U.S. patent application number 14/463296 was filed with the patent office on 2014-12-04 for salt of ivabradine with adipic acid.
This patent application is currently assigned to ratiopharm GmbH. The applicant listed for this patent is ratiopharm GmbH. Invention is credited to Jens GEIER, Ramesh Matioram GIDWANI, Mayur Vilas KOLHATKAR, Dominique MEERGANS, Ralph STEFAN.
Application Number | 20140357860 14/463296 |
Document ID | / |
Family ID | 44524908 |
Filed Date | 2014-12-04 |
United States Patent
Application |
20140357860 |
Kind Code |
A1 |
GIDWANI; Ramesh Matioram ;
et al. |
December 4, 2014 |
SALT OF IVABRADINE WITH ADIPIC ACID
Abstract
The present invention relates to pharmaceutical compositions
with delayed release which contain ivabradine adipate as active
substance. The present invention furthermore relates to processes
for the preparation of this composition and certain salts of
ivabradine.
Inventors: |
GIDWANI; Ramesh Matioram;
(Mumbai, IN) ; KOLHATKAR; Mayur Vilas; (Thane (W),
IN) ; MEERGANS; Dominique; (Munich, DE) ;
STEFAN; Ralph; (Ebenweiler, DE) ; GEIER; Jens;
(Oberdischingen, DE) |
|
Applicant: |
Name |
City |
State |
Country |
Type |
ratiopharm GmbH |
Ulm |
|
DE |
|
|
Assignee: |
ratiopharm GmbH
Ulm
DE
|
Family ID: |
44524908 |
Appl. No.: |
14/463296 |
Filed: |
August 19, 2014 |
Related U.S. Patent Documents
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Application
Number |
Filing Date |
Patent Number |
|
|
13704459 |
Jan 7, 2013 |
|
|
|
PCT/EP11/59864 |
Jun 14, 2011 |
|
|
|
14463296 |
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Current U.S.
Class: |
540/523 |
Current CPC
Class: |
A61K 9/2027 20130101;
A61K 47/38 20130101; A61K 9/146 20130101; A61K 9/0002 20130101;
A61K 47/10 20130101; A61K 9/14 20130101; A61K 9/1652 20130101; A61K
9/2095 20130101; A61K 9/2054 20130101; A61K 9/2846 20130101; Y10T
428/2982 20150115; C07D 223/16 20130101; A61K 47/32 20130101; A61K
9/2031 20130101; C07C 55/14 20130101; A61K 47/36 20130101; A61K
31/55 20130101; A61K 9/20 20130101 |
Class at
Publication: |
540/523 |
International
Class: |
C07D 223/16 20060101
C07D223/16; C07C 55/14 20060101 C07C055/14 |
Foreign Application Data
Date |
Code |
Application Number |
Jun 14, 2010 |
EP |
10.165881.3 |
Jun 14, 2010 |
EP |
10.165884.7 |
Jun 23, 2010 |
IN |
1760/CHE/2010 |
Claims
1. A salt of ivabradine with adipic acid.
Description
PRIORITY
[0001] This application is a divisional of U.S. application Ser.
No. 13/704,459 filed Jan. 7, 2013, which, in turn, corresponds to
the national phase of International Application No.
PCT/EP2011/059864 filed Jun. 14, 2011, which, in turn, claims
priority to European Patent Application No. 10.165881.3 filed Jun.
14, 2010, European Patent Application No. 10.165884.7 filed Jun.
14, 2010, and Indian Patent Application No. 1760/CHE/2010 filed
Jun. 23, 2010. The entire contents of these prior applications are
hereby are incorporated by reference herein.
FIELD OF THE INVENTION
[0002] The invention relates to an oral administration form with
modified release, containing (a) ivabradine adipate and a
combination of (b) water-soluble excipient and (c) water-insoluble
excipient; and a process for the preparation thereof. The present
invention furthermore relates to certain salts of ivabradine and a
process for stabilizing these salts in a pharmaceutical
composition.
BACKGROUND OF THE INVENTION
[0003] Ivabradine has the chemical composition
(S)-3-{3-[(3,4-dimethoxybicyclo[4.2.0]octa-1,3,5-trien-7-ylmethyl)methyla-
mino]propyl}-7,8-dimethoxy-2,3,4,5-tetrahydro-1H-3-benzazepin-2-one.
Ivabradine has the following structural formula:
##STR00001##
[0004] Synthesis routes for the preparation of ivabradine and its
use for preventing and treating various clinical conditions of
myocardial ischaemia, supraventricular arrhythmias and coronary
arteriosclerotic episodes are reported to be disclosed in EP 534
859.
[0005] Ivabradine is an active substance reported to have a
bradycardic effect for the treatment of stable angina pectoris, in
particular in patients for whom beta-blockers are contraindicated
or intolerance of beta-blockers is present. Ivabradine is reported
to selectively inhibit the I.sub.f-ion current which, as an
intrinsic pacemaker in the heart, controls the spontaneous
diastolic depolarisation in the sinoatrial node and thus regulates
the heart rate. Under physiological conditions, ivabradine, the
S-enatiomer of a racemate, is reported to have a very good water
solubility (>10 mg/ml).
[0006] The prior art apparently discloses administration forms of
ivabradine which release the active substance substantially without
a time delay. The administration form Procoralan.RTM. (Servier)
releases ivabradine rapidly and almost completely after oral
intake. WO 2003-061662 apparently discloses an
ivabradine-containing, orally dispersible tablet, which releases
the active substance very rapidly in the mouth.
[0007] However, administration of ivabradine with immediate release
has disadvantages since it can lead to very high plasma
concentrations too quickly in certain patients.
[0008] In general, non-retarded oral or parenteral administration
forms do not result in the rapid build-up of plasma levels after a
single administration. After the end of the resorption, however,
there is a more or less rapid drop in the plasma concentration of
the active substance, depending on the magnitude of the elimination
constant. In the case of substances having a fast elimination
constant, this leads to considerable variations in the plasma level
on repeated administration and may cause a temporary decline in the
effect and, if a higher dose is required, also the possible
occurrence of side-effects.
[0009] An administration form with modified release can avoid these
peak values of the plasma concentration and ensure a uniform
concentration of the active substance in the blood.
Sustained-release dosage forms have the advantage that they can
avoid subtherapeutic and toxic plasma or tissue concentrations and
instead maintain suitable plasma or tissue concentrations over a
longer period. An advantage of an administration form with modified
release is that frequently the total dose can be reduced while
achieving a comparable effect or the duration of action is
prolonged. Furthermore, the patient compliance is generally
improved and the frequency of intake can be decreased.
[0010] The modified release of ivabradine would thus make it
possible to provide an improved therapeutic index. However, it is
necessary for this purpose to ensure an active substance release
which is modified over time.
[0011] One possibility for achieving the modified release of the
active substance is based on the embedding of the active substance
in a matrix which is formed from a polymer. There is a multiplicity
of known polymers which can be used for forming such a matrix.
However, in the case of ivabradine, the preparation of
pharmaceutical compositions with modified release is complicated by
specific preparation problems. In particular, it is found that the
stability of the active substance in the course of the preparation
process is a substantial factor.
[0012] Moreover, in the case of highly water-soluble active
substances, such as ivabradine salts, the preparation of drugs with
modified release is not easy and difficulties frequently occur,
such as, for example, [0013] a complicated preparation process,
[0014] the stability of the active substances and the excipients,
[0015] the correct establishment of the desired release profile,
[0016] the reproducibility of the batches.
[0017] These and further problems are discussed in WO
2002/051387.
[0018] WO 2002/051387 claims to disclose a process for the
preparation of solid pharmaceutical formulations for the controlled
release of ivabradine through the use of specific thermoforming
techniques. Exclusively polymethacrylates are used as excipients,
it not being permitted for any plasticiser or agent which modulates
the release of the active substance to be present. However, the
thermoforming techniques described are extremely complicated and
require high material consumption and necessitate very exact
temperature control. The most complicated disadvantage is the
necessary increase in temperature which, depending on the salt or
polymorph of ivabradine used, leads to more or less pronounced
decomposition thereof. In this publication no composition is
disclosed comprising a combination of water-soluble and
water-insoluble excipients.
[0019] Ivabradine may be present in various polymorphic forms,
which additionally complicates the development of ivabradine
formulations. Various polymorphic forms of ivabradine hydrochloride
are reported to be described in the prior art. WO 2005/110993 A1
apparently discloses polymorph alpha, WO 2006/092493 A1 apparently
discloses polymorph beta and WO 2006/092491 A1 apparently discloses
polymorph beta d (dehydrated). Furthermore, polymorph gamma,
polymorph gamma d, polymorph delta and polymorph delta d are
apparently disclosed in the prior art. In addition, WO2008/065681
apparently reports the so-called Form I of Ivabradine HCl. WO
2008/146308 A2 apparently discloses amorphous ivabradine.
[0020] Various salts of ivabradine are apparently also disclosed in
the prior art. WO 2008/146308 A2 apparently discloses ivabradine
oxalate and WO 2009/124940 A1 apparently discloses ivabradine
hydrobromide.
[0021] In the case of the salts and polymorphs of ivabradine, in
particular the polymorphs of the hydrochloride, there is the
problem that these salt forms are not sufficiently stable under all
conditions. This in turn can lead to problems in the processing and
storage and to undesired reactions with the excipients used in the
preparation of the pharmaceutical composition.
[0022] The different solubility profiles of the polymorphic forms
lead to an undesirable nonuniform uptake of the active substance in
the patient. It was therefore also an object of the present
invention to provide stable forms of ivabradine which can be
processed to give an administration form which permits as uniform
an uptake as possible in the patient. Both interindividual and
intraindividual deviations should be substantially avoided.
[0023] There is therefore a need for ivabradine-containing
formulations with modified release, which can provide both a rapid
onset of action and a long-lasting release.
[0024] There is in particular a need for defined control of the
release rate and of the bioavailability of the active substance. In
addition, it is desirable to improve the chemical stability of the
active substance and the stability of the polymorphs, in particular
to hydrolytic degradation and under thermal load. A further problem
consists in the improvement of the processability of ivabradine to
pharmaceutical compositions, in particular those with modified
release, in the reduction of the hygroscopicity of the composition
and the improvement of the storage stability of corresponding
compositions. Finally, it is intended to provide novel salt forms
of ivabradine which can be particularly advantageously stabilized
in a composition with modified release.
SUMMARY OF THE INVENTION
[0025] It has now surprisingly been found that the abovementioned
objects can be achieved by the combination of the active substance
ivabradine in the form of its adipate salt (a) with a water-soluble
(b) and a water-insoluble excipient (c) in a pharmaceutical
composition with modified release. By embedding the active
substance (a) in a mixture of the water-insoluble and the
water-soluble excipient, surprisingly not only can the active
substance advantageously be released in a modified manner but it is
also stabilized in its polymorphic form as well as chemically.
Corresponding compositions show little hygroscopicity and
outstanding modified release. Corresponding mixtures can be further
processed in an excellent manner to give pharmaceutical
compositions, in particular tablets.
[0026] Furthermore, it was found that some salts of ivabradine are
particularly suitable for the compositions according to the
invention with modified release and can be used in the drugs
according to the invention with modified release. These salts are
novel compounds, and the invention also relates to these salts. The
novel salts are advantageously stabilized in the novel
formulations.
[0027] The present invention therefore relates to a pharmaceutical
composition for modified release, which comprises ivabradine
adipate and a combination of a water-insoluble and a water-soluble
excipient. The active substance ivabradine is present as adipate,
i.e. in the form of its salt with adipic acid. In the context of
this invention, ivabradine salts can be used both in amorphous form
and in crystalline form. The composition is intended for oral
administration. Preferably the pharmaceutical composition is a
stable pharmaceutical composition.
[0028] Here, "active substance" or "ivabradine" is understood as
meaning ivabradine in the form of the adipate salt, i.e. the salt
of ivabradine with adipic acid.
[0029] The present invention also relates to the following salts of
ivabradine which have been found to be advantageous for achieving
the above object: L-aspartate, D-aspartate, sorbate, acinotate,
gluconate, glucoheptonate, glucuronate, hippurate,
8-chlorotheophyllinate, xinafoate, malate, sulphamate, oxalate form
I, oxalate form II, oxalate form III and salts of ivabradine with
ethanesulphonic acid, ethane-1,2-disulphonic acid,
naphthalenesulphonic acid, naphthalenecarboxylic acid, embonic
acid, mandelic acid, lactobionic acid or adipic acid. The salts of
ivabradine can be obtained according to processes for the
preparation of ivabradine salts reported to be known to the person
skilled in the art, e.g. by reacting the free base of ivabradine
with the corresponding acid or by the presence of the corresponding
acid in the synthesis of ivabradine, as reported to be described,
for example, in US 2005/0228177 A1.
BRIEF DESCRIPTION OF THE DRAWINGS
[0030] FIG. 1 shows an XRD pattern of ivabradine adipate.
[0031] FIGS. 2 and 3 show dissolution profiles of the compositions
of examples 2 and 3, respectively.
DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS:
[0032] Ivabradine adipate can be obtained by adding adipic acid,
e.g. about one equivalent, in a suitable solvent, such as ethanol,
to a solution of ivabradine in a suitable solvent, such as
dichlormethane. Crystalline ivabradine adipate product can be
obtained by removal of the solvent, e.g. under vacuum at about
40.degree. C. Crystalline ivabradine adipate can also be obtained
by adding a solution of adipic acid in water to a solution of
ivabradine in ethanol, and removal of the solvent.
[0033] The DSC thermogramm of ivabradine adipate shows a peak at
about 115.degree. C. The melting point is in the range of about
113.degree. C. to about 117.degree. C.
[0034] Ivabradine adipate is characterized by an XRD pattern having
a characteristic peak at 20.6.+-.0.2 degrees 2-theta, in particular
having characteristic peaks at 14.6.+-.0.2, 16.0.+-.0.2,
18.8.+-.0.2, 20.6.+-.0.2, 23.2.+-.0.2, 24.3.+-.0.2, 25.9.+-.0.2 and
26.3.+-.0.2 degrees 2-theta and preferably further at 8.6.+-.0.2,
9.6.+-.0.2, 12.1.+-.0.2 and 12.9.+-.0.2 degrees 2-theta. The XRD
pattern of ivabradine adipate is shown in FIG. 1.
[0035] Ivabradine oxalate I is characterized by an XRD pattern
having a characteristic peaks at 17.7.+-.0.2 and 23.0.+-.0.2
degrees 2-theta, in particular having characteristic peaks at
16.7.+-.0.2, 17.1.+-.0.2, 17.7.+-.0.2, 20.9.+-.0.2, 23.0.+-.0.2,
23.6.+-.0.2, 24.4.+-.0.2 and 27.5.+-.0.2 degrees 2-theta or at
16.7.+-.0.2, 17.7.+-.0.2, 19.0.+-.0.2, 20.9.+-.0.2, 23.6.+-.0.2,
24.4.+-.0.2 and 27.5.+-.0.2 degrees 2-theta.
[0036] Ivabradine oxalate II is characterized by an XRD pattern
having a characteristic peaks at 17.3.+-.0.2 degrees 2-theta, in
particular having characteristic peaks at 13.5.+-.0.2, 17.3.+-.0.2,
18.2.+-.0.2, 19.1.+-.0.2, 21.1.+-.0.2, 23.3.+-.0.2, 25.6.+-.0.2 and
27.3.+-.0.2 degrees 2-theta or at 13.5.+-.0.2, 17.3.+-.0.2,
21.1.+-.0.2, 23.3.+-.0.2, 25.6.+-.0.2 and 27.3.+-.0.2 degrees
2-theta.
[0037] Ivabradine oxalate Ill is characterized by an XRD pattern
having characteristic peaks at 20.9.+-.0.2 and 23.1.+-.0.2 degrees
2-theta, in particular having characteristic peaks at 16.9.+-.0.2,
17.5.+-.0.2, 18.8.+-.0.2, 19.9.+-.0.2, 20.9.+-.0.2, 23.1.+-.0.2,
25.5.+-.0.2 and 32.3.+-.0.2 degrees 2-theta or at 16.9.+-.0.2,
17.5.+-.0.2, 20.9.+-.0.2, 23.1.+-.0.2, and 32.3.+-.0.2 degrees
2-theta.
[0038] Corresponding to the preparation of ivabradine adipate,
ivabradine-(S)-mandalate, ivabradine-1-hydroxy-2-naphthanoate,
ivabradine-L-aspartate, ivabradine-D-aspartate, ivabradine
ethanesulphonate and ivabradine-L-malate can be prepared by
reacting ivabradine free base in a suitable solvent, e.g.
acetronitrile or dichloromethane, with the corresponding acid.
[0039] Furthermore, amorphous ivabradine, in the form of the above
described salts, in particular the adipate salt is preferably used
in the pharmaceutical compositions with modified release of the
present invention.
[0040] The invention also relates to the use of a combination of
water-soluble and water-insoluble excipients for the preparation of
an ivabradine-containing, in particular ivabradine
adipate-containing, oral administration form, preferably of a
tablet with modified release.
[0041] Preferably, the pharmaceutical compositions of the present
invention contain about 1 - 80% by weight, more preferably about
2-60% by weight, in particular about 2-40% by weight, e.g. about
2-20% by weight, of ivabradine, based on the weight of free base in
the composition.
[0042] All pharmaceutically acceptable excipients having sufficient
water solubility can be used in the pharmaceutical compositions
with modified release as suitable water-soluble excipients
(component (b)), provided that they do not counteract the desired
modified release. Such excipients are known to the person skilled
in the art. Preferably, the solubility in water of the
water-soluble excipients is greater than or equal to 33 mg/ml,
measured at 25.degree. C., in particular greater than or equal to
100 mg/ml, measured at 25.degree. C. Suitable water-soluble
excipients are cellulose derivatives, such as, for example,
hydroxypropylmethylcellulose, hydroxyethylcellulose,
hydroxypropylcellulose, sodium carboxymethylcellulose (sodium-CMC),
cellulose acetate phthalate and hydroxypropylmethylcellulose
phthalate, or polyvinylpyrrolidone (PVP), copolymers of PVP and
vinyl acetate and polyvinyl alcohol, polyethylene glycol (PEG) and
xylitol, sorbitol or other sugar alcohols, or sodium chloride.
Preferably, the water-soluble excipients consist chemically of more
than one monomer, i.e. they are polymers, preferably the cellulose
derivatives and/or polyvinylpyrrolidone (PVP) or its copolymers and
PEG. In the context of this invention, the water solubility is
determined according to EU-Directive RL67-548-EEC, Annex V Section
A6, at pH=7.
[0043] All pharmaceutically acceptable excipients having
insignificant water solubility at 25.degree. C. can be used in the
pharmaceutical compositions with modified release as suitable
water-insoluble excipients (component (c)), provided that they do
not counteract the desired modified release. Such excipients are
known to the person skilled in the art. Preferably, the solubility
in water of the water-insoluble excipients is less than 33 mg/ml,
measured at 25.degree. C., in particular 10 mg/ml or less, measured
at 25.degree. C. Particularly preferably, the water solubility of
these excipients is 1 mg/ml or less, likewise at 25.degree. C.
Suitable water-insoluble excipients are water-insoluble cellulose
derivatives, such as, for example, ethylcellulose,
ethylhydroxyethylcellulose, microcrystalline cellulose or cellulose
powder, polyvinyl acetate, starches, stearic acid, waxes, glyceryl
palmitate stearate, but also ion exchange resins, such as
polacrilin potassium, sodium polystyrenesulphonate and/or
colestyramine resinate. Water solubility is determined according to
EU Directive RL67-548-EEC, Annex V Section A6 at pH=7.
[0044] Water-soluble and/or water-insoluble cellulose derivatives
having a weight average molecular weight of, preferably, in the
range from 5000 to 1 million g/mol, particularly preferably in the
range from 10000 to 100000 g/mol, are preferably used as
excipients.
[0045] The water-soluble and/or water-insoluble excipients which
are used in combination in the pharmaceutical compositions with
modified release according to the present invention are typically
each present in an amount of about 2-80% by weight, preferably
about 5-60% by weight, in particular about 8-30% by weight, based
on the total weight of the composition. The sum of the proportions
of the ingredients of the composition is in each case 100% by
weight.
[0046] The finished administration forms may be oral administration
forms, for example tablets, capsules, sachets or powders.
Preferably, the pharmaceutical composition according to the
invention is present in the form of a tablet. The preparation of
tablets by means of granulation or direct compression of the
ingredients is known in the prior art. Tablets according to the
invention are preferably prepared by direct compression.
[0047] The pharmaceutical composition may contain one or more
pharmaceutically acceptable excipients which may be water-soluble
or water-insoluble, provided that they do not counteract the
desired modified release. For example, fillers, glidants, flow
regulators and/or release agents may be mentioned by way of example
("Lexikon der Hilfsstoffe fur Pharmazie, Kosmetik und angrenzende
Gebiete [Lexikon of excipients for pharmacy, cosmetics and
ancillary areas]", edited by H. P Fiedler, 4.sup.th edition, and
"Handbook of Pharmaceutical Excipients", 3.sup.rd edition, edited
by Arthur H. Kibbe, American Pharmaceutical Association,
Washington, USA und Pharmaceutical Press, London).
[0048] Filler: The pharmaceutical composition may contain one or
more fillers. In general, a filler is a substance which increases
the bulk volume of the mixture and hence the size of the resulting
dosage form. Preferred examples of fillers are lactose and calcium
hydrogen phosphate. The filler may have a proportion of about 0% to
99% by weight, preferably between about 40% and 96% by weight, of
the total weight of the composition.
[0049] Glidant: The function of the glidants is to ensure that the
tablet compression and the ejection take place without major
friction between the solids and the walls. The glidant is
preferably an alkaline earth metal stearate, such as magnesium
stearate, or a fatty acid, such as stearic acid. The glidant is
usually present in an amount of about 0% -2% by weight, preferably
between about 0.5% and 1.5% by weight, of the total weight of the
pharmaceutical composition.
[0050] Flow regulator/release agent: For example, colloidal silica
or magnesium stearate can be used as a flow regulator and/or
release agent. The flow regulator/release agent is preferably
present in an amount of about 0% -8% by weight, more preferably in
an amount between about 0.1% and 3% by weight, of the total weight
of the composition.
[0051] Methods for controlling the release of the active substance,
by means of which the release rate, the time or the site (e.g.
stomach or intestine) of the release of the active substance or of
the active substances can be adjusted as intended, are generally
known in the art.
[0052] In the pharmaceutical compositions according to the present
invention, the release is preferably modified by the formation of a
suitable hydrophilic matrix. Preferably, a hydrophilic matrix which
releases the active substance in a modified manner is formed by the
combination of the water-insoluble and of the water-soluble
excipient according to the invention.
[0053] Furthermore preferred according to the invention is a drug
formulation having a core which comprises the active substance and
the combination, according to the invention, of a water-insoluble
and a water-soluble excipient and which is provided with a coating
which modifies, i.e. in particular retards, the release. The core
without the coating preferably releases the active substance
rapidly. The release-controlling coatings are known in the prior
art, for example those which are based on polymethacrylates, such
as coating materials of the Eudragit series.
[0054] Further known methods for modifying the release of an active
substance can likewise be used according to the invention, for
example retardation by embedding in fat, the use of ion exchange
resins, the use of epoxy resin beads, retardation by formation of a
solid solution or by complex formation with the active substance,
and osmotic systems.
[0055] In a preferred embodiment, the pharmaceutical composition is
a film-coated tablet. In a preferred embodiment, the constituents
(a), (b) and (c) and optionally the further excipients described
above therefore form a tablet core, the tablet core preferably
being provided with a coating (=component (d)).
[0056] In this invention, three different coatings (d) are in
general preferred: [0057] (d1) coatings without any influence on
the active substance release; [0058] (d2) enteric coatings; and
[0059] (d3) sustained-release coatings.
[0060] Coatings without any influence on the active substance
release are usually water-soluble (they preferably have a water
solubility of more than 250 mg/ml). Enteric coatings have a
pH-dependent solubility. Sustained-release coatings are usually
water-insoluble (they preferably have a water solubility of less
than 10 mg/ml).
[0061] Macromolecular substances, for example modified celluloses,
polymethacrylates, polyvinylpyrrolidone, polyvinyl acetate
phthalate, zein and/or schellac or natural gum, such as, for
example, carrageenan, are usually used for the coating (d).
[0062] Preferred examples of coating polymers which have no
influence on the active substance release (d1) are water-soluble
polymers, such as, for example, low-viscosity
hydroxypropylmethylcellulose (HPMC), hydroxypropylcellulose (HPC),
hydroxyethylcellulose (HEC), polvinylpyrrolidone (PVP) and mixtures
thereof. Said polymers should usually have a weight average
molecular weight of 10000 to 150000 g/mol. HPMC is preferably used,
in particular HPMC having a weight average molecular weight of
10000 to 150000 g/mol and/or an average degree of substitution of
--OCH3 groups of 1.2 to 2.0.
[0063] Examples of enteric coatings (d2) are those which are based
on cellulose acetate phthalate (CAP), hydroxypropylmethylcellulose
phthalate and polyvinyl acetate phathalate (PVAP).
[0064] Examples of sustained-release coatings (d3) are those which
are based on ethyl cellulose (EC, commercially available, for
example, as Surelease.RTM.) and polymethacrylates (commercially
available, for example, as Eudragit.RTM. RL or RS and L/S).
[0065] The coating (d) may be free of active substance. However, it
is also possible for the coating (d) to contain active substance
(a).
[0066] In one preferred embodiment in the pharmaceutical
compositions according to the invention the active substance is not
present as a mixture with a polyacrylate or a polymethacrylate.
[0067] In addition to the active substance ivabradine adipate (or
another salt, solvate or hydrate or polymorph thereof), the
pharmaceutical composition according to the invention may also
contain active substances differing from ivabradine adipate;
preferably, the pharmaceutical composition according to the
invention contains exclusively ivabradine adipate as the only
active substance (or another salt, solvate, hydrate or polymorph
thereof) and no further active substance.
[0068] The pharmaceutical composition according to the present
invention and which is preferably present in the form of a tablet
which contains the constituents (a), (b) and (c) and optionally
(d), is a composition with modified release. In the context of this
invention, the term modified release is understood as meaning
delayed release, prolonged release, sustained release or extended
release. According to the invention, the term "modified release" is
preferably used in the sense of "sustained release". The above
terms are usual in the technical area and reference may be made,
for example, to the textbook Voit, "Pharmazeutische Technologie",
9.sup.th edition (2000).
[0069] Here, modified release is preferably understood as meaning
that the composition, preferably in the form of pellets or tablets,
releases the active substance after a time delay, i.e. has a
release profile, so that the total active substance is not released
in less than 2 hours, preferably not released in less than 4 hours.
In a preferred embodiment of the present invention, the
pharmaceutical composition according to the invention has a release
profile of the active substance wherein 1-35%, preferably 5-30% of
the active substance are released after one hour, 5-40%, preferably
10-35%, after two hours, 10-50%, preferably 15-40%, after six hours
and 15-100%, preferably 50-80%, after 16 hours. More preferred
compositions are those having a release profile wherein 1-35%,
preferably 5-30% of the active substance are released after one
hour, 5-50%, preferably 15-45%, after two hours, 10-80%, preferably
25-70%, after six hours and 20-100%, preferably 50-97%, after 16
hours.
[0070] The pharmaceutical compositions according to the invention
are usually distinguished by release and absorption which lead to
advantageous values of c.sub.max (maximum plasma level).
[0071] In a preferred embodiment, the oral administration of the
formulation according to the invention to a human as a patient
leads to a plasma level profile which is distinguished by a
c.sub.max, based on a single daily intake of 10 mg of the active
substance ivabradine, in the steady state, of about 5 to 40 ng/ml,
preferably 10 to 30 ng/ml.
[0072] The abovementioned values for the plasma level are
preferably mean values, obtained by investigations of blood samples
of a group of 10 test subjects (having an average body weight of 70
kg), the corresponding blood samples having been taken 0, 1, 2, 3,
4, 6, 8, 12, 24 and 48 hours after oral administration of the
composition according to the invention in the steady state. The
determination of the plasma level values can preferably be carried
out by suitable HPLC-MSMS methods.
[0073] In the context of the present invention, "release profile"
is understood as meaning the variation of the amount of the active
substance which is present in solution, based on the total amount
of the active substance, as a function of time. According to the
invention, the release profile is determined by dissolving a solid
administration form of the pharmaceutical composition of the
present invention in a USP apparatus I (basket apparatus) in 500 ml
of USP buffer (phosphate buffer) at pH 6.8, 37.degree. C. and a
stirrer speed of 50 rpm and measuring the amount of dissolved
active substance over a period, e.g. 24 hours, at the desired
times. The content of active substance released can be determined
in a known manner, for example by absorption of light of a certain
wavelength or by means of HPLC or another suitable detection
method. Otherwise, the test conditions for determining the release
profile correspond to the methods of the US Pharmacopoeia.
[0074] The pharmaceutical compositions according to the invention
are preferably present as tablets which contain ivabradine adipate
in an amount of preferably 1 mg to 25 mg, more preferably of 3 mg
to 20 mg, in particular of 10 mg to 15 mg, based on ivabradine free
base. The invention therefore relates in particular to tablets
containing 5 mg, 10 mg and 15 mg of ivabradine adipate, based on
ivabradine free base.
[0075] The pharmaceutical compositions according to the invention
are preferably administered once daily, in particular in the form
of a tablet.
[0076] Finally, the tablets according to the invention usually have
a content uniformity of 95 to 105%, preferably of 98 to 102%, in
particular of 99 to 101%, of the average content (this means that
all tablets have an active substance content between 95 and 105%,
preferably between 98 to 102%, in particular between 99 and 101%,
of the average active substance content.) The "content uniformity"
is determined according to Ph. Eur. 6.0, Section 2.9.6.
[0077] The present invention furthermore relates to a process for
the preparation of a pharmaceutical composition, in particular of a
composition according to the present invention as described above,
comprising the steps of mixing ivabradine adipate with a
water-insoluble and a water-soluble excipient, optionally with
further pharmaceutically acceptable excipients, optionally
isolating the composition obtained and optionally converting the
composition into a solid pharmaceutical dosage form, preferably a
tablet, optionally followed by coating of the dosage form. The
production of tablets, for example by means of granulation or
direct compression of the ingredients, is known in the art. The
tablet according to the invention is preferably produced by direct
compression.
[0078] Methods for the preparation of drugs with modified release
are known to the person skilled in the art, and reference may be
made, for example, to the textbook Bauer,
[0079] Fromming and Fuhrer, "Lehrbuch der Pharmazeutischen
Technologie", 6.sup.th edition 1999. According to the invention,
the methods described in this textbook can be used analogously.
[0080] The present invention furthermore relates to the use of a
combination of a water-insoluble and a water-soluble excipient, in
particular those mentioned above as being preferred, in a
pharmaceutical composition with modified release, containing
ivabradine adipate, in particular for delaying the release of the
active substance ivabradine adipate.
[0081] The present invention furthermore relates to the use of a
combination of a water-soluble and a water-insoluble excipient as a
mixture with the active substance ivabradine adipate in a
pharmaceutical composition with modified release for stabilizing
the active substance.
[0082] XRD samples were analysed on a Bruker-AXS D8 Advance powder
X-Ray diffractometer. The measurement conditions were as
follows:
Measurement in Bragg-Brentano-Geometry on Vertical Goniometer
(Reflection, Theta/Theta,
[0083] 435 mm measurement circle diameter) with sample rotation (30
rpm) on 9 position sample stage [0084] Radiation: Cu
K.alpha.1(1.5406.ANG.), Tube (Siemens FLCu2K), power 40 kV/40 mA
[0085] Detector: position sensitive detector VANTEC-1 [0086]
3.degree. capture angle (2theta), [0087] Anti scatter slit 6.17 mm
[0088] Detector slit 10.39 mm [0089] 4.degree. soller slit, [0090]
primary beam stop (<2.degree. 2theta) [0091] Monochromator: None
[0092] Second .beta. filter: Ni filter 0.1 mm (0.5%) [0093] Start
angle: 2.degree. [0094] End Angle: 55.degree. [0095] Measurement
time: 11 min [0096] Step: 0.016.degree. 2Theta [0097] Software: EVA
(Bruker-AXS, Karlsruhe).
[0098] DSC samples were analyzed on a Mettler Toledo Model DSC
822.
[0099] The measurement conditions were as follows: Heating range
for the samples 30 to 300.degree. C.; heating rate=10.degree.
C./min. Purge gas=nitrogen 50 ml/min; 40 micron aluminum
crucible.
[0100] The present invention will now be explained in more detail
with reference to the following examples, which are not intended as
being limiting.
EXAMPLES
Example 1
Retardation by Coating
[0101] A tablet of the following composition was produced:
[0102] Core:
TABLE-US-00001 Ivabradine adipate 6.56 mg Avicel PH101 45.97 mg
Sorbitol 45.97 mg Aerosil 1.00 mg Magnesium stearate 0.50 mg 100.0
mg
[0103] Coating:
TABLE-US-00002 Eudragit RS 30D 6.35 mg
[0104] The cores were produced by mixing the ingredients
ivabradine, Avicel, sorbitol and Aerosil and subsequently adding
the magnesium stearate. The cores were then coated with an aqueous
suspension containing Eudragit RS 30D.
[0105] In this formulation, sorbitol is a water-soluble excipient
and Avicel PH101 is a water-insoluble excipient.
Example 2
Retardation by Formation of a Hydrophilic Matrix
TABLE-US-00003 [0106] Ivabradine adipate 6.51 mg Hypromellose 40.91
mg Calciumhydrogenphosphate 15.00 mg Avicel PH 101 35.00 mg Aerosil
1.58 mg Magnesium stearate 1.00 mg 100.00 mg
[0107] The ingredients were mixed in a mixer and then pressed to
give tablets.
[0108] In this formulation, in particular the HPMC (Methocel K15M)
is a water-soluble excipient and the Avicel PH101 is a
water-insoluble excipient
[0109] The dissolution profile (conditions: 500 mL 50 mM Phosphate
buffer pH 6.8-37.degree. C. -50 rpm baskets (USP app. I)) of the
tablet according to Example 2 is shown in FIG. 2.
Example 3
Retardation by Formation of a Hydrophilic Matrix
TABLE-US-00004 [0110] Ivabradine HCl 5.42 mg Hypromellose 42.00 mg
Calciumhydrogenphosphate 15.00 mg Avicel PH 101 35.00 mg Aerosil
1.58 mg Magnesium stearate 1.00 mg 100.00 mg
[0111] The ingredients were mixed in a mixer and then pressed to
give tablets.
[0112] In this formulation, in particular the HPMC (Methocel K15M)
is a water-soluble excipient and the Avicel PH101 is a
water-insoluble excipient
[0113] The dissolution profile (Conditions: 500 mL 50 mM Phosphate
buffer pH 6.8 - 37.degree. C. -50 rpm baskets (USP app. I)) of the
tablet according to Example 3 is shown in FIG. 3.
Example 4
Release Profiles
[0114] For the dosage forms according to example 1 and example 2,
release profiles were measured. The release profile was determined
by dissolving a solid administration form of the pharmaceutical
composition of the present invention in a USP apparatus I (basket
apparatus) in 500 ml of a USP buffer (phosphate buffer) and pH 6.8,
37.degree. C. and a stirrer speed of 50 rpm and measuring the
amount of dissolved active substance at the stated times. The
content of active substance released was determined by means of
HPLC. An active substance release according to the following table
was found:
TABLE-US-00005 Time (h) Release (%) 1 1-35 2 5-50 6 10-80 16
20-100
Example 5a
Ivabradine Adipate
##STR00002##
[0116] A solution of 0.095 g (0.649 mmol, 1.0 eq) adipic acid in
1.5 ml ethanol was added to a solution of 0.304 g (0.649 mmol)
ivabradine freebase in 2 ml dichloromethane at room temperature.
After 16 h the solvent was evaporated in vacuo and the residue was
triturated with 4 ml dry diethyl ether. The solid was filtered and
washed with 2 ml dry diethyl ether, dried at 40.degree. C. under
vacuum for 4 h to give 0.336 g (84%, 0.546 mmol) of ivabradine
adipate as white solid.
[0117] IR: 2999.8, 2943.9, 2913, 2861.4, 2833.4, 1697.3, 1643.4,
1518.3, 1486.7, 1466.7, 1370.9, 1306.7, 1245.1, 1224.5, 1210.7,
1105.4, 1060.8, 862.8, 828, 771.2, 638.2, 499.4, 458.
[0118] DSC: 115.6.degree. C. (-121.40 J/g). M. P.: 113-117.degree.
C.
[0119] HPLC: 98.55%
[0120] The XRD pattern of ivabradine adipate is shown in FIG.
1.
Example 5b
Ivabradine Adipate
[0121] A solution of 0.064 g (0.437 mmol, 1.0 eq) adipic acid in
1.5 ml water was added to a solution of 0.205 g (0.437 mmol)
ivabradine freebase in 2 ml ethanol. After stirring at room
temperature for 2 h the solvent was evaporated in vacuo and the
residue was triturated with 6 ml dry diethyl ether, followed by
stirring for 30 min. The solid was filtered, washed with 2 ml dry
diethyl ether, and dried at 45.degree. C. under vacuum for 4 h to
give 0.237 g (88%, 0.385 mmol) of ivabradine adipate as white
solid.
[0122] IR: 2999.1, 2944, 2913, 2862.2, 2833.6, 1704, 1644.6,
1518.5, 1486.7, 1466.7, 1371.1, 1306.2, 1245.7, 1224.3, 1210.7,
1105.7, 1060.8, 862.7, 828.3, 771.2, 638.2, 500.1, 458.
[0123] DSC shows a sharp endothermic peak at 113.2.degree. C.
confirming the crystalline nature of the salt.
Example 6
Ivabradine-(S)-Mandelate
[0124] A solution of 0.032 g (0.213 mmol, 1.0 eq) (S)-(+)-mandelic
acid in 0.5 ml acetonitrile was added to 0.100 g (0.213 mmol, 1.0
eq) ivabradine freebase in 0.5 ml dichloromethane at room
temperature. Reaction was stirred at room temperature for 2 h and
subsequently evaporated to dryness. The residue was triturated with
4 ml dry diethyl ether and then with 4 ml n-hexane, solvent was
decanted out and the solid was dried at 40.degree. C. for 2 h to
give 0.106 g (80%, 0.171 mmol) of ivabradine-(s)-mandelate.
[0125] DSC and XRD show amorphous nature of the salt.
Example 7
Ivabradine-1-Hydroxy-2-Naphthanoate
[0126] A solution of 0.044 g (0.235 mmol, 1.0 eq)
1-hydroxy-2-naphthoic acid in 0.7 ml ethanol was added to a
solution of 0.110 g (0.235 mmol) ivabradine freebase in 0.5 ml
dichloromethane at room temperature. After 1 h, the solvent was
evaporated in vacuo to give a foamy residue which was triturated
with 4 ml dry diethyl ether. The supernatant solvent was decanted
out. Trituration was repeated with dry diethyl ether, the
supernatant solution was decanted out and the solid was dried at
40.degree. C. under vacuum for 2.5 h to give 0.138 g (90%, 0.210
mmol) of light brown solid. DSC and XRD confirm the amorphous
nature of the salt.
Example 8
Ivabradine-L-Aspartate
[0127] A solution of 0.030 g (0.224 mmol, 1.0 eq) L-Aspartic acid
was prepared in 2 ml water by refluxing. A solution of 0.105 g
(0.224 mmol, 1.0 eq) ivabradine freebase in 1 ml acetonitrile was
added at reflux temperature and refluxed for 15 min. Reaction
mixture was stirred at room temperature for overnight. The solvents
were evaporated in vacuo and the residue was triturated with 4 ml
dry diethyl ether. Solid obtained was dried at 40.degree. C. under
vacuum for 2 h to give 0.116 g (86%, 0.193 mmol) of the salt.
[0128] DSC and IR confirm amorphous nature of the salt.
Example 9
Ivabradine-D-Aspartate
[0129] A solution of 0.029 g (0.218 mmol, 1.0 eq) D-Aspartic acid
was prepared in 1.5 ml water by refluxing. A solution of 0.102 g
(0.218 mmol, 1.0 eq) ivabradine freebase in 1 ml acetonitrile was
added at reflux temperature and refluxed for 15 min. Reaction
mixture was stirred at room temperature for overnight. The solvents
were evaporated in vacuo and the residue was triturated with 4 ml
dry diethyl ether followed by 4-5 ml n-hexane and solvents decanted
out. Trituration was repeated once again and solvent decanted out.
The solid was dried at 40.degree. C. under vacuum for 2 h to give
0.100 g (76%, 0.166 mmol) of the salt.
[0130] DSC showed the amorphous nature of the salt.
Example 10
Ivabradine Ethanesulphonate
[0131] To a solution of 0.102 g ivabradine freebase (0.218 mmol,
1.0 eq) in 0.5 ml dichloromethane, 0.018 g (0.218 mmol, 1.0 eq)
ethane sulphonic acid was added at room temperature and the mixture
was stirred for overnight. The reaction mixture was evaporated to
dryness and triturated with 2 ml dry diethyl ether, followed by 2
ml n-hexane. The resulting foamy solid was evaporated to dryness at
40.degree. C. under vacuum for 2h to give 0.101 g (80%, 0.174 mmol)
of white solid. DSC and XRD confirm the amorphous nature of the
salt.
Example 11
Ivabradine-L-Malate
[0132] A solution of 0.086 g (0.64 mmol) L-malic acid in 1.5 ml
acetonitrile was added to a solution of 0.3 g (0.64 mmol)
ivabradine freebase in 1 ml acetonitrile at room temperature and
was stirred for overnight. The solution was evaporated to dryness
and the residue was triturated with 4 ml dry diethyl ether,
followed by trituration with 4 ml n-hexane. The solvent was
evaporated and the solid was dried at 40.degree. C. under vacuum
for 2 h to yield 0.302 g of solid.
[0133] HPLC =98%
[0134] DSC and XRD confirm the amorphous nature of the salt.
Example 12a
Ivabradine Oxalate I
[0135] To the solution of 100 mg ivabradine (0.213 mmol, 1.0 eq) in
0.5 ml acetone was added a solution of 19 mg oxalic acid (0.213
mmol, 1.0 eq) in 0.5 ml acetone. Within minutes a solid separated
and additional 2 ml acetone were added to enable stirring.
[0136] The solid was isolated by filtration and washed with
2.times.2 ml acetone. It was dried for 3 h at 45.degree. C. to give
96 mg (81%, 0.172 mmol) of ivabradine oxalate.
[0137] IR : 2937.8, 2834.8, 1714.5, 1642.3, 1519.2, 1485.8, 1467.0,
1322.2, 1304.9, 1280.3, 1248.0, 1210.9, 1185.3, 1110.9, 1070.7,
1030.8, 832.4, 699.4, 472.2
[0138] MP : 102.3-115.6.degree. C. (Not sharp, melted over a
range)
[0139] DSC : 109.3.degree. C. (-65.2 J/g), 152.3.degree. C. (-0.5
J/g), 158.6.degree. C. (-4.5 J/g)
[0140] Ivabradine oxalate I is characterized by an XRD pattern
having peaks at 16.7.+-.0.2, 17.7.+-.0.2, 19.0.+-.0.2, 20.9.+-.0.2,
23.0.+-.0.2, 24.4.+-.0.2 and 27.5.+-.0.2 degrees 2-theta.
Example 12b
Ivabradine Oxalate II
[0141] To the solution of 320 mg ivabradine (0.683 mmol, 1.0 eq) in
4 ml DCM was added a solution of 61.5 mg oxalic acid (0.683 mmol,
1.0 eq) in 1 ml ethanol and the mixture was stirred at room
temperature for 2 h. The solvent was evaporated in vacuo to give a
solid which was dried for 4 h at 40.degree. C., yielding 340 mg
(89%, 0.609 mmol) of ivabradine oxalate.
[0142] IR : 2943.5, 2914.5, 1730.3, 1651.7, 1521, 1484.4, 1466.0,
1304.6, 1248, 1221.8, 1210.1, 1105, 1074.5, 706.5, 486.4
[0143] DSC : 145.4.degree. C. (-53.0 J/g) HPLC : 95.4%
[0144] Ivabradine oxalate II is characterized by an XRD pattern
having peaks at 13.5 .+-.0.2, 17.3 .+-.0.2, 21.1 .+-.0.2, 23.3
.+-.0.2, 25.6 .+-.0.2 and 27.3 .+-.0.2 degrees 2-theta.
[0145] Example 12c: Ivabradine oxalate III
[0146] To the solution of 225 mg ivabradine (0.480 mmol, 1.0 eq) in
2 ml acetone was added a solution of 43 mg oxalic acid (0.480 mmol,
1.0 eq) in 1 ml acetone at room temperature. Within minutes a solid
separated. After addition of 3 ml more acetone the mixture was
stirred at room temperature for 1 h. The solid was then isolated by
filtration and washed with 4 ml acetone. It was dried at first for
4 h at 40 .degree. C. and then at 60 .degree. C. for 8 h to give
213 mg (79%, 0.381 mmol) of ivabradine oxalate.
[0147] IR : 2943.6, 2834.3, 1718.9, 1643.5, 1519.8, 1485.4, 1464.7,
1304.5, 1248.0, 1221.9, 1210.0, 1183.8, 1107.0, 1071.2, 862.9,
832.4, 700.6, 178.8
[0148] DSC : 101.3.degree. C. (-38.2 J/g)
[0149] HPLC : 96.3%
[0150] Ivabradine oxalate III is characterized by an XRD pattern
having peaks at 16.9.+-.0.2, 17.5.+-.0.2, 20.9.+-.0.2, 23.1.+-.0.2,
and 32.3.+-.0.2 degrees 2-theta.
Example 13
[0151] The stability of ivabradine adipate in comparison to
ivabradine hydrochloride form I was investigated at different
temperatures and humidities in open or closed containers for
different storage times. The results are summarized in the
following table.
TABLE-US-00006 TABLE Stabilty of Ivabradine adipate versus
Ivabradine HCl, form I Temp./humidity, Container, days HCl Form I
Adipate 25.degree. C./60% closed, 33 d unchanged 25.degree. C./60%
closed, 57 d unchanged 25.degree. C./60% open, 33 d .beta. +
unident. cryst. phase 25.degree. C./60% open, 57 d unchanged
30.degree. C./65% closed, 33 d unchanged 30.degree. C./65% closed,
57 d unchanged 30.degree. C./65% open, 33 d .beta. 30.degree.
C./65% open, 57 d unchanged 40.degree. C./75% closed, 33 d
unchanged 40.degree. C./75% closed, 57 d unchanged 40.degree.
C./75% open, 33 d .beta. 40.degree. C./75% open, 57 d unchanged
[0152] Ivabradine adipate according to the present invention is
stable at various conditions. The Ivabradine HCl form I undergoes
phase transition into Ivabradine HCl, form beta, in particular in
open containers.
* * * * *