combination with
an alpha 1 adrenoceptor antagonist, by way of example and with preference
prazosin.
In a preferred embodiment of the invention, the compound of the formula (II)
according to the
invention or the dosage forms according to the invention are administered in
combination with
a beta receptor blocker, by way of example and with preference propranolol,
atenolol, timolol,
pindolol, alprenolol, oxprenolol, penbutolol, bupranolol, metipranolol,
nadolol, mepindolol,
carazalol, sotalol, metoprolol, betaxolol, celiprolol, bisoprolol, carteolol,
esmolol, labetalol,
caryedilol, adaprolol, landiolol, nebivolol, epanolol or bucindolol.
In a preferred embodiment of the invention, the compound of the formula (II)
according to the
invention or the dosage forms according to the invention are administered in
combination with
an angiotensin All antagonist, by way of example and with preference losartan,
candesartan,
valsartan, telmisartan or embursatan.
In a preferred embodiment of the invention, the dosage forms according to the
invention are
administered in combination with an ACE inhibitor, by way of example and with
preference
enalapril, captopril, lisinopril, ramipril, delapril, fosinopril, quinopril,
perindopril or trandopril.
In a preferred embodiment of the invention, the compound of the formula (II)
according to the
invention or the dosage forms according to the invention are administered in
combination with
an endothelin antagonist, by way of example and with preference bosentan,
darusentan,
ambrisentan or sitaxsentan.
In a preferred embodiment of the invention, the compound of the formula (II)
according to the
invention or the dosage forms according to the invention are administered in
combination with
a renin inhibitor, by way of example and with preference aliskiren, SPP-600 or
SPP-800.
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In a preferred embodiment of the invention, the compound of the formula (II)
according to the
invention or the dosage forms according to the invention are administered in
combination with
a mineralocorticoid receptor antagonist, for example spironolactone or
eplerenone, particularly
preferably with a non-steroidal mineralocorticoid receptor antagonist such as
finerenone.
In a preferred embodiment of the invention, the compound of the formula (II)
according to the
invention or the dosage forms according to the invention are administered in
combination with
a diuretic, by way of example and with preference furosemide, bumetanide,
torsemide,
bendroflumethiazide, chlorothi azi de,
hydrochlorothiazide, hydroflumethiazide,
methyclothiazide, polythiazide, trichlormethiazide, chlorthalidone,
indapamide, metolazone,
quinethazone, acetazolamide, dichlorphenamide, methazolamide, glycerol,
isosorbide,
mannitol, amiloride or triamterene.
Lipid metabolism modifiers are preferably understood to mean compounds from
the group of
the CETP inhibitors, thyroid receptor agonists, cholesterol synthesis
inhibitors such as HMG-
CoA reductase inhibitors or squalene synthesis inhibitors, the ACAT
inhibitors, MTP inhibitors,
PPAR-alpha, PPAR-gamma and/or PPAR-delta agonists, cholesterol absorption
inhibitors,
polymeric bile acid adsorbers, bile acid reabsorption inhibitors, lipase
inhibitors and the
lipoprotein(a) antagonists.
In a preferred embodiment of the invention, the compound of the formula (II)
according to the
invention or the dosage forms according to the invention are administered in
combination with
a CETP inhibitor, by way of example and with preference torcetrapib (CP-
5294/4), HT-705 or
CETP vaccine (Avant).
In a preferred embodiment of the invention, the compound of the formula (II)
according to the
invention or the dosage forms according to the invention are administered in
combination with
a thyroid receptor agonist, by way of example and with preference D-thyroxine,
3,5,3'-
triiodothyronine (T3), CGS 23425 or axitirome (CGS 26214).
In a preferred embodiment of the invention, the compound of the formula (II)
according to the
invention or the dosage forms according to the invention are administered in
combination with
an HMG-CoA reductase inhibitor from the class of statins, by way of example
and with
preference lovastatin, simvastatin, pravastatin, fluvastatin, atorvastatin,
rosuvastatin or
pitavastatin.
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In a preferred embodiment of the invention, the compound of the formula (II)
according to the
invention or the dosage forms according to the invention are administered in
combination with
a squalene synthesis inhibitor, by way of example and with preference BMS-
188494 or TAK-
475.
.. In a preferred embodiment of the invention, the compound of the formula
(II) according to the
invention or the dosage forms according to the invention are administered in
combination with
an ACAT inhibitor, by way of example and with preference avasimib, melinamide,
pactimib,
eflucimib or SMP-797.
In a preferred embodiment of the invention, the compound of the formula (II)
according to the
invention or the dosage forms according to the invention are administered in
combination with
an MTP inhibitor, by way of example and with preference implitapide, BMS-
201038, R-
103757 or JTT-130.
In a preferred embodiment of the invention, the compound of the formula (II)
according to the
invention or the dosage forms according to the invention are administered in
combination with
.. a PPAR-gamma agonist, by way of example and with preference pioglitazone or
rosiglitazone.
In a preferred embodiment of the invention, the compound of the formula (II)
according to the
invention or the dosage forms according to the invention are administered in
combination with
a PPAR-delta agonist, by way of example and with preference GW 501516 or BAY
68-5042.
In a preferred embodiment of the invention, the compound of the formula (II)
according to the
.. invention or the dosage forms according to the invention are administered
in combination with
a cholesterol absorption inhibitor, by way of example and with preference
ezetimib, tiqueside or
pamaqueside.
In a preferred embodiment of the invention, the compound of the formula (II)
according to the
invention or the dosage forms according to the invention are administered in
combination with
.. a lipase inhibitor, by way of example and with preference orlistat.
In a preferred embodiment of the invention, the compound of the formula (II)
according to the
invention or the dosage forms according to the invention are administered in
combination with
a polymeric bile acid adsorber, by way of example and with preference
cholestyramine,
colestipol, colesolvam, Cholestagel or colestimide.
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In a preferred embodiment of the invention, the compound of the formula (II)
according to the
invention or the dosage forms according to the invention are administered in
combination with
a bile acid reabsorption inhibitor, by way of example and with preference ASBT
(= IBAT)
inhibitors, e.g. AZD-7806, S-8921, AK-105, BARI-1741, SC-435 or SC-635.
In a preferred embodiment of the invention, the compound of the formula (II)
according to the
invention or the dosage forms according to the invention are administered in
combination with
a lipoprotein(a) antagonist, by way of example and with preference gemcabene
calcium (CI-
1027) or nicotinic acid.
In a preferred embodiment of the invention, the compound of the formula (II)
according to the
invention or the dosage forms according to the invention are administered in
combination with
acetylcholinesterase inhibitors, by way of example and with preference
donepezil, galantamine
or rivastigmine.
In a preferred embodiment of the invention, the compound of the formula (II)
according to the
invention or the dosage forms according to the invention are administered in
combination with
NMDA receptor antagonists, by way of example and with preference memantine.
In a preferred embodiment of the invention, the compound of the formula (II)
according to the
invention or the dosage forms according to the invention are administered in
combination with
sGC stimulators, by way of example and with preference riociguat, nelociguat,
vericiguat,
praliciguat (IW-1973) or olinciguat (IW-1701).
In a preferred embodiment of the invention, the compound of the formula (II)
according to the
invention or the dosage forms according to the invention are administered in
combination with
antidiabetics, by way of example and with preference metformin.
In a preferred embodiment of the invention, the compound of the formula (II)
according to the
invention or the dosage forms according to the invention are administered in
combination with
SGLT-2 inhibitors, by way of example and with preference dapagliflozin,
empagliflozin,
canagliflozin, ipragliflozin and/or tofogliflozin.
In a preferred embodiment of the invention, the compound of the formula (II)
according to the
invention or the dosage forms according to the invention are administered in
combination with
substances for the treatment of bone disorders such as, by way of example and
with preference
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vitamin D or metabolites thereof, strontium ranelate, selective oestrogen
receptor modulators
(SERM) and/or RANKL modulators.
In a preferred embodiment of the invention, the compound of the formula (II)
according to the
invention or the dosage forms according to the invention are administered in
combination with
bisphosphonates, by way of example and with preference etidronate, clodronate,
tiludronate,
teriparatide, pamidronate, neridronate, olpadronate, alendronate, ibandronate,
risedronate or
zoledronate.
The invention furthermore provides the compound of the formula (II),
preferably in crystalline
form of modification 1, for the treatment and/or prevention of diseases.
The invention furthermore provides the compound of the formula (II),
preferably in crystalline
form of modification 1, for the treatment and/or prevention of renal and
cardiorenal disorders,
in particular chronic kidney disease (CKD) and diabetic kidney disease (DKD),
cardiac and
cardiovascular disorders, in particular heart failure (HFpEF and HFrEF),
myocardial infarction,
angina pectoris, cardiomyopathies, hypertension and arteriosclerosis,
pulmonary and
cardiopulmonary disorders, in particular pulmonary hypertension (PH),
disorders of the central
nervous system, in particular dementia, bone disorders, in particular
osteogenesis imperfecta,
thromboembolic disorders, muscular dystrophies, ischaemias, vascular
disorders, impaired
microcirculation, fibrotic disorders, in particular systemic sclerosis,
ophthalmic disorders,
inflammatory disorders, and metabolic disorders, in particular metabolic
syndrome,
dyslipidaemia and diabetes.
The invention furthermore provides the compound of the formula (II),
preferably in crystalline
form of modification 1, for the treatment and/or prevention of renal and
cardiorenal disorders,
in particular chronic kidney disease (CKD) and diabetic kidney disease (DKD).
The invention furthermore provides the compound of the formula (II),
preferably in crystalline
form of modification 1, for the treatment and/or prevention of cardiac and
cardiovascular
disorders, in particular heart failure (HFpEF and HFrEF), myocardial
infarction, angina
pectoris, cardiomyopathies, hypertension and arteriosclerosis.
The invention furthermore provides the compound of the formula (II),
preferably in crystalline
form of modification 1, for the treatment and/or prevention of pulmonary and
cardiopulmonary
.. disorders, in particular pulmonary hypertension (PH).
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The invention furthermore provides the compound of the formula (II),
preferably in crystalline
form of modification 1, for the treatment and/or prevention of disorders of
the central nervous
system, in particular dementia.
The invention furthermore provides the compound of the formula (II),
preferably in crystalline
form of modification 1, for the treatment and/or prevention of disorders of
the central nervous
system, in particular vascular and Alzheimer dementia.
The invention furthermore provides the compound of the formula (II),
preferably in crystalline
form of modification 1, for the treatment and/or prevention of metabolic
disorders, in particular
metabolic syndrome, dyslipidaemia and diabetes.
The invention furthermore provides the use of an osmotic release system
according to the
invention comprising the compound of the formula (II), preferably in
crystalline form of
modification 1, for the treatment and/or prevention of diseases.
The invention furthermore provides the use of an osmotic release system
according to the
invention comprising the compound of the formula (II), preferably in
crystalline form of
modification 1, for the treatment and/or prevention of renal and cardiorenal
disorders, in
particular chronic kidney disease (CKD) and diabetic kidney disease (DKD),
cardiac and
cardiovascular disorders, in particular heart failure (HFpEF and HFrEF),
myocardial infarction,
angina pectoris, cardiomyopathies, hypertension and arteriosclerosis,
pulmonary and
cardiopulmonary disorders, in particular pulmonary hypertension (PH),
disorders of the central
.. nervous system, in particular dementia, bone disorders, in particular
osteogenesis imperfecta,
thromboembolic disorders, muscular dystrophies, ischaemias, vascular
disorders, impaired
microcirculation, fibrotic disorders, in particular systemic sclerosis,
ophthalmic disorders,
inflammatory disorders, and metabolic disorders, in particular metabolic
syndrome,
dyslipidaemia and diabetes.
The invention furthermore provides the use of an osmotic release system
according to the
invention comprising the compound of the formula (II), preferably in
crystalline form of
modification 1, for the treatment and/or prevention of renal and cardiorenal
disorders, in
particular chronic kidney disease (CKD) and diabetic kidney disease (DKD).
The invention furthermore provides the use of an osmotic release system
according to the
invention comprising the compound of the formula (II), preferably in
crystalline form of
modification 1, for the treatment and/or prevention of cardiac and
cardiovascular disorders, in
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particular heart failure (HFpEF and HFrEF), myocardial infarction, angina
pectoris,
cardiomyopathies, hypertension and arteriosclerosis.
The invention furthermore provides the use of an osmotic release system
according to the
invention comprising the compound of the formula (II), preferably in
crystalline form of
modification 1, for the treatment and/or prevention of pulmonary and
cardiopulmonary
disorders, in particular pulmonary hypertension (PH).
The invention furthermore provides the use of an osmotic release system
according to the
invention comprising the compound of the formula (II), preferably in
crystalline form of
modification 1, for the treatment and/or prevention of disorders of the
central nervous system,
in particular dementia.
The invention furthermore provides the use of an osmotic release system
according to the
invention comprising the compound of the formula (II), preferably in
crystalline form of
modification 1, for the treatment and/or prevention of disorders of the
central nervous system,
in particular vascular and Alzheimer dementia.
The invention furthermore provides the use of an osmotic release system
according to the
invention comprising the compound of the formula (II), preferably in
crystalline form of
modification 1, for the treatment and/or prevention of metabolic disorders, in
particular
metabolic syndrome, dyslipidaemia and diabetes.
The invention furthermore provides medicaments comprising the compound of the
formula (II)
in combination with one or more other active ingredients selected from the
group consisting of
organic nitrates, NO donors, cGMP-PDE inhibitors, stimulators of guanylate
cyclase,
antithrombotics, antihypertensive agents, MR antagonists, IP receptor
agonists, compounds
having anti-inflammatory action, antidementives, antidiabetics, active
compounds which
modify fat metabolism and active compounds for the treatment of bone and
muscle disorders.
In the dosage forms according to the invention, the compound of the formula
(II) is preferably
present in an amount of about 1 to 240 mg, particularly preferably in an
amount of about 1 mg
to 120 mg, very particularly preferably in an amount of about 2.5 mg to 50 mg.
The present
invention provides the above-mentioned pharmaceutical dosage forms according
to the
invention comprising the compound of the formula (II) preferably in an amount
of 1 mg, 2 mg,
2.5 mg, 3 mg, 4 mg, 5 mg, 6 mg, 7 mg, 8 mg, 9 mg, 10 mg, 12 mg, 15 mg, 20 mg,
25 mg, 30
mg, 35 mg, 40 mg, 50 mg, 60 mg, 70 mg, 75 mg, 80 mg, 90 mg, 100 mg, 110 mg,
120 mg,
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125 mg, 150 mg, 175 mg, 200 mg, 225 mg and 240 mg. The amounts of the compound
of the
formula (II) refer to the nominal amounts in the pharmaceutical dosage form,
in certain
circumstances an excess of up to 20% of the amount of active ingredient may
additionally be
present.
In general, it has been found to be advantageous to administer about 0.01 to
10 mg/kg of body
weight per day to obtain effective results.
It may nevertheless be necessary in some cases to deviate from the stated
amounts, and
specifically as a function of body weight, route of administration, individual
response to the
active ingredient, nature of the preparation and time at which or interval
over which
administration takes place. Thus in some cases it may be sufficient to manage
with less than the
aforementioned minimum amount, while in other cases the upper limit mentioned
must be
exceeded. In the case of administration of greater amounts, it may be
advisable to divide them
into several individual doses over the day.
Experimental section
Abbreviations and acronyms
cp centipoise
HPLC high-pressure/high-performance liquid chromatography
K Kelvin
min minute
ml millilitre
Ill microlitre
mm millimetre
[MI micrometre
mPa millipascal
Ph. Eur. European Pharmacopeia
s second
r revolution
USP United States Pharmacopeia
UV ultraviolet
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Workin2 Examples
Exemplary compound 1
Sodium (3 S)-3-(4-chloro -3-1112S,3R)-2-(4-chloropheny1)-4,4,4-trifluoro-3-
methy lbutanoy 11 amino 1 pheny1)-3-cyclopropy 1propanoate in crystalline
modification 1
0
-0
N a + CI
H N 0
H 3 C,,,,,..õ.=-=õ1011
F4F CI
F
Preparation Method 1
Under a nitrogen atmosphere, a reaction vessel was filled with 1425 g of the
compound of the
formula (I) (preparation disclosed in WO 2012/139888, Example 22 and
EP17204842.3
(published as WO 2019/105881)) and 13.3 kg of acetonitrile. The mixture is
stirred until a
solution has formed. 117 g of solid sodium hydroxide are added and the
resulting suspension is
stirred vigorously for 25 hours. The suspension is filtered. The solids
obtained are washed with
1.2 kg of acetonitrile and dried under reduced pressure at 30 C for 19 hours.
Yield: 1375 g (92 %)
Content of the compound of the formula (II): 96.4% (HPLC Method 1)
Content of the compound of the formula (III): <0.20% (HPLC Method 2)
Sodium content: 4.8%
XRPD: modification 1
Preparation Method 2
Under a nitrogen atmosphere, a reaction vessel is filled with 34.4 kg of
acetonitrile and 4.0 kg
of the compound of the formula (I) (content determination 99.1%) (preparation
disclosed in
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WO 2012/139888, Example 22 and EP17204842.3 (published as WO 2019/105881)).
The
mixture is stirred at 20 C. The resulting solution is filtered and the filter
is washed with 3 kg of
acetonitrile. The filtrate is cooled to 0 C. 3.9 kg of a tetrahydrofuran
solution of sodium tert-
butoxide (content determination 19.6%) are added slowly at a temperature of
from -5 C to
+5 C. After addition of about 2/3 of the sodium tert-butoxide solution, seed
crystals of the
compound of the formula (II) in crystalline modification 1 are added. After
completion of the
metered addition, the line used for the metered addition is rinsed with an
additional 3.0 kg of
tetrahydrofuran. The resulting mixture is stirred at 0 C for 17 hours. The
suspension is filtered
and the solids obtained are washed twice with 5.6 kg of cold acetonitrile. The
product is dried
under reduced pressure at 40 C for 16 hours.
Yield: 4.0 kg (97 %)
Content of the compound of the formula (II): 98.7% (HPLC Method 1)
Content of the compound of the formula (III): 0.19% (HPLC Method 2)
Sodium content: 4.4%
XRPD: modification 1
Analytical methods
HPLC Method 1:
The tests for content determination and for impurities are carried out on a
reversed-phase HPLC
column with UV detection at 210 nm. The stationary phase is a Zorbax Eclipse
Plus RRHD
.. C18 HPLC column (50 mm x 2.1 mm, particle size 1.8 pm) or a suitable
alternative.
Gradient elution was chosen for optimal separation of the maxima. The gradient
of the mobile
phase is shown in Table 1 below.
Mobile phase A is water with 0.1% trifluoroacetic acid, mobile phase B is
acetonitrile with
0.1% trifluoroacetic acid.
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Table 1
Time [min] % A % B
0.0 95 5
25.0 20 80
The flow rate is 1.0 ml/min, the column temperature is 20 C, the injection
volume is 2 pl. Test
solutions are prepared by dissolution in a mixture of equal parts of
acetonitrile and water to a
concentration of 0.46 mg/ml.
Quantification is carried out either by external calibration using a reference
standard or via
mass balance. The retention time of the compound of the formula (II) is about
16.2 min, the
retention time of the compound of the formula (III) is about 12.0 min.
HPLC Method 2:
The tests for impurities are carried out on a normal-phase HPLC column with UV
detection at
220 nm. The stationary phase is a Chiralpak AD-H HPLC column (250 mm x 4.6 mm,
particle
size 5 pm) or a suitable alternative.
Isocratic elution was chosen for optimal separation of the maxima.
The mobile phase consists of 93% by volume of isohexane and 7% by volume of a
mixture of
2-propanol with 0.2% trifluoroacetic acid and 1% water.
The flow rate is 1.25 ml/min, the column temperature is 30 C, the injection
volume is 5 pl. Test
solutions are prepared by dissolution in a mixture of isohexane and 2-propanol
(3/1, by volume)
to a concentration of 0.5 mg/ml.
Quantification is carried out by external calibration using a reference
standard. The retention
time of the compound of the formula (II) is about 11.4 min, the retention time
of the compound
of the formula (III) is about 9.7 min.
Method 3 (sodium analysis):
Sodium is analysed by an ICP-MS method as semiquantitative summary analysis.
Sample
preparation takes place by microwave digestion with nitric acid.
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Method 4 - x-ray diffractometry for the measurement of the compound of the
formula (I) in
crystalline form of modification 1:
Sample preparation: sample as even powder layer between two films.
Instrument: X-ray powder diffractometer (STOE STADI P)
Generator: 40 kV / 40 mA
Detector: location-sensitive detector
Radiation: germanium-monochromatized Cul(a1 radiation
Measurement mode: transmittance
Measurement range: 2 < 20 < 40
Step width: 0.50
Measurement time: 15 s/step
Table 2: X-ray diffractometry of the compound of the formula (I) in
crystalline
modification 1
Reflections
Modification 1
6.5 17.2 24.1 28.6 32.7 38.1
7.6 17.5 24.4 28.8 33.1 38.5
8.1 18.0 24.7 29.0 33.7 38.7
9.6 18.8 25.1 29.3 34.0 38.9
10.3 19.4 25.2 29.5 34.7 39.4
11.0 19.8 25.5 29.8 35.5 39.6
14.7 21.0 25.8 30.4 35.8 39.8
15.1 21.4 26.5 30.8 36.1
15.6 21.7 26.8 31.2 36.3
16.0 22.3 27.2 31.6 36.7
16.4 22.6 28.1 32.3 37.7
The X-ray diffractogram of the compound of the formula (I) in crystalline
modification 1 is
shown in Figure 10.
Method 5 - IR spectroscopy for the measurement of the compound of the formula
(I) in
crystalline form of modification 1:
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Sample preparation: Sample was prepared as KBr disc
Instrument Bruker Vertex 80v
Number of scans 32
Resolution 2 cm-1
Technique transmission
Table 3: IR spectra of the compound of the formula (I) in crystalline
modification 1
Band maximum [cm-1]
Modification 1
3381 1524 1245 975 735 532
3066 1492 1185 937 721 516
2997 1458 1169 906 712 492
2975 1419 1135 895 669 447
2954 1389 1108 844 654 422
2914 1376 1101 827 628
1691 1312 1069 817 593
1595 1286 1044 788 566
1565 1263 1022 753 546
The IR spectrum of the compound of the formula (I) in crystalline modification
1 is shown in
Figure 11.
Osmotic release systems and the preparation thereof are shown below. The
osmotic release
systems always contain excess active ingredient since, for technical reasons,
some of the active
ingredient remains in the osmotic release system.
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Osmotic release system 1 (two-chamber system, polyethylene oxide as
hydrophilic
swellable polymer)
Tablet composition in mg/tablet:
Core
Active ingredient layer
compound of the formula (II), micronized 2.75 mg
hydroxypropylmethylcellulose (5 cp) 5.70 mg
polyethylene oxide * 100.45 mg
finely divided silica (Aerosil 200, Degussa) 0.90 mg
magnesium stearate 0.30 mg
110.1 mg
Osmosis layer
hydroxypropylmethylcellulose (5 cp) 3.69 mg
sodium chloride 21.51 mg
polyethylene oxide ** 47.60 mg
iron oxide red 0.72 mg
magnesium stearate 0.18 mg
73.70 mg
total (core) 183.8 mg
Shell
cellulose acetate 12.40 mg
polyethylene glycol 3350 1.60 mg
14.0 mg
total (osmotic release system) 197.8 mg
After about 5 to 6 hours, 80% of the compound of the formula (II) had been
released. The
release profile of the compound of the formula (II) from the osmotic release
system 1 is shown
in Figure 12.
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Osmotic release system 2 (two-chamber system, polyethylene oxide as
hydrophilic
swellable polymer)
Tablet composition in mg/tablet:
Core
Active ingredient layer
compound of the formula (II), micronized 6.00 mg
hydroxypropylmethylcellulose (5 cp) 5.70 mg
polyethylene oxide * 97.40 mg
finely divided silica (Aerosil 200, Degussa) 0.90 mg
magnesium stearate 0.30 mg
110.3 mg
Osmosis layer
hydroxypropylmethylcellulose (5 cp) 3.69 mg
sodium chloride 21.51 mg
polyethylene oxide ** 47.60 mg
iron oxide red 0,72 mg
magnesium stearate 0.18 mg
73.7 mg
total (core) 184.0 mg
Shell
cellulose acetate 12.60 mg
polyethylene glycol 3350 1.40 mg
14.0 mg
total (osmotic release system) 198.0 mg
After about 6 hours, 80% of the compound of the formula (II) had been
released. The release
profile of the compound of the formula (II) from the osmotic release system 2
is shown in
Figure 13.
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Osmotic release system 3 (two-chamber system, polyethylene oxide as
hydrophilic
swellable polymer)
Tablet composition in mg/tablet:
The composition of the active ingredient layer and the osmosis layer (core)
corresponds to
Working Example 2.
Shell
cellulose acetate 25.20 mg
polyethylene glycol 3350 2.80 mg
28.0 mg
total (osmotic release system) 212.0 mg
After about 11 hours, 80% of the compound of the formula (II) had been
released. The release
profile of the compound of the formula (II) from the osmotic release system 3
is shown in
Figure 14.
Osmotic release system 4 (two-chamber system, polyethylene oxide as
hydrophilic
swellable polymer)
Tablet composition in mg/tablet:
The composition of the active ingredient layer and the osmosis layer (core)
corresponds to
Working Example 2.
Shell
cellulose acetate 34.20 mg
polyethylene glycol 3350 3.80 mg
38.0 mg
total (osmotic release system) 222.0 mg
After about 15 hours, 80% of the compound of the formula (II) had been
released. The release
profile of the compound of the formula (II) from the osmotic release system 4
is shown in
Figure 15.
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Osmotic release system 5 (two-chamber system, polyethylene oxide as
hydrophilic
swellable polymer)
Tablet composition in mg/tablet:
Core
.. Active ingredient layer
compound of the formula (II), micronized 5.75 mg
hydroxypropylmethylcellulose (5 cp) 5.70 mg
polyethylene oxide * 97.65 mg
finely divided silica (Aerosil 200, Degussa) 0.90 mg
magnesium stearate 0.30 mg
110.3 mg
Osmosis layer
hydroxypropylmethylcellulose (5 cp) 3.69 mg
sodium chloride 21.51 mg
polyethylene oxide ** 47.60 mg
iron oxide red 0.72 mg
magnesium stearate 0.18 mg
73.7 mg
total (core) 184.0 mg
Shell
cellulose acetate 27.00 mg
polyethylene glycol 3350 3.00 mg
30.0 mg
total (osmotic release system) 214.0 mg
The osmotic release system 5 was tested for the content of the compound of the
formula (II)
(active ingredient content) (n = 10). Based on 100% of the declared active
ingredient content, a
minimum active ingredient content of 93.8% and a maximum active ingredient
content of
103.7% were measured. The standard deviation was 3.1%.
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After about 10 hours, 80% of the compound of the formula (II) had been
released. The release
profile of the compound of the formula (II) from the osmotic release system 5
is shown in
Figure 16.
Osmotic release system 6 (two-chamber system, polyethylene oxide as
hydrophilic
swellable polymer)
Tablet composition in mg/tablet:
Core
Active ingredient layer
compound of the formula (II), micronized 17.24 mg
hydroxypropylmethylcellulose (5 cp) 5.70 mg
polyethylene oxide * 86.16 mg
finely divided silica (Aerosil 200, Degussa) 0.90 mg
magnesium stearate 0.30 mg
110.3 mg
Osmosis layer
hydroxypropylmethylcellulose (5 cp) 3.69 mg
sodium chloride 21.51 mg
polyethylene oxide ** 47.60 mg
iron oxide red 0,72 mg
magnesium stearate 0.18 mg
73.70 mg
total (core) 184.0 mg
Shell
cellulose acetate 27.00 mg
polyethylene glycol 3350 3.00 mg
30.00 mg
total (osmotic release system) 214.0 mg
The osmotic release system 6 was tested for the content of the compound of the
formula (II)
(active ingredient content) (n = 10). Based on 100% of the declared active
ingredient content, a
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minimum active ingredient content of 96.3% and a maximum active ingredient
content of
101.2% were measured. The standard deviation was 1.4%.
After about 10 hours, 80% of the compound of the formula (II) had been
released. The release
profile of the compound of the formula (II) from the osmotic release system 6
is shown in
Figure 17.
Osmotic release system 7 (two-chamber system, Kollidon VA 64 as hydrophilic
swellable
polymer)
Tablet composition in mg/tablet:
Core
Active ingredient layer
compound of the formula (II), micronized 5.75 mg
hydroxypropylmethylcellulose (5 cp) 5.70 mg
Kollidon VA 64 97.65 mg
finely divided silica (Aerosil 200, Degussa) 0.90 mg
magnesium stearate 0.30 mg
110.3 mg
Osmosis layer
hydroxypropylmethylcellulose (5 cp) 3.69 mg
sodium chloride 21.51 mg
polyethylene oxide ** 47.60 mg
iron oxide red 0.72 mg
magnesium stearate 0.18 mg
73.70 mg
total (core) 184.0 mg
Shell
cellulose acetate 27.00 mg
polyethylene glycol 3350 3.00 mg
30.00 mg
total (osmotic release system) 214.0 mg
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After about 8.5 hours, 80% of the compound of the formula (II) had been
released. The release
profile of the compound of the formula (II) from the osmotic release system 7
(which is
additionally coated with 6 mg of a coating composition, as described below) is
shown in
Figure 18.
Osmotic release system 8 (one-chamber system, Kollidon VA 64 and xanthan 2um
as
hydrophilic swellable polymers)
Tablet composition in mg/tablet:
Core
compound of the formula (II), micronized 6.00 mg
xanthan gum (60 mesh) 100.0 mg
Kollidon VA 64 55.0 mg
sodium chloride 55.0 mg
sodium bicarbonate 17.0 mg
sodium carboxymethyl starch (Explotab) 23.0 mg
hydroxypropylmethylcellulose (3 cp) 10.0 mg
finely divided silica (Aerosil 200, Degussa) 1.50 mg
magnesium stearate 1.50 mg
total (core) 269.0 mg
Shell
cellulose acetate 12.00 mg
polyethylene glycol 3350 8.00 mg
20.00 mg
total (osmotic release system) 289.0 mg
After about 18 hours, 80% of the compound of the formula (II) had been
released. The release
profile of the compound of the formula (II) from the osmotic release system 8
is shown in
Figure 19.
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Osmotic release system 9 (one-chamber system, polyethylene oxide as
hydrophilic
swellable polymer)
Tablet composition in mg/tablet:
Core
compound of the formula (II), micronized 5.75 mg
hydroxypropylmethylcellulose (5 cp) 10.0 mg
polyethylene oxide * 60.65 mg
polyethylene oxide ** 57.0 mg
sodium chloride 25.0 mg
finely divided silica (Aerosil 200, Degussa) 1.0 mg
magnesium stearate 0.6 mg
total (core) 160.0 mg
Shell
cellulose acetate 21.6 mg
polyethylene glycol 3350 2.4 mg
24.00 mg
total (osmotic release system) 184.0 mg
After about 14 hours, 80% of the compound of the formula (II) had been
released. The release
profile of the compound of the formula (II) from the osmotic release system 9
is shown in
Figure 20.
viscosity 5% strength aqueous solution (25 C, Brookfield viscosimeter Model
RVT,
spindle No. 1, speed of rotation: 50 rpm): 40-100 mPa.s (e.g. POLYOXIm Water-
Soluble
Resin NF WSR N-80; Dow)
** viscosity 1% strength aqueous solution (25 C, Brookfield viscosimeter Model
RVF,
spindle No. 2, speed of rotation: 2 rpm): 5000-8000 mPa.s (e.g. POLYOXIm Water-
Soluble Resin NF WSR Coagulant; Dow)
Optionally, a coat may be applied to the osmotic release systems presented.
For the osmotic
release systems 5, 6 and 7, a coat of the following composition was prepared
and applied in an
amount of 6 mg per osmotic release system.
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Coat
polyvinyl alcohol 2.4 mg
polyethylene glycol 3350 1.212 mg
talc 0.888 mg
titanium dioxide 1.02 mg
iron oxide yellow 0.2784 mg
iron oxide red 0.2016 mg
total (coat) 6.0 mg
The person skilled in the art is aware that the amount of coat can be adjusted
depending, for
example, on the size and the surface of the osmotic release system. Here, the
composition of the
components of the coat in percentage terms remains unchanged.
Preparation of the osmotic release systems 1 to 6:
To produce the active ingredient layer, the compound of the formula (II) in
micronized form,
hydroxypropylmethylcellulose (corresponds to Ph. Eur. (Edition 9) monography
-Hypromellose", viscosity 5 mPa.s; measured in a 2% strength aqueous solution,
25 C) and
polyethylene oxide (corresponds to Ph. Eur. (Edition 9) monography -Macrogols,
High
Molecular Mass"; viscosity 40 to 100 mPa.s; measured in a 5% strength aqueous
solution,
C; POLYOXTM Water-Soluble Resin NF WSR N-80; Dow) were mixed in a blender.
This
premix was sieved, mixed again and then subjected to dry granulation by roller
granulation and
20 finally sieved. Granules obtained were mixed with finely divided silica
(corresponds to Ph. Eur.
(Edition 9) monography -Silica, colloidal anhydrous"; silicon dioxide,
Aerosil0 200). Addition
of sieved magnesium stearate (corresponds to Ph. Eur. (Edition 9) monography
``Magnesium
Stearate") was followed by a final mixing to yield the mixture ready for
compression.
To produce the osmosis layer, iron oxide red (for example CAS number 1309-37-
1),
25 hydroxypropylmethylcellulose (corresponds to Ph. Eur. (Edition 9)
monography
-Hypromellose"; viscosity 5 mPa.s; measured in a 2% strength aqueous solution,
25 C),
polyethylene oxide (corresponds to Ph. Eur. (Edition 9) monography -Macrogols,
High
Molecular Mass"; viscosity 5000 to 8000 mPa.s; measured in a 1% strength
aqueous solution,
25 C; POLYOXTM Water-Soluble Resin NF WSR Coagulant; Dow) and sodium chloride
.. (corresponds to Ph. Eur. (Edition 9) monography -Sodium Chloride") were
mixed in a blender.
This premix was subjected to dry granulation and then sieved. Addition of
sieved magnesium
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stearate (corresponds to Ph. Eur. (Edition 9) monography ``Magnesium
Stearate") was followed
by final mixing to yield the mixture ready for compression.
The bilayer tablets were produced by tabletting on a bilayer tabletting press.
First, the tabletting
press was adjusted to the tabletting weight of the active ingredient layer
(lower part of the
tablet). Then the granules for the osmosis layer (upper part of the tablet)
were added to the pre-
pressed lower part of the tablet such that the respective total tablet weight
of the bilayer tablet
core (diameter about 8 mm) was obtained.
To produce the shell, cellulose acetate (corresponds to Ph. Eur. (Edition 9)
monography
-Cellulose acetate") was dissolved in acetone. An aqueous solution comprising
polyethylene
glycol 3350 (corresponds to Ph. Eur. (Edition 9) monography -Macrogols"; mean
molecular
mass 3350 g/mol) was added to the cellulose acetate solution and they were
mixed. Using a
coating unit suitable for organic coatings, this solution was sprayed onto the
tablet cores of the
bilayer tablets.
A hole having an approximate size (diameter) of 1 mm was drilled into the
shell on the side of
the active ingredient layer using, for example, a semiautomatic drill.
Differentiation of the
active ingredient layer from the osmosis layer was possible by the colour. The
active ingredient
layer was white to slightly orange. Owing to the added iron oxide, the osmosis
layer was
orange-red.
Optionally, a coat may be applied which for its part may optionally comprise
auxiliaries such as
pigments for colouring. To this end, polyvinyl alcohol (corresponds to Ph.
Eur. (Edition 9)
monography -Poly(vinyl alcohol)") and polyethylene glycol 3350 (corresponds to
Ph. Eur.
(Edition 9) monography -Macrogols"; mean molecular mass 3350 g/mol) are
dissolved in water
at room temperature and mixed with stirring. With stirring, talc (corresponds
to Ph. Eur.
(Edition 9) monography -Talc"), titanium dioxide (corresponds to Ph. Eur.
(Edition 9)
monography Titanium dioxide") and iron oxide (for example CAS number 1309-37-1
for iron
oxide red and CAS numbers 51274-00-1 or 20344-49-4 for iron oxide yellow) are
added a little
at a time. The coat suspension obtained is applied to the tablet cores using a
suitable coating
unit, e.g. a Glatt coater. Such a coating was carried out in the case of
osmotic release systems 5
and 6.
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Preparation of the osmotic release system 7:
To produce the active ingredient layer, the compound of the formula (II) in
micronized form,
hydroxypropylmethylcellulose (corresponds to Ph. Eur. (Edition 9) monography
-Hypromellose"; viscosity 5 mPa.s; measured in a 2% strength aqueous solution,
25 C) and
Kollidon VA 64 (corresponds to Ph. Eur. (Edition 9) monography -Copovidone")
were mixed
in a blender. This premix was sieved, mixed again and then subjected to dry
granulation by
roller granulation and finally sieved. The granules obtained were mixed with
finely divided
silica (corresponds to Ph. Eur. (Edition 9) monography -Silica, colloidal
anhydrous"; silicon
dioxide, Aerosil0 200). Addition of sieved magnesium stearate (corresponds to
Ph. Eur.
(Edition 9) monography -Magnesium Stearate") was followed by final mixing to
yield the
mixture ready for compression.
To produce the osmosis layer, iron oxide red (for example CAS number 1309-37-
1),
hydroxypropylmethylcellulose (corresponds to Ph. Eur. (Edition 9) monography
-Hypromellose"; viscosity 5 mPa.s; measured in 2% strength aqueous solution,
25 C),
polyethylene oxide (corresponds to Ph. Eur. (Edition 9) monography -Macrogols,
High
Molecular Mass"; viscosity 5000 to 8000 mPa.s; measured in a 1% strength
aqueous solution,
C; POLYOXTM Water-Soluble Resin NF WSR N-80; Dow) and sodium chloride
(corresponds to Ph. Eur. (Edition 9) monography -Sodium Chloride") were mixed
in a blender.
This premix was subjected to dry granulation and then sieved. Addition of
sieved magnesium
20 stearate (corresponds to Ph. Eur. (Edition 9) monography -Magnesium
Stearate") was followed
by final mixing to yield the mixture ready for compression.
The bilayer tablets were produced by tabletting on a bilayer tabletting press.
First, the tabletting
press was adjusted to the tabletting weight of the active ingredient layer
(lower part of the
tablet). Then the granules for the osmosis layer (upper part of the tablet)
were added to the pre-
25 pressed lower part of the tablet such that the respective total tablet
weight of the bilayer tablet
core (diameter about 8 mm) was obtained.
To produce the shell, cellulose acetate (corresponds to Ph. Eur. (Edition 9)
monography
-Cellulose acetate") was dissolved in acetone. An aqueous solution comprising
ethylene glycol
3350 (corresponds to Ph. Eur. (Edition 9) monography -Macrogols"; mean
molecular mass
3350 g/mol) was added to the cellulose acetate solution and they were mixed.
Using a coating
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unit suitable for organic coatings, this solution was sprayed onto the tablet
cores of the bilayer
tablets.
A hole having an approximate size (diameter) of 1 mm was drilled into the
shell on the side of
the active ingredient layer using a semiautomatic drill. Differentiation of
the active ingredient
.. layer from the osmosis layer was possible by the colour. The active
ingredient layer was white
to slightly orange. Owing to the added iron oxide, the osmosis layer was
orange-red.
Subsequently, coating was carried out using a coat comprising pigments for
colouring. To this
end, polyvinyl alcohol (corresponds to Ph. Eur. (Edition 9) monography -
Poly(vinyl alcohol")
and polyethylene glycol 3350 (corresponds to Ph. Eur. (Edition 9) monography -
Macrogols";
.. mean molecular mass 3350 g/mol) were dissolved in water at room temperature
and mixed with
stirring. With stirring, talc (corresponds to Ph. Eur. (Edition 9) monography -
Talc"), titanium
dioxide (corresponds to Ph. Eur. (Edition 9) monography -Titanium dioxide")
and iron oxide
(for example CAS number 1309-37-1 for iron oxide red and CAS numbers 51274-00-
1 or
20344-49-4 for iron oxide yellow) were added a little at a time.
Alternatively, a finished coat of
the same composition may be suspended in water. In a suitable coating unit,
the aqueous coat
suspension obtained was sprayed onto the tablet cores.
Preparation of the osmotic release system 8:
The compound of the formula (II) in micronized form, xanthan (-Xanthan FN
Lebensmittelqualitat normal" (produced by Jungbunzlauer Ladenburg GmbH)
corresponding to
Ph. Eur. (Edition 9) monography -Xanthan gum", Kollidon VA 64 (corresponds to
Ph. Eur.
(Edition 9) monography -Copovidone"), sodium chloride (corresponds to Ph. Eur.
(Edition 9)
monography -Sodium Chloride"), sodium bicarbonate and sodium carboxymethyl
starch
(Explotab) were mixed in a blender (premix). Hydroxypropylmethylcellulose
(corresponds to
Ph. Eur. (Edition 9) monography -Hypromellose"; viscosity 3 mPa.s; measured in
a 2%
strength aqueous solution, 25 C) was dissolved in water (granulation liquid).
The premix was introduced into a fluidized-bed granulator and, in the
fluidized bed, granulated
with the granulation liquid. The granules were then dried in the fluidized
bed. The dried and
sieved granules were mixed with finely divided silica (corresponds to Ph. Eur.
(Edition 9)
monography -Silica, colloidal anhydrous"; silicon dioxide, Aerosil0 200).
Addition of sieved
magnesium stearate (corresponds to Ph. Eur. (Edition 9) monography -Magnesium
Stearate")
was followed by final mixing to yield the mixture ready for compression.
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Tabletting was carried out using a tablet diameter of about 9 mm and a tablet
breaking strength
of about 50-60 N.
To produce the shell, cellulose acetate (corresponds to Ph. Eur. (Edition 9)
monography
-Cellulose acetate") was dissolved in acetone. An aqueous solution comprising
polyethylene
glycol 3350 (corresponds to Ph. Eur. (Edition 9) monography "Macrogols"; mean
molecular
mass 3350 g/mol) was added to the cellulose acetate solution and they were
mixed. Using a
coating unit suitable for organic coatings, the solution was sprayed onto the
tablet cores.
A hole having an approximate size (diameter) of 1 mm was drilled into the
shell using a
semiautomatic drill.
Preparation of the osmotic release system 9:
To produce the tablet cores, the compound of the formula (II) in micronized
form,
hydroxypropylmethylcellulose (corresponds to Ph. Eur. (Edition 9) monography
-Hypromellose"; viscosity 5 mPa.s; measured in a 2% strength aqueous solution,
25 C),
sodium chloride (corresponds to Ph. Eur. (Edition 9) monography "Sodium
Chloride") and
polyethylene oxide were mixed in a blender. This premix was sieved, mixed
again and then
mixed with finely divided silica (corresponds to Ph. Eur. (Edition 9)
monography "Silica,
colloidal anhydrous"; silicon dioxide. Aerosil0 200). Addition of sieved
magnesium stearate
(corresponds to Ph. Eur. (Edition 9) monography ``Magnesium Stearate") was
followed by final
mixing to yield the mixture ready for compression. Alternatively, the premix
can be subjected
to dry granulation by roller granulation and finally sieved.
Tabletting was carried out using a tablet diameter of about 8 mm and a tablet
breaking strength
of about 80-110 N.
To produce the shell, cellulose acetate (corresponds to Ph. Eur. (Edition 9)
monography
-Cellulose acetate") was dissolved in acetone. An aqueous solution comprising
polyethylene
glycol 3350 (corresponds to Ph. Eur. (Edition 9) monography "Macrogols"; mean
molecular
mass 3350 g/mol) was added to the cellulose acetate solution and they were
mixed. Using a
coating unit suitable for organic coatings, the solution was sprayed onto the
tablet cores.
A hole having an approximate size (diameter) of 1 mm was drilled into the
shell using, for
example, a semiautomatic drill.
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Unless specified in more detail, the substances used for preparing the osmotic
release systems
refer to pharmaceutical auxiliaries known to the person skilled in the art
under the name
employed and, if listed in one of the pharmacopeias, meet the respective
requirements of the
pharmacopeia monographies of the European (Ph. Eur. 9), American (USP 41 and
NF 36)
and/or Japanese (JP, 17th edition) pharmacopeia.
Release characteristics
The release of the active ingredient from the tablets was determined by the
method of US
Pharmacopoeia USP 39 (Chapter <711> Dissolution) using apparatus 2 (paddle
test). To
determine the release rate, a tablet was introduced into each release vessel
of the USP apparatus
2 and the amount of active ingredient that has gone into solution, after the
undissolved
constituents have been filtered off, is determined by HPLC. The release medium
used was
phosphate buffer pH 6.8 without addition of surfactant, and the paddle stirrer
of the USP
apparatus 2 had a speed of rotation of 100 revolutions per minute. Unless
stated otherwise, the
release rate of at least six test specimens was determined. In each case, the
mean amount of
active ingredient released is reported.
Figure 12 shows the release in per cent of the compound of the formula (II)
from the osmotic
release system 1 as a function of time.
Figure 13 shows the release in per cent of the compound of the formula (II)
from the osmotic
release system 2 as a function of time.
Figure 14 shows the release in per cent of the compound of the formula (II)
from the osmotic
release system 3 as a function of time.
Figure 15 shows the release in per cent of the compound of the formula (II)
from the osmotic
release system 4 as a function of time.
Figure 16 shows the release in per cent of the compound of the formula (II)
from the osmotic
release system 5 as a function of time.
Figure 17 shows the release in per cent of the compound of the formula (II)
from the osmotic
release system 6 as a function of time.
Figure 18 shows the release in per cent of the compound of the formula (II)
from the osmotic
release system 7 as a function of time.
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Figure 19 shows the release in per cent of the compound of the formula (II)
from the osmotic
release system 8 as a function of time.
Figure 20 shows the release in per cent of the compound of the formula (II)
from the osmotic
release system 9 as a function of time.
Thermoanalytical investigation of binary physical mixtures
In order to represent compatibilities in thermoanalytical investigations, the
compounds of the
formulae (II) and (I) were initially charged with equal parts of hydrophilic
swellable polymers
in a flat round bowl and, using a pestle, ground to a homogeneous powder
mixture (trituration
in a ratio of 1:1, binary mixture). Investigated as hydrophilic swellable
polymers were
polyethylene oxide (corresponds to Ph. Eur. (Edition 9) monography -Macrogols,
High
Molecular Mass"; viscosity 40 to 100 mPa.s; measured in a 5% strength aqueous
solution,
25 C; POLYOXTM Water-Soluble Resin NF WSR N-80; Dow), xanthan (-Xanthan FN
Lebensminelqualitat normal" produced by Jungbunzlauer Ladenburg GmbH),
corresponds to
Ph. Eur. (Edition 9) monography -Xanthan gum", vinylpyrrolidone/vinyl acetate
copolymer
(Kollidon VA 64), corresponds to Ph. Eur. (Edition 9) monography -Copovidone",
polyvinylpyrrolidone (PVP 25), corresponds to Ph. Eur. (Edition 9) monography -
Povidone",
methacrylic acid/methyl methacrylate copolymer (Eudragit0 L100), corresponds
to Ph. Eur.
(Edition 9) monography -Methacrylic acid - Methyl Methacrylate Copolymer
(1:1)",
methacrylic acid/methyl methacry late copolymer (Eudragit0 RL PO), corresponds
to Ph. Eur.
(Edition 9) monography -Ammonio Methacrylate Copolymer (TYPE
A)",
hydroxypropylcellulose (HPC LM Nisso), corresponds to Ph. Eur. (Edition 9)
monography
-Hydroxypropylcellulose" and polyacrylic acid (corresponds to Ph. Eur.
(Edition 9)
monography -Carbomers"; Name: Polyacrylic acid, MW 1,080,000 aver. MN 135,000;
Acros
Organics).
The physical mixtures and the respective individual components were
characterized
thermoanalytically. The thermograms were recorded on a differential scanning
calorimeter. To
this end, in each case about 5 mg of the sample were heated in an aluminium
pan under
nitrogen (50 ml/min) using a heating rate of 10 K/min to the end of the
melting point of the
compound in question.
Figure 1 shows thermograms of the compound of the formula (I), of polyethylene
oxide and of the
binary mixture of the compound of the formula (I) with polyethylene oxide.
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Figure 2 shows thermograms of the compound of the formula (II), of
polyethylene oxide and of the
binary mixture of the compound of the formula (II) with polyethylene oxide.
Figure 3 shows thermograms of the compound of the formula (II), of xanthan and
of the binary mixture
of the compound of the formula (II) with xanthan.
.. Figure 4 shows thermograms of the compound of the formula (II), of
vinylpyrrolidone/vinyl acetate
copolymer and of the binary mixture of the compound of the formula (II) with
vinylpyrrolidone/vinyl
acetate copolymer.
Figure 5 shows thermograms of the compound of the formula (II), of PVP25 and
of the binary mixture
of the compound of the formula (II) with PVP25.
.. Figure 6 shows thermograms of the compound of the formula (II), of HPC LM
and of the binary mixture
of the compound of the formula (II) with HPC LC.
Figure 7 shows thermograms of the compound of the formula (II), of Eudragit
L100 and of the binary
mixture of the compound of the formula (II) with Eudragit L100.
Figure 8 shows thermograms of the compound of the formula (II), of Eudragit RL
PO and of the binary
.. mixture of the compound of the formula (II) with Eudragit RL PO.
Figure 9 shows thermograms of the compound of the formula (II), of polyacrylic
acid and of the binary
mixture of the compound of the formula (II) with polyacrylic acid.
Date Recue/Date Received 2021-01-21
