U.S. patent application number 13/704521 was filed with the patent office on 2013-04-04 for ivabradine-containing pharmaceutical composition.
This patent application is currently assigned to ratiopharm GmbH. The applicant listed for this patent is Jens Geier, Dominique Meergans, Katrin Rimkus. Invention is credited to Jens Geier, Dominique Meergans, Katrin Rimkus.
Application Number | 20130084335 13/704521 |
Document ID | / |
Family ID | 44524908 |
Filed Date | 2013-04-04 |
United States Patent
Application |
20130084335 |
Kind Code |
A1 |
Meergans; Dominique ; et
al. |
April 4, 2013 |
IVABRADINE-CONTAINING PHARMACEUTICAL COMPOSITION
Abstract
The present invention relates to a pharmaceutical composition
containing ivabradine or a pharmaceutically acceptable salt
thereof. The invention further relates to a method for the
preparation of such a composition.
Inventors: |
Meergans; Dominique;
(Munich, DE) ; Rimkus; Katrin; (Munich, DE)
; Geier; Jens; (Oberdischingen, DE) |
|
Applicant: |
Name |
City |
State |
Country |
Type |
Meergans; Dominique
Rimkus; Katrin
Geier; Jens |
Munich
Munich
Oberdischingen |
|
DE
DE
DE |
|
|
Assignee: |
ratiopharm GmbH
Ulm
DE
|
Family ID: |
44524908 |
Appl. No.: |
13/704521 |
Filed: |
June 14, 2011 |
PCT Filed: |
June 14, 2011 |
PCT NO: |
PCT/EP2011/059865 |
371 Date: |
December 14, 2012 |
Current U.S.
Class: |
424/474 ;
424/400; 428/402; 514/212.07 |
Current CPC
Class: |
A61K 47/32 20130101;
A61K 9/2054 20130101; A61K 9/2031 20130101; Y10T 428/2982 20150115;
A61K 31/55 20130101; A61K 9/1652 20130101; A61K 9/146 20130101;
A61K 9/2846 20130101; C07D 223/16 20130101; A61K 9/0002 20130101;
A61K 9/2095 20130101; A61K 9/14 20130101; A61K 9/2027 20130101;
A61K 47/38 20130101; A61K 47/10 20130101; A61K 47/36 20130101; C07C
55/14 20130101; A61K 9/20 20130101 |
Class at
Publication: |
424/474 ;
424/400; 514/212.07; 428/402 |
International
Class: |
A61K 9/14 20060101
A61K009/14 |
Foreign Application Data
Date |
Code |
Application Number |
Jun 14, 2010 |
EP |
10 165 881.3 |
Jun 14, 2010 |
EP |
10 165 884.7 |
Jun 23, 2010 |
IN |
1760/CHE/2010 |
Claims
1. A pharmaceutical composition containing ivabradine adipate as
active substance, wherein at least 95% by weight of the active
substance based on the total weight of the active substance has an
average particle size in the range of 0.5 mm to 250 mm.
2. The pharmaceutical composition according to claim 1 wherein at
least 95% by weight of the active substance based on the total
weight of the active substance has an average particle size in the
range of 1 mm to 150 mm.
3. The pharmaceutical composition according to claim 1, wherein the
composition additionally contains at least one adhesion
enhancer.
4. The pharmaceutical composition according to claim 3, wherein the
adhesion enhancer is selected from the group consisting of
polymers, fats, waxes, and non-polymeric compounds having at least
one polar side group.
5. The pharmaceutical composition according to claim 4, wherein the
polymer is selected from the group consisting of polysaccharides,
microcrystalline cellulose, guar gum, alginic acid, alginates,
polyvinylpyrrolidone, polyvinylacetates, polyvinyl alcohols,
polymers of the acrylic acid and its salts, polyacrylamides,
polymethacrylates, vinylpyrrolidone vinylacetate copolymers,
polyalkylene glycols, co-block polymers of polyethylene glycol, and
mixtures comprising two or more of the afore-mentioned
polymers.
6. The pharmaceutical composition according to claim 5, wherein the
polymer is selected from the group consisting of
polyvinylpyrrolidone, copolymers of vinylpyrrolidone and
vinylacetate, polyethylene glycols, hydroxypropylmethylcellulose,
microcrystalline cellulose and mixtures comprising two or more of
the afore-mentioned polymers.
7. The pharmaceutical composition according to claim 4, wherein the
non-polymeric compounds having at least one polar side group are
selected from the group consisting of sugar alcohols and
disaccharides.
8. The pharmaceutical composition according to claim 7, wherein the
sugar alcohol or disaccharide is selected from the group consisting
of lactose, mannitol, sorbitol, xylitol, isomalt, glucose,
fructose, maltose and mixtures comprising two or more of the
afore-mentioned sugar alcohols and disaccharides.
9. The pharmaceutical composition according to claim 3, wherein the
weight ratio of ivabradine adipate based on the free base to
adhesion enhancer is in the range of 10:1 to 1:100.
10. The pharmaceutical composition according to claim 3, wherein
the adhesion enhancer has a volume average particle size D50 of
<500 mm.
11. The pharmaceutical composition according to claim 1, wherein
the composition is obtained by a direct compression method in the
absence of a solvent.
12. The pharmaceutical composition according to claim 1, wherein
the composition is in the form of an optionally film-coated
tablet.
13. A method for the preparation of a pharmaceutical composition
according to claim 1, said method comprising the steps of: a)
obtaining ivabradine adipate as active substance wherein at least
95% by weight of the active substance based on the total weight of
the active substance has an average particle size in the range of
0.5 mm to 250 mm; and b) mixing the active substance with one or
more pharmaceutically acceptable excipients.
14. The method according to claim 13, further comprising the
additional step of mixing the active substance and excipients with
an adhesion enhancer.
15. The method according to claim 13, further comprising the
additional step of directly compressing the mixture that results
from step (b) in the absence of a solvent.
16. The pharmaceutical composition according to claim 5, wherein
the polymer is a polysaccharides selected from the group consisting
of hydroxypropylmethylcellulose, carboxymethylcellulose,
ethylcellulose, methylcellulose, hydroxyethylcellulose,
ethylhydroxyethylcellulose, and hydroxypropylcellulose.
17. The pharmaceutical composition according to claim 5, wherein
the polymer is a polyalkylene glycol selected from the group
consisting of poly(propylene glycol) and polyethylene glycol.
18. The pharmaceutical composition according to claim 5, wherein
the polymer is a co-block polymer of the polyethylene glycol and
poly(propylene glycol).
19. The pharmaceutical composition according to claim 9, wherein
the weight ratio of ivabradine adipate based on the free base to
adhesion enhancer is in the range of 1:5 to 1:35.
20. The pharmaceutical composition according to claim 10, wherein
the adhesion enhancer has a volume average particle size D50 in the
range of 5 mm to 200 mm.
Description
[0001] The present invention relates to a pharmaceutical
composition containing ivabradine or a pharmaceutically acceptable
salt thereof. Further, the invention relates to a method for the
preparation of such a composition.
[0002] Ivabradine has the chemical designation
(S)-3-{3-[(3,4-dimethoxybicyclo[4.2.0]octa-1,3,5-triene-7-ylmethyl)methyl-
amino]propyl}-7,8-dimethoxy-2,3,4,5-tetrahydro-1H-3-benzazepine-2-one.
Ivabradine has the following structural formula (I):
##STR00001##
[0003] 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.
[0004] Ivabradine is an active substance reported to have a
bradycardiceffect for the treatment of stable angina pectoris, in
particular in patients for whom beta-blockers are contraindicated
or an 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 sino-atrial node and thus regulates
the heart rate. Under physiological conditions, ivabradine, the
S-enantiomer of a racemate, is reported to have a very good
solubility (>10 mg/ml).
[0005] 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), which is prepared by wet granulation, 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.
[0006] Moreover, various polymorphic forms of the ivabradine
hydrochloride are reported to be described in the state of the art.
WO 2005/110993 A1 apparently discloses polymorph alpha, WO
2006/092493 A1 apparently discloses polymorph beta, WO 2006/092491
A1 apparently discloses polymorph beta d (dehydrated). In addition,
polymorph gamma, polymorph gamma d, polymorph delta, and polymorph
delta d are reported to be known in the art. In addition,
WO2008/065681 apparently reports the so-called Form I of Ivabradine
HCl. WO 2008/146308 A2 apparently discloses amorphous
ivabradine.
[0007] Also various salts of ivabradine are apparently known in the
art. WO 2008/146308 A2 apparently discloses ivabradine oxalate, WO
2009/124940 A1 discloses ivabradine hydrobromide.
[0008] The problem with the salts and polymorphs of the ivabradine,
in particular the polymorphs of the hydrochloride, is that these
salt forms are not sufficiently stable under all conditions. This,
in turn can lead to problems in the processing as well as the
storage and to undesired reactions with the excipients employed in
the preparation of the pharmaceutical composition.
[0009] Thus, it is an object of the present invention to provide a
pharmaceutical composition in the preparation and later storage of
which the employed polymorphic form of the active substance is
stable.
[0010] A further problem with the ivabradine-containing
pharmaceutical compositions is that the amount of active substance
in the formulation to be administered is usually only small. This
leads to problems in the preparation of the corresponding
compositions due to possible variations in content that are for
example conditional on separation tendencies of the active
substances and excipients. Therefore, it is important that at first
active substances and excipients can be mixed as homogenous as
possible and corresponding mixtures do not separate again during
further processing to the final formulation. An inhomogeneous
distribution of the active substance can result in undesired side
effects up to symptoms of poisoning. Also the bioavailability as
well as the effectiveness of corresponding formulations may be
affected adversely in an inhomogeneous distribution of the active
substance.
[0011] It has been shown that neither problems regarding the
stability of the employed polymorphic form of the active substance
nor problems regarding the homogeneous distribution of the active
substance in the final formulation can be solved by simply mixing
and compressing the constituents.
[0012] Thus, a further object of the present invention is to
provide a pharmaceutical composition that ensures a distribution of
the active substance in the final formulation that is as
homogeneous as possible. At the same time, the employed polymorphic
form should remain stable both in the preparation of the
composition and the later storage.
[0013] Now, it has surprisingly been found that the above-mentioned
problems can be solved in that at least 95% by weight of the active
substance in the pharmaceutical composition have an average
particle size in the range of 0.5 .mu.m to 250 .mu.m.
[0014] Thus, the present invention relates to a pharmaceutical
composition containing ivabradine as active substance or a
pharmaceutically acceptable salt thereof wherein at least 95% by
weight of the active substance based on the total weight of the
active substance have an average particle size in the range of 0.5
.mu.m to 250 .mu.m.
[0015] Presently, by "active substance" ivabradine in the form of
the free base or a pharmaceutically acceptable salt thereof is
meant. A suitable pharmaceutically acceptable salt is for example
the hydrochloride, the hydrobromide, the oxalate, the sulfate, the
phosphate, the acetate, the propionate, however also salts of the
ivabradine with propionic acid, maleic acid, fumaric acid, tartaric
acid, nitric acid, benzoic acid, methanesulfonic acid, isethionic
acid, benzenesulfonic acid, citric acid, toluenesulfonic acid,
trifluoroacetic acid, and camphoric acid and also the lactate,
pyruvate, malonate, succinate, glutarate, and ascorbate of the
ivabradine. Further, the following salts can be employed:
L-aspartate, glutamate, sorbate, acinotate, gluconate, hippurate,
and salts of the ivabradine with ethanesulfonic acid, mandelic
acid, adipic acid, or sulfamic acid. The salts of the ivabradine
can be obtained in accordance to methods reported to be known in
the art by reacting the free base of the ivabradine with the
corresponding acid or by the presence of the corresponding acid in
the synthesis of the ivabradine, as reported to be described for
example in US 2005/0228177 A1. Preferred are ivabradine
hydrochloride, hydrobromide, and oxalate, particularly preferred is
ivabradine adipate.
[0016] In particular, if ivabradine is used as adipate salt, the
pharmaceutical composition according to the present invention is
stable under usual storage conditions.
[0017] The active substance can be present in the pharmaceutical
composition of the present invention both in the crystalline and
amorphous form. The active substance includes all polymorphic forms
of ivabradine or a pharmaceutically acceptable salt thereof,
including hydrates and solvates. Preferably, the active substance
is present in the crystalline form.
[0018] 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.
[0019] 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.
[0020] 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 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.
[0021] It has been shown that the uniformity of the content of
active substance of ivabradine-containing pharmaceutical
compositions can be ensured when the average particle size of the
active substance is in the range of 0.5 .mu.m to 250 .mu.m. This
way, the separation tendency in the preparation of the composition
is reduced so that the variations in content in the finished
composition can be prevented. Moreover, it has surprisingly shown
that the pharmaceutical composition can be prepared by simple
mixing and compressing with correspondingly small active substance
particles without leading to a change of otherwise instable
polymorphic forms of the active substance. This way it is possible
to obtain the pharmaceutical composition according to the invention
without the necessity of an otherwise usual and for the commercial
ivabradine-containing drug Procoralan.RTM. used wet granulation by
a simple dry processing of the constituents. So, the employment of
special machines necessary for the wet granulation can be avoided.
Moreover, the employment of solvents for the preparation of the wet
mass can be avoided. It is also not necessary to expose the active
substance for a longer period to the granulation liquid until the
completion of the drying. In addition, the drying step following
the wet granulation requires additional energy and the active
substance is exposed to thermal influences over a longer period. In
contrast, using the active substance with a particle size in the
range of 0.5 .mu.m to 250 .mu.m permits the preparation of the
pharmaceutical composition according to the invention by direct
compressing or dry compaction in the absence of solvents so that
the above-mentioned problems in the preparation of conventional
ivabradine-containing formulations are overcome. The preparation of
the pharmaceutical composition according to the invention by direct
compressing is particularly preferred.
[0022] The pharmaceutical composition according to the invention
contains at least 95% by weight, in particular at least 98% by
weight of the active substance based on the total weight of the
active substance in an average particle size in the range of 0.5
.mu.m to 250 .mu.M, preferably in the range of 0.8 .mu.m to 200
.mu.m, in particular in the range of 1 .mu.m to 150 .mu.m.
[0023] In a further embodiment of the present invention the
pharmaceutical composition contains particles of the active
substance having an average particle size D50 in the range of 1
.mu.m to 70 .mu.m, preferably of 5 .mu.m to 50 .mu.m, most
preferably of 10 .mu.m to 25 .mu.m.
[0024] In a further embodiment of the present invention the
pharmaceutical composition contains particles of the active
substance having an average particle size D90 in the range of 0.5
.mu.m to 250 .mu.m, preferably of 30 .mu.m to 80 .mu.m, most
preferably of 40 .mu.m to 60 .mu.m.
[0025] The term "particle size" according to the present invention
relates to the maximum diameter of the equivalent product assuming
spherical opaque particles showing the same light scattering
pattern and the same diffraction as the active substance particles.
According to the invention the particle size is determined by means
of laser light diffraction. The determination of the size
distribution results from the analysis of the diffraction pattern
that is obtained if particles are exposed to a monochromatic light
beam. The particles refract the light with small particles
refracting the light in a greater angle than large particles. The
refracted light is measured by a number of photo detectors arranged
in different angles. On the other hand, the light spectra of the
small particles have to be recorded by light-sensitive detectors in
greater angles over the laser beam. Large particles result in
greater intensity maxima with small angles, small particles to
weaker intensity maxima with greater angles. Thus, in the laser
light diffraction the pattern resulting from the interaction of the
light with the particles is used for the determination of the
particle size.
[0026] The "particle size distribution" is a statistical frequency
distribution. Here, the particles are divided into classes
according to their size.
[0027] The particle size distribution of the particle size D50
value includes 50% of the particles based on their volume with a
particle size smaller than the D50 value and 50% of the particles
based on their volume with a particle size greater than the D50
value.
[0028] The particle size distribution of the particle size D90
value includes 90% of the particles based on their volume with a
particle size smaller than the D90 value and 90% of the particles
based on their volume with a particle size greater than the D90
value.
[0029] The particle size distribution according to the present
invention can be monomodal or bimodal. In the preferred embodiment
of the invention the particle size distribution of the active
substance is monomodal. The term "monomodal" relates to the peak
resulting in a histogram and/or graph representing the distribution
frequency. Generally, in the graphical representation of a particle
size distribution there are plotted the diameter x on the abscissa
and the measure of a set Q on the ordinate.
[0030] According to the invention the particle size is determined
by means of laser diffractometry. For that, a Mastersizer 2000 by
Malvern Instruments having the corresponding sample dispersing unit
Hydro S is used. The wet measurement (2500 rpm, ultrasound 10-20
min., shading 5 to 20%) takes place in a dispersion of sunflower
oil with the particle spacing in the dispersion being about 3-5
times greater than the particle diameter.
[0031] Here, the average particle size of the active substance is
determined according to the following method: In principle, the
Fraunhofer diffraction theory is used for particle fractions the
particle size of which is significantly greater than the wave
length of the laser light. (ISO 13320)
[0032] Moreover, the Mie theory defines the secondary scattering
caused by the refraction of the light on small particles, as in the
international rules of the laser diffraction measurement. (ISO
13320)
[0033] The determination of the particle size for particles D50
smaller than 5.0 .mu.m is carried out according to the Mie method
and for particles D50 greater than 5.0 .mu.m according to the
Fraunhofer method.
[0034] In a further aspect of the present invention it has been
shown that the separation tendency of ready-made mixtures
containing the active substance and the excipients is reduced in
the further processing by addition of an adhesion enhancer.
Additionally, it has been shown that an adhesion enhancer is
suitable to stabilize the polymorphic form of the employed active
substance in compacted or compressed form. By adding the adhesion
enhancer it usually comes to an enlargement of the interparticle
surfaces at which more easily (e.g. in the compressing operation)
contact points can be formed. Moreover, adhesion enhancers are
wherein they increase the plasticity of the tabletting mixture so
as to form solid tablets during compressing.
[0035] Particularly suitable as adhesion enhancers are polymers,
fats, waxes, non-polymeric compounds having at least one polar side
group. The employed adhesion enhancer should be in the solid form
at room temperature.
[0036] In one embodiment of the present invention the employed
adhesion enhancer is a polymer that has a glass transition
temperature (Tg) of >15.degree. C., preferably 40.degree. C. to
150.degree. C., and in particular 50.degree. C. to 100.degree. C.
Here, the glass transition temperature is that temperature at which
the amorphous or partly crystalline polymer changes from the solid
to the liquid state. Here, a significant change of physical
parameters such as hardness and elasticity occurs. Typically, below
the glass transition temperature a polymer is glassy and hard,
above the glass transition temperature it changes into a
rubber-like to viscous state. The determination of the glass
transition temperature takes place in the context of this invention
by means of differential scanning calorimetry (DSC). For that, for
example a device of Mettler Toledo DSC 1 can be used. It works with
a heating rate of 10.degree. C.
[0037] The polymer used as the adhesion enhancer preferably has a
number average molecular weight of 1,000 g/mol to 500,000 g/mol,
more preferred of 2,000 g/mol to 90,000 g/mol. Additionally, the
polymer used should have a viscosity of 0.1 mPa/s to 8 mPa/s,
preferably of 0.3 mPa/s to 7 mPa/s, and in particular of 0.5 mPa/s
to 4 mPa/s in a 2% by weight solution in water, each measured at
25.degree. C.
[0038] Preferably, there can be employed hydrophilic polymers as
the adhesion enhancers. This refers to polymers having hydrophilic
groups, for example hydroxy, alkoxy, acrylate, methacrylate,
sulfonate, carboxylate, and quarternary ammonium groups.
[0039] According to the invention the polymer used as the adhesion
enhancer can be selected from the group consisting of
polysacharides, such as hydroxypropylmethylcellulose (HPMC),
carboxymethylcellulose (CMC), ethylcellulose, methylcellulose,
hydroxyethyl-cellulose, ethylhydroxyethylcellulose, and
hydroxypropylcellulose (HPC), micro-crystalline cellulose, guar
gum, alginic acid, alginates, polyvinylpyrrolidone,
polyvinylacetates (PVAC), polyvinyl alcohols (PVA), polymers of the
acrylic acid and its salts, polyacrylamides, polymethacrylates,
vinylpyrrolidone vinylacetate copolymers, polyalkylene glycoles,
such as poly(propylene glycol) and polyethylene glycol,
co-blockpolymers of the polyethylene glycol, in particular
co-blockpolymers of polyethylene glycol and poly(propylene glycol)
as well as mixtures of two or more of the mentioned polymers.
[0040] Preferably used as the adhesion enhancers are
polyvinylpyrrolidone, especially having a weight average molecular
weight of 10,000 g/mol to 60,000 g/mol, in particular 12,000 g/mol
to 40,000 g/mol, copolymers from vinylpyrrolidone and vinylacetate,
in particular having a weight average molecular weight of 40,000
g/mol to 70,000 g/mol, polyethylene glycol, in particular having a
weight average molecular weight of 2,000 g/mol to 10,000 g/mol, as
well as HPMC, in particular having a weight average molecular
weight of 20,000 g/mol to 90,000 g/mol and/or a proportion of
methyl groups of 10% to 35% and/or a proportion of hydroxy groups
of 1% to 35%. Further, microcrystalline cellulose can be used, in
particular those having a specific surface area of 0.7 m.sup.2/g to
1.4 m.sup.2/g. The determination of the specific surface area takes
place by means of the gas adsorption method in accordance to
Brunauer, Emmet and Teller.
[0041] Suitable non-polymeric compounds having at least one polar
side group are in particular sugar alcohols and disaccharides,
wherein the term sugar alcohols in this case also comprises
monosaccharides. Examples of suitable sugar alcohols/disaccharides
are lactose, mannitol, sorbitol, xylitol, isomalt, glucose,
fructose, maltose, and mixtures of two or more of these
compounds.
[0042] Alternatively, also waxes such as for example hexadecyl
palmitate or carnauba wax can be used as adhesion enhancers. Also,
fats such as glycerol fatty acid esters (e.g., glycerolpalmitate,
glycerolbehenate, glycerollaurate, and glycerolstearate) or PEG
glycerol fatty acid esters can be used.
[0043] All of the above-mentioned adhesion enhancers can be
employed alone or as a mixture of two or more of the mentioned
compounds.
[0044] It is advantageous if the adhesion enhancer is used in the
particulate form and has a volume average particle size (D50) of
less than 500 .mu.m, preferably 5 .mu.m to 200 .mu.m.
[0045] The weight ratio of the active substance to the adhesion
enhancer in the pharmaceutical composition according to the
invention can be freely selected by the skilled person depending on
the active substance used and the adhesion enhancer as well as the
desired composition. Preferably, the weight ratio of ivabradine
based on the free base to adhesion enhancer is in the range of 10:1
to 1:100, more preferred in the range of 1:1 to 1:75, more
preferred in the range of 1:2 to 1:50, and most preferred in the
range of 1:5 to 1:35.
[0046] For example, the pharmaceutical composition of the present
invention can contain 1-80% by weight, more preferred 2-60% by
weight, in particular 2-40% by weight, and especially 3-5% by
weight ivabradine, based on the free base of the active substance
and the total weight of the composition. Here and in the following,
by total weight of the composition the weight of the composition
without optionally present film coatings is to be understood.
[0047] Additionally, the pharmaceutical composition can contain one
or more further pharmaceutically acceptable excipients, such as
e.g. fillers, glidants, flow regulators, release agents, and
disintegrants. ("Lexikon der Hilfsstoffe fur Pharmazie, Kosmetik
and angrenzende Gebiete", 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, and Pharmaceutical Press,
London).
[0048] Fillers: The pharmaceutical composition can contain one or
more filler(s). In general, a filler is a substance that increases
the bulk volume of the mixture and thus the size of the resulting
pharmaceutical dosage form. Preferred examples of fillers are
lactose and calcium hydrogenphosphate. The filler may be present in
a proportion of 0 to 80% by weight, preferred between 10 and 60% by
weight of the total weight of the composition.
[0049] Glidants: The function of the glidant is to ensure that the
pelletizing and the ejection take place without much friction
between the solids and the walls. Preferably, the glidant is an
alkaline earth metal stearate, e.g. magnesium stearate, or a fatty
acid, such as stearic acid. Typically, the glidant is present in an
amount of 0 to 2% by weight, preferably between 0.5 and 1.5% by
weight of the total weight of the pharmaceutical composition.
[0050] Disintegrants: Usually, by a disintegrant is meant a
substance that is capable of breaking up the tablet into smaller
pieces as soon as it is in contact with a liquid. Preferred
disintegrants are croscarmellose sodium, sodium carboxymethyl
starch, cross-linked polyvinylpyrrolidone (crospovidon), sodium
carboxymethyl glycolate (e.g. explotab) and sodium bicarbonate,
Typically, the disintegrant is present in an amount of 0 to 20% by
weight, preferably between 1 and 15% by weight of the total weight
of the composition.
[0051] Flow regulators: As the flow regulator there can be used
e.g. colloidal silica. Preferably the flow regulator is present in
an amount of 0 to 8% by weight, more preferably in an amount
between 0.1 and 3% by weight of the total weight of the
composition.
[0052] Release agents: The release agent can be e.g. talcum and is
present in an amount between 0 and 5% by weight, preferably in an
amount between 0.5 and 3% by the weight of the composition.
[0053] Normally, the pharmaceutical composition according to the
invention has a uniformity of the active substance content (content
uniformity) of 85% to 115%, preferably 90% to 110%, in particular
95% to 105% of the average content. That is, all dosage forms, for
example tablets, have a content of active substance between 85% and
115%, preferably between 90% and 110%, in particular between 95%
and 105% of the average active substance content. The "content
uniformity" is determined according to Ph. Eur. 6.0, section
2.9.6.
[0054] The pharmaceutical composition of the present invention may
be for example in the form of tablets, granules, or pellets. Here,
the granule or the pellets for example may be present in capsules
or sachets. Preferred are tablets that may have a film coating.
[0055] In a further preferred embodiment the pharmaceutical
composition of the present invention is obtainable by dry
granulation methods or direct compression methods in the absence of
solvents.
[0056] Moreover, the present invention relates to a method for the
preparation of a pharmaceutical composition as described above
wherein the method comprises the steps: [0057] a) obtaining
ivabradine or a pharmaceutically acceptable salt thereof as active
substance wherein at least 95% by weight of the active substance
based on the total weight of the active substance has an average
particle size in the range of 0.5 .mu.m to 250 .mu.m, preferably of
0.8 .mu.m to 200 .mu.m, most preferably of 1 .mu.m to 150 .mu.m;
and [0058] b) mixing the active substance with one or more
pharmaceutically acceptable excipients.
[0059] In the above step a) the active substance is obtained in the
mentioned average particle size. This can be done in that the
active substance is either provided with the desired particle size
or an active substance having a greater particle size is at first
transferred to particles of a smaller particle size, for example by
grinding and/or screening.
[0060] In a preferred embodiment of the method according to the
invention as an additional step there is admixed an adhesion
enhancer. Suitable adhesion enhancers are the above-mentioned
compounds. When an adhesion enhancer is admixed, it is preferred
that at least a part of the adhesion enhancer, preferably the
complete adhesion enhancer, is (pre-)mixed with the active
substance some time, preferably about 5 to about 30 min., more
preferably about 5 to about 10 min., e.g. about 10 min., before
subjecting the mixture and optionally further excipients, to
further process steps, e.g. dry granulation or direct compression,
preferably direct compression. It has been surprisingly found that
premixing the active substance and at least part of the adhesion
enhancer followed by a short time delay advantageously influences
the dissolution profile of the obtained composition, in particular
of tablets.
[0061] Finally, the method according to the invention in a further
preferred embodiment comprises the additional step of dry
granulation or direct compressing in the absence of solvents,
preferably direct compression. Doing so, there may be obtained for
example tablets, which if desired subsequently can be provided with
a film coating.
[0062] Preferably, the pharmaceutical composition according to the
invention is present as a tablet containing ivabradine in an amount
preferably of 1 mg to 20 mg, more preferred 3 mg to 15 mg, in
particular 5 mg to 10 mg, based on ivabradine free base. Thus,
object of the invention are in particular tablets containing 5 mg
or 7.5 mg ivabradine, based on ivabradine free base.
[0063] Preferably, the pharmaceutical composition according to the
invention is administered twice a day.
[0064] 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 (maximum plasma level) based on a twice daily intake of 5
mg of the active substance ivabradine, in the steady state, of
about 5 to 40 ng/ml, preferably 10 to 30 ng/ml.
[0065] 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, 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.
[0066] Attached FIG. 1 shows an XRD pattern of ivabradine
adipate.
[0067] FIGS. 2 and 3 show dissolution profiles of the compositions
of examples 5 and 6, respectively.
[0068] XRD samples were analysed on a Bruker-AXS D8 Advance powder
X-Ray diffractometer. The measurement conditions were as follows:
[0069] Measurement in Bragg-Brentano-Geometry on vertical
goniometer (reflection, theta/theta, 435 mm measurement circle
diameter) [0070] with sample rotation (30 rpm) on 9 position sample
stage [0071] Radiation: Cu K.alpha.1 (1.5406 .ANG.), Tube (Siemens
FLCu2K), power 40 kV/40 mA [0072] Detector: position sensitive
detector VANTEC-1 [0073] 3.degree. capture angle (2theta), [0074]
Anti scatter slit 6.17 mm [0075] Detector slit 10.39 mm [0076]
4.degree. soller slit, [0077] primary beam stop (<2.degree.
2theta) [0078] Monochromator: None [0079] Second .beta. filter: Ni
filter 0.1 mm (0.5%) [0080] Start angle: 2.degree. [0081] End
Angle: 55.degree. [0082] Measurement time: 11 min [0083] Step:
0.016.degree. 2Theta [0084] Software: EVA (Bruker-AXS,
Karlsruhe).
[0085] Now, the present invention is explained in more detail with
respect to the following examples without these should be
interpreted as being restrictive.
EXAMPLE 1
Direct Compression
TABLE-US-00001 [0086] Ivabradine adipate 6.51 mg Avicel PH101 50.00
mg Calcium hydrogenate phosphate 25.00 mg Sodium croscarmelose
14.91 mg Aerosil 2.58 mg Magnesium Stearate 1.00 mg
[0087] Ivabradine adipate together with Avicel PH101 was sieved
through a 355 .mu.m sieve and pre-mixed for 10 minutes in the
tumbling mixer (Turbula T10B). Subsequently, all the other
constituents except for magnesium stearate were added through the
355 .mu.m sieve and stirred for further 30 minutes in the tumbling
mixer. After the addition of magnesium stearate it was stirred
again for 2 minutes in the tumbling mixer. The finished mixture was
compressed on a rotary press (Riva Piccola) with 7 mm round
biconvex punch. The tablets had a hardness of about 50-85 N.
EXAMPLE 2
Direct Compression
TABLE-US-00002 [0088] Ivabradine adipate 6.51 mg Povidon VA 64
10.00 mg Prosolv SMCC 90 64.00 mg Sodium Bicarbonate 14.91 mg
Talcum 1.00 mg Aerosil 2.58 mg Magnesium Stearate 1.00 mg
[0089] Ivabradine adipate together with Povidon VA 64 and Prosolv
SMCC 90 was sieved through a 355 .mu.m sieve and pre-mixed for 10
min, in the tumbling mixer (Turbula T10B).
[0090] Subsequently, all the other constituents except for
magnesium stearate were added through the 355 .mu.m sieve, and
stirred for further 30 min. in the tumbling mixer. After the
addition of magnesium stearate it was stirred again for 2 min. in
the tumbling mixer. The finished mixture was compressed on a rotary
press (Riva Piccola) with 7 mm round biconvex punch. The tablets
had a hardness of about 50-85 N.
EXAMPLE 3
Dry Compacting (Mixture Corresponding to Example 2)
TABLE-US-00003 [0091] Ivabradine adipate 6.51 mg Povidon VA 64
10.00 mg Prosolv SMCC 90 64.00 mg Sodium Bicarbonate 14.91 mg
Talcum 1.00 mg Aerosil 2.58 mg Magnesium Stearate 1.00 mg
[0092] Ivabradine adipate together with Povidon VA 64 and half of
the Prosolv SMCC 90, magnesium stearate, Aerosil and the total
amount of sodium bicarbonate were pre-mixed for 5 min. in the
tumbling mixer (Turbula T10B) and compacted. Subsequently, the
material was broken over a 1000 .mu.m screen-type mill (Comil), the
remaining excipients were added and the composition was mixed for 5
min. in the tumbling mixer. The finished mixture was compressed on
a rotary press (Riva Piccola) with 7 mm round biconvex punch. The
tablets had a hardness of about 50-85 N.
EXAMPLE 4
Direct Compression
TABLE-US-00004 [0093] Ivabradine HCl form I 5.42 mg Avicel PH101
50.00 mg Calcium hydrogen phosphate 26.09 mg Sodium croscarmelose
14.91 mg Aerosil 2.58 mg Magnesium stearate 1.00 mg
[0094] Ivabradine together with Avicel PH101 was pre-mixed for 10
min. in the tumbling mixer (Turbula T10B). Subsequently, all other
constituents except for magnesium stearate were added, and stirred
for further 30 min. in the tumbling mixer. After the addition of
magnesium stearate it was stirred again for 2 min. in the tumbling
mixer. The finished mixture was compressed on a rotary press (Riva
Piccola) with 7 mm round biconvex punch. The tablets had a hardness
of about 50-85 N.
EXAMPLE 5
Direct Compression
TABLE-US-00005 [0095] Ivabradine HCl form I 5.42 mg Povidon VA 64
11.09 mg Prosolv SMCC 90 64.00 mg Sodium bicarbonate 14.91 mg
Talcum 1.00 mg Aerosil 2.58 mg Magnesum stearate 1.00 mg
[0096] Ivabradine together with Povidon VA 64 and Prosolv SMCC 90
was sieved through a 355 .mu.m sieve and pre-mixed for 10 min. in
the tumbling mixer (Turbula T10B). Subsequently, all other
constituents except for magnesium stearate were added through the
355 .mu.m sieve and stirred for further 30 min. in the tumbling
mixer. After the addition of magnesium stearate it was stirred
again for 2 min. in the tumbling mixer. The finished mixture was
compressed on a rotary press (Riva Piccola) with 7 mm round
biconvex punch. The tablets had a hardness of about 50-85 N.
[0097] The dissolution profile (conditions: 500 mL 0.1 nHCl pH 1.2,
37.degree. C., 50 rpm baskets (USP app. l)) of the tablets of
Example 5 is shown in FIG. 2.
EXAMPLE 6
Dry Compacting (Mixture According to Example 5)
TABLE-US-00006 [0098] Ivabradine HCl form I 5.42 mg Povidon VA 64
10.00 mg Prosolv SMCC 90 64.00 mg Sodium bicarbonate 15.00 mg
Talcum 1.00 mg Aerosil 2.58 mg Magnesum stearate 1.00 mg
[0099] Ivabradine and Povidon VA 64 together with half of the
Prosolv SMCC 90, magnesium stearate, Aerosil and the total amount
of sodium bicarbonate were pre-mixed for 5 min. in the tumbling
mixer (Turbula T10B) and compacted. Subsequently, the material was
broken over a 1000 .mu.m screen-type mill (Comil), the remaining
excipients were added, followed by mixing for 5 min. in the
tumbling mixer (Turbula T10B). The finished mixture was compressed
on a rotary press (Riva Piccola) with 7 mm round biconvex punch.
The tablets had a hardness of about 50-85 N.
[0100] The dissolution profile (conditions: 500 mL 0.1 nHCl pH 1.2,
37.degree. C., 50 rpm baskets (USP app. I)) of the tablets of
Example 6 is shown in FIG. 3.
[0101] As can be seen in comparison to Example 5 (direct
compression), the direct compression of the same amount of active
agents provide an improved dissolution profile compared to the
dissolution profile of tablets obtained by compacting.
[0102] The pre-mixing of the active agent with the adhesion
enhancer for 10 min. prior to further processing of the mixture
provides an advantageous effect on the dissolution profile.
EXAMPLE 7
Stability of Ivabradine Adipate Vs. Ivabradine HCl
[0103] 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-00007 TABLE Stabilty of Ivabradine adipate versus
Ivabradine HCl, form I Temp./humidity, HCl Container, days Form I
Adipate 25.degree. C./60% unchanged closed, 33 d 25.degree. C./60%
unchanged closed, 57 d 25.degree. C./60% .beta. + open, 33 d
unident. cryst. phase 25.degree. C./60% unchanged open, 57 d
30.degree. C./65% unchanged closed, 33 d 30.degree. C./65%
unchanged closed, 57 d 30.degree. C./65% .beta. open, 33 d
30.degree. C./65% unchanged open, 57 d 40.degree. C./75% unchanged
closed, 33 d 40.degree. C./75% unchanged closed, 57 d 40.degree.
C./75% .beta. open, 33 d 40.degree. C./75% unchanged open, 57 d
Particle size D50 in .mu.m 19.10 18.35 Particle size D90 in .mu.m
44.11 52.71
[0104] 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, or form d, in
particular in open containers.
* * * * *