Note: Descriptions are shown in the official language in which they were submitted.
CA 02617280 2008-01-30
WO 2007/017219 PCT/EP2006/007783
- 1 -
PHARMACEUTICAL FORM WITH SUSTAINED pH-INDEPENDENT
ACTIVE INGREDIENT RELEASE FOR ACTIVE INGREDIENTS HAVING
STRONG pH-DEPENDENT SOLUBILITY
Technical field
The invention relates to a solid pharmaceutical
formulation for a sustained pH-independent active
ingredient release comprising at least one layer of one
or more water-insoluble polymers, at least one layer of
one or more pH-dependent water-soluble polymers and an
active ingredient-containing core, where the core
comprises an active ingredient having strong
pH-dependent water solubility and at least one
osmotically active ingredient.
Active ingredients having strong pH-dependent water
solubility are for example substances which have very
poor solubility at basic pH values, normally having a
solubility in water of less than 0.1 mg/ml, whereas the
solubility at acidic pH values (pH < 4) extends up to
values of 1 mg/ml or higher.
Generally pH-dependent water-soluble active ingredients
can also be defined as substances having a difference
of at least 10-fold in the water solubility at acidic
and basic pH values.
One example of an active ingredient having strong
pH-dependent solubility in water is (2R)-1-((4-chloro-
2-(ureido)phenoxy)methyl)carbonyl-2-methyl-4-(4-fluoro-
benzyl)piperazine or a salt thereof.
(2R) -1- ( (4-chloro-2- (ureido)phenoxy)methyl)carbonyl-2-
methyl-4-(4-fluorobenzyl)piperazine is called
piperazineurea hereinafter and has the following
structure:
CA 02617280 2008-01-30
WO 2007/017219 PCT/EP2006/007783
2 -
GHa
F
N
1 II
. ~~~~ 1~.: ~=.,~~=~:
Cl" NH
ii=II~.NN
pz
(2R)-1-((4-chloro-2-(ureido)phenoxy)methyl)carbonyl-2-
mathvl -a- /a-flõu~v"'~v~i-.u iic.yc~"".,'t/~1 ~_...-1r1CLd"G--- --=
l... ~. 1i1C and its SaltS are
prepared by the method described in Example 2 in
WO 98/56771.
Salts thereof are, for example, the hydrochloride,
dihydrogen phosphate, hydrogen sulphate, sulphate,
mesylate, ethylsulphonate, malate, fumarate and
tartrate.
The following invention further relates to a matrix
pellet for a sustained pH-independent active ingredient
release comprising at least one layer of one or more
water-insoluble polymers in which the pore-forming
substances are present and are dissolved out after
contact with the aqueous medium and thus form a
microporous membrane, and comprising at least one layer
of one or more pH-dependently water-soluble polymers,
and an active ingredient-containing core, where the
core comprises piperazineurea and at least one water-
soluble ionic substance from the group of magnesium
chloride, magnesium sulphate, lithium chloride, sodium
chloride, potassium chloride, lithium sulphate, sodium
sulphate, potassium sulphate, lithium phosphate, sodium
phosphate, potassium phosphate, ammonium chloride,
ammonium sulphate, ammonium phosphate as osmager.t.
Further solid pharmaceutical formulations within the
meaning of the invention are single-unit systems such
as, for example, tablets and multiparticulate systems.
Multiparticulate systems may be for example granular
particles, pellets or mini tablets. These may be packed
CA 02617280 2008-01-30
WO 2007/017219 PCT/EP2006/007783
- 3 -
into hard or soft gelatin capsules, and compressed to
tablets. The original forrri-ulation usually disintegrates
into many subunits in the stomach. The minidepots then
gradually pass from the stomach into the intestine. The
minidepots are moreover normally able to pass through
the pylorus when the sphincter is closed.
Sustained release formulations are medicaments which
can be administered orally anu have a longer-lasting
effect of the medicament. In these cases, the active
pharmaceutical ingredient is released slowly.
Prior art
Various pharmaceutical formulations for controlled
active ingredient release are present in the
literature.
An elementary osmotic pump (EOP) for example, are
tablets which consist of an osmotically active tablet
core which is coated with a semipermeable membrane
which comprises a release orifice.
The tablet core may comprise an osmotically active
medicinal substance or, in the case of a medicinal
substance of low osmotic activity, osmotically active
additives, also generally defined as osmagents. Water
flowing through the semipermeable membrane (SPM) into
the pharmaceutical form generates a hydrostatic
pressure which forces the dissolved medicinal substance
through the release aperture.
The object of an EOP is controlled active ingredient
release, achieving 0 order release kinetics. Thus, the
amount of medicinal substance released from the
pharmaceutical form per unit time remains the same.
A precondition for an EOP is a moderately water-soluble
active ingredient.
CA 02617280 2008-01-30
WO 2007/017219 PCT/EP2006/007783
- 4 -
Push and pull osmotic pumps (PPOPs) have been
established also to allow controlled release of
slightly soluble medicinal substances.
These comprise multichamber tablet systems whose core
comprises an osmotic active ingredient compartment and
a swellable osmotically active polymer, with the two
compartments being separated by an elastic diaphragm.
The entire tablet core is in turn enveloped by an SPM
which comprises a release orifice on the active
ingredient containing side.
Water penetrates into both compartments, whereupon the
polymer swells and thus forces the diaphragm into the
active ingredient compartment. The active ingredient is
then delivered through the release aperture. The aim in
this case too is to create plasma levels which remain
the same owing to the 0 order active ingredient
release.
Hence, systems which operate osmotically, such as the
elementary osmotic pump (EOP) and push and pull osmotic
pumps (PPOP) release at least moderately water-soluble
active ingredients from tablets which consist of a
semipermeable membrane around an osmotically active
core which comprises at least one substance having an
osmotic effect (osmagent) and, in the case of the PPOP,
an expanding polymer push compartment.
Since semipermeable membranes are permeable only by the
medium but not by the active ingredient, the active
constituent is released through at least one orifice in
the semipermeable membrane.
The essential aim of osmotic pi?mps as known in the
state of the art is 0 order active ingredient release.
In contrast to EOP and PPOP, pharmaceutical forms
CA 02617280 2008-01-30
WO 2007/017219 PCT/EP2006/007783
- 5 -
without semipermeable membranes have also been
described, for example: Controlled Porosity Osmotic
Pumps (CPOP).
CPOPs were also developed in order to replace the
elaborate manufacture of the above-described systems in
which release orifices must be bored by drilling
machines or lasers.
These CPOP formulations have a water-insoluble polymer
membrane into which water-soluble ingredients are
incorporated and, after contact with the aqueous
medium, are dissolved out and thus form a microporous
membrane which is now permeable by medium and active
ingredient.
In these systems, in detail the osmotic tablet core is
enveloped by an insoluble polymer membrane into which
water-soluble substances have been incorporated. After
the pharmaceutical form is introduced into the medium,
these water-soluble substances are dissolved out.
This results in pores through which the active
ingredient release takes place. These systems also
comprise tablets which show controlled release.
In these cases, the active ingredient release depends
in particular on the water-solubility of the medicinal
substance and thus shows a pH-dependent release for
pH-dependently soluble active ingredients.
Delayed release pellet formulations have been described
for ~vsiTiageiit-CoiLtaiiiiiig iTiatrix peiiet cores whiCh have
been coated with a semipermeable membrane. This
membrane is stretched owing to the swelling of the
core, resultinq after a laq time in pores which make
the membrane permeable by medium and active ingredient
and thus bring about a delayed active ingredient
release. Such delayed release formulations are utilized
CA 02617280 2008-01-30
WO 2007/017219 PCT/EP2006/007783
6 -
for accurately targeted active ingredient release in
the GI tracL or release according to chrono-
pharmacological aspects or are used when the kinetics
of absorption of a medicinal substance are non-linear.
Asymmetric membranes which can be applied to tablets
and also to pellet cores bring about an improved
release of active ingredients of low solubility.
j.uv we vo ,.i- +- L. ,-. .. .~, r------ -'
~, 111C.7C Lc.,~~~iuiaLions also do not show
pH-independent active ingredient release for
pH-dependently soluble substances. A pH-independent
release has been described for such systems when pH
adjusters have been incorporated in the core
formulation for buffering. Such excipients either acids
or bases alter the pH within the formulation to such an
extent that the active ingredient solubility is
improved, even in pH-unfavourable media.
Further systems described in the literature for
pH-independent active ingredient release by means of pH
adjusters in the core of tablets or pellets are also
described for systems which do not operate osmotically.
Multilayer coating combinations have been described for
the combination of water-soluble and water-insoluble
polymer layers, where the water-soluble polymers do not
show pH-dependent solubility and thus any control of
the release of pH-dependently soluble active
constituents either.
There have furthermore been descriptions of
combinations of water-insoluble and pH-dependently
soluble polymer layers and polymer mixtures, a
pH-independent active ingredient release being achieved
solely on the basis of differences in the permeability
of the polymer coating. The permeabilities of the
polymer film can be adjusted accurately in these cases.
The pH-dependently soluble polymer component always
shows a contrary solubility to the active ingredient.
CA 02617280 2008-01-30
WO 2007/017219 PCT/EP2006/007783
- 7 -
Weak active ingredient bases are coated with an acid-
insoluble polymer, whereas an alkali-insoluble polymer
is used as pH-dependently soluble component in the case
of weak active ingredient acids. The result is a
thinner or more porous coating in the medium in which
the active substance is less soluble. The diffusion
barrier in the medium having lower active ingredient
solubility is thus reduced, resulting in an improved
active ingredient liberation.
The present invention relates to a solid pharmaceutical
formulation for a sustained pH-independent active
ingredient release comprising at least one layer of one
or more water-insoluble polymers, at least one layer of
one or more pH-dependent water-soluble polymers and an
active ingredient-containing core, where the core
comprises an active ingredient having strong
pH-dependent solubility in water and at least one
osmagent.
In a preferred form of the present invention, the layer
of one or more water-insoluble polymers comprises pore-
forming substances which are dissolved out after
contact with the aqueous medium and thus form a
microporous membrane.
In a further embodiment of the invention, the layer of
one or more pH-dependent water-soluble polymers is the
outer layer on the solid pharmaceutical formulation,
and the layer of one or more water-insoluble polymers
is the inner one.
The present invention further relates to a~~atrix
pellet for a sustained pH-independent active ingredient
release comprising at least one inner layer of one or
more water-insoluble polymers in which pore-forming
substances are present and, after contact with the
aqueous medium, are dissolved out and thus form a
microporous membrane, and comprising at least one outer
CA 02617280 2008-01-30
WO 2007/017219 PCT/EP2006/007783
8 -
layer of one or more pH-dependent water-soluble
polymers, and an active ingredient-containing core,
where the core comprises piperazineurea and at least
one water-soluble ionic substance from the group of
magnesium chloride, magnesium sulphate, lithium
chloride, sodium chloride, potassium chloride, lithium
sulphate, sodium sulphate, potassium sulphate, lithium
phosphate, sodium phosphate, potassium phosphate,
ammonium chloride, ammonium sulphate, ammonium
phosphate.
Surprisingly, simply mixing water-insoluble with
pH-dependently soluble polymers and application of
layers thereof is insufficient for sustained
pH-independent active ingredient release.
This phenomenon was observable even on application of
very small amounts of pH-dependently water-soluble
polymer, for example 2.5 and 5% (w/w) based on the
total mass of the formulation.
Only by use of osmotically active substances according
to the present invention was a pH-independent active
ingredient release achieved. Only an osmotically active
addition to the core formulation with a high active
ingredient loading, for example up to 90% w/w,
preferably up to 60% w/w, based on the mass of the core
formulation brings about rapid penetration of medium
into the core, followed by the formation of a saturated
active ingredient solution which, driven by the osmotic
pressure, is forced out of the solid pharmaceutical
formulation.
It is possible in this way to increase significantly
the release of the active substance in the medium with
low active ingredient solubility.
Only there is the pH-dependently soluble polymer layer
stretched, owing to the increased penetration in of
CA 02617280 2008-01-30
WO 2007/017219 PCT/EP2006/007783
9 -
medium, to such an extent that a significant emergence
of active ingredient is in fact achieved.
According to the present invention, a pH-dependently
water-soluble polymer layer is necessary even for a
core with osmagent.
Additionally, according to a further preferred
embodiment of the invention, pore-torming substances
may be an addition to the water-insoluble membrane.
Owing to incorporated pore formers, the membrane
rapidly becomes permeable not only by medium but also
by the active ingredient. The rapid permeability of the
water-insoluble membrane is very important in
particular for active ingredients having a very low
solubility in water.
It is now possible to adjust a pH-independent release
of the active substance in the solid pharmaceutical
formulation according to the present invention through
the combination of water-insoluble polymer with or
without further water-soluble substances for pore
formation and a pH-dependently water-soluble polymer.
In addition, the release of the active substance from
the solid pharmaceutical formulation according to the
present invention is not only pH-independent but also
substantially increased by comparison with known
pharmaceutical formulations without osmagent in the
core.
Brief description of the drawings
The invention is explained in more detail below by
means of the drawing. This shows in:
Figure 1 a preferred embodiment of the solid
pharmaceutical formulation according to the present
CA 02617280 2008-01-30
WO 2007/017219 PCT/EP2006/007783
- 10 -
invention.
Figure 2 a solid pharmaceutical formulation of Figure 1
with pH-dependently water-soluble polymer layer without
osmagent in the core. Formulations with pH-dependently
water-soluble polymer layer without osmagent in the
core show a very greatly reduced active ingredient
release in the medium with the actually highest active
ingredient solubility.
Figures 3a-3c show release investigations on a solid
pharmaceutical formulation of Figure 1 with
pH-dependently water-soluble polymer layer without
osmagent in the core. The release investigations were
carried out in a USPXXV basket apparatus at 100
revolutions per minute and with a medium temperature of
37 C ( 0.5 C). The media used were 0.1 N HC1 and
phosphate buffer of pH 6.8. Quantification took place
by HPLC.
Figure 4 a solid pharmaceutical formulation of Figure 1
without pH-dependently water-soluble polymer layer with
osmagent in the core.
Figure 5 a solid pharmaceutical formulation of Figure 1
with pH-dependently water-soluble polymer layer and
osmagent in the core. A pH-independent active
ingredient release was achieved through the
introduction of osmotically active substances.
Figures 6a-6c and 7a-7c show release investigations on
the solid pharmaceutical formulation of Figure 1 with
pH-dependently water-soluble poly<<<er layer with
osmagent in the core (Figure 6a-6c for Examples 2 and
Figures 7a-7c for Examples 3). The release
investigations were carried out in a USPXXV basket
apparatus at 100 revolutions per minute and with a
medium temperature of 37 C ( 0.5 C). The media used
were 0.1 N HC1 and phosphate buffer of pH 6.8.
CA 02617280 2008-01-30
WO 2007/017219 PCT/EP2006/007783
- 11 -
Quantification took place by HPLC.
Embodiment(s) of the invention
The solid pharmaceutical formulation 1 according to the
invention (Fig. 1) comprises at least one layer 3 of
one or more water-insoluble polymers, at least one
layer 2 of one or more pH-dependently water-soluble
polymers.
The formulation core 5 according to the invention is
loaded with a strong pH-dependent water-soluble active
ingredient 6 and at least one osmagent 7.
In a preferred embodiment of the invention, the layer 3
of one or more water-insoluble polymers comprises pore-
forming substances 4 which are dissolved out after
contact with the aqueous medium 8 and thus form a
microporous membrane.
The one or more pore-forming substances 4 may be water-
soluble polymers or other water-soluble additions such
as salts or sugars.
The one or more pore-forming substances 4 may be
selected from the group comprising for example poly-
vinylpyrrolidone (PVP), crospovidone (crosslinked
N-vinyl-2-pyrrolidone, Cl-PVP), hydroxypropylmethyl-
cellulose (HPMC), polyethylene glycol (PEG), hydroxy-
propylcellulose (HPC) and mixtures thereof.
Formulations of an active ingredient-containing core
wltiiGut GSllageilt and Gf twG iayers of pGi'y'iT'ier (F1g. 2) ,
where the inner layer consisted of a water-insoluble
and the outer layer of a pH-dependently water-soluble
polymer, still showed a strong pH-dependent release of
the active substance.
The very greatly reduced active ingredient release in
CA 02617280 2008-01-30
WO 2007/017219 PCT/EP2006/007783
- 12 -
the medium with the actually highest active ingredient
solubility was particularly noteworthy.
For example, a piperazineurea-containing core without
osmagent according to Figure 2 with higher solubility
at acidic pH values (pH < 4) was unable to achieve an
efficient active ingredient release (Fig. 3a-c) . The
active ingredient release of piperazineurea in medium
of pH 1 was less than expected.
A pH-independently active ingredient release is not
achieved even with a formulation without pH-dependently
water-soluble polymer film (Fig. 4).
Efficient sustained pH-independent active ingredient
releases of 0 or lst order can easily be achieved by
the solid pharmaceutical formulation according to the
invention.
An example of the production of the solid
pharmaceutical formulation for a sustained
pH-independent active ingredient release according to
the present invention is described below.
A dry powder mixture was prepared by introducing the
sieved ingredients into a Muller drum with subsequent
mixing in a Turbula mixer.
The dry powder mixture was subsequently moistened in a
high-speed mixer, the amount of binder solution
necessary for extrusion and spheronization having been
determined by preliminary tests. The resulting moist
granules .vere tiien eXtruded in an extruder and rounded
in a spheronizer.
The produced pellets in a preferred embodiment of the
invention were then dried in a fluidized bed (GPCGl
from Glatt).
CA 02617280 2008-01-30
WO 2007/017219 PCT/EP2006/007783
- 13 -
After sieving, the pellet fraction from 0.8 mm to
1.25 mm diameter was used for further production.
The polymer dispersions were applied in a fluidized bed
granulator with Wurster insert, with application of the
first layer being followed by a brief drying pause and
then application of the second layer.
The formulation layer of one or more water-insoluble
polymers (subcoating formulation) is for example from
1% to 40% w/w, preferably from 1% to 10% w/w,
preferably from 2% to 5% w/w based on the total mass of
formulation. The water-insoluble polymers may be
selected from the group comprising polyvinyl acetate;
alkylcelluloses, acrylate-methacrylate copolymers,
vinyl acetate-methacrylate copolymers and -acrylate
copolymers; ethylcellulose, ethyl acrylate-methyl
methacrylate copolymer and ethyl acrylate-methyl
acrylate-trimethylammoniummethyl methacrylate chloride
terpolymer and mixtures thereof.
In a preferred embodiment of the invention, pore-
forming substances were used in the formulation layer
of one or more water-insoluble polymers (subcoating
formulation). The one or more pore-forming substances
may be water-soluble polymers or other water-soluble
additions such as salts or sugars. In a preferred
embodiment of the invention, the one or more pore-
forming substances may be selected from the group
comprising for example polyvinylpyrrolidone (PVP),
crospovidone (crosslinked N-vinyl-2-pyrrolidone,
Cl-PVP), hydroxypropylmethylcellulose (HPMC),
ol='eth ==lene 1'-col ~PE~v' droxY-~ceiliiiose l'HPC'! Y Y ~ Y ~ I, ~'ly P-~-
uPYl 1
and mixtures thereof.
The formulation laver of one or more pH-dependent
water-soluble polymers (topcoating formulation) is for
example from 1% to 40 % w/w, preferably from 1% to 10%
w/w, preferably from 2% to 5% w/w, based on the total
CA 02617280 2008-01-30
WO 2007/017219 PCT/EP2006/007783
- 14 -
mass of formulation.
The acid-insoluble polymers may be selected from the
group comprising acrylate-methacrylic acid copolymers,
carboxyalkylcelluloses, cellulose acetate phthalates,
cellulose acetate succinates, cellulose acetate
trimelliates, hydroxyalkylcellulose phthalates,
hydroxyalkylcellulose acetate succinates, vinyl acetate
phthalates, vinyl acetate succinate; ethylacrylate-
methacrylic acid copolymer, methyl methacrylate-
methacrylic acid copolymer, methyl methacrylate-methyl
acrylate-methacrylic acid copolymer, carboxymethyl-
cellulose, cellulose acetate phthalate; hydroxypropyl-
methylcellulose phthalate, hydroxypropylmethylcellulose
acetate phthalate, hydroxypropylmethylcellulose acetate
succinate, polyvinyl acetate phthalate, shellac and
mixtures thereof.
Alkali-insoluble polymers which can be used are
acrylate-methacrylate copolymers, basic natural
polysaccharides, dimethylaminoethyl methacrylate-methyl
methacrylate-butyl methacrylate terpolymer, chitosan
and mixtures thereof.
Osmotically active substances (osmagents) which can be
used for targeted pH-independent active ingredient
release are water-soluble ionic or nonionic substances
and hydrophilic polymers, alone or as mixture.
The water-soluble ionic substance may be selected from
the group comprising magnesium chloride, magnesium
sulphate, lithium chloride, sodium, chloride, potassium
chloride, lithium sulphate, sodium sulphate, potassium
sulphate, lithium phosphate, sodium phosphate,
potassium phosphate, sodium carbonate, ammonium
chloride, ammonium sulphate, ammonium phosphate alone
or as mixture.
The content of water-soluble ionic osmotic substance in
CA 02617280 2008-01-30
WO 2007/017219 PCT/EP2006/007783
- 15 -
the core may be from 2% to 50% w/w based on the total
mass of cores and in particular from 2% to 20% w/w
based on the total mass of cores.
A water-soluble nonionic substance may be selected from
the group comprising for example sucrose, mannitol,
lactose, dextrose, sorbitol, alone or as mixture.
The content of water-soluble nonionic osmotic substance
in the core may be from 2% to 50% w/w based on the
total mass of cores and in particular from 10% to 40%
w/w based on the total mass of cores.
The hydrophilic polymers may be selected from the group
comprising hydroxypropylmethylcellulose (HPMC),
hydroxypropylcellulose (HPC), xanthan gum, alginate,
sodium carboxylmethylcellulose, polyvinylpyrrolidone
(PVP), Cl-polyvinylpyrrolidone (Cl-PVP), polyethylene
oxide, carbopols, polyacrylamides, gum arabic and
mixtures thereof.
Water-soluble ionic substances preferably used
according to the present invention are those which
achieve a high osmotic effect with relatively small
amounts.
It is possible to use cellulose or cellulose
derivatives as additional formulating agent for
influencing the mechanical strength of the
pharmaceutical form. Microcrystalline cellulose is
particularly advantageous.
CA 02617280 2008-01-30
WO 2007/017219 PCT/EP2006/007783
- 16 -
Examples
Example 1: Production of coated matrix pellets with pH-
dependent water-soluble polymer layer without osmagent
in the core (Fig. 3a-c; state of the art)
Core formulation (% w/w):
Active ingredient (piperazineurea) 60%
Microcrystalline cellulose 40%
Formulation layer of one or more water-insoluble
polymers (subcoating formulation) (% w/w):
Polyvinyl acetate 70%
Polyvinylpyrrolidone 30%
Coating level of the
subcoating formulation: 5% w/w based on total
mass of pellets.
Formulation layer of one or more pH-dependent water-
soluble polymers (topcoating formulation) (% w/w):
Methacrylic acid-ethyl acrylate copolymer 100%
Coating level of the topcoating
formulation (% w/w) :
0% (Fig. 3a); 2.5% (Fig. 3b); 5% (Fig. 3c) w/w
based on total mass of pellets.
Microcrystalline cellulose and active ingredient are
sieved and mixed in a Turbula mixer for 20 minutes.
The dry powder mixture is mixed with the required
amount of binder solution (water) in a high-speed
mixer. The resulting moist granules are -subsequently
extruded through a 1 mm screen in an extruder.
The produced extrudate is rounded in portions in a
spheronizer at 400 rpm. The pellets are subsequently
dried in a GPCG1 fluidized bed granulator at 60 C.
After sieving, the pellet fraction from 0.8 mm to
CA 02617280 2008-01-30
WO 2007/017219 PCT/EP2006/007783
- 17 -
1.25 mm diameter was used for further production.
The matrix pellet cores are equilibrated at 50 C in a
GPCG1 fluidized bed granulator with Wurster insert for
10 minutes. Then a 15% (w/w) polyvinyl acetate
dispersion which comprises the water-soluble pore
former polyvinylpyrrolidone is applied at an inlet air
temperature of 50 C.
After intermediate drying for 10 min, the
pH-dependently soluble methacrylic acid-ethyl acrylate
copolymer (15% w/w) is sprayed on at an inlet air
temperature of 50 C.
After the polymer has been applied, the coated matrix
pellets are equilibrated at 40 C for 24 h.
Example 2: Production of coated matrix pellets with
pH-dependent water-soluble polymer layer with osmagent
(KC1) in the core (Fig. 6a-c)
Core formulation (% w/w):
Active ingredient (piperazineurea) 60%
Osmotically active substance (KC1) 15%
Microcrystalline cellulose 25%
Formulation layer of one or more water-insoluble
polymers (subcoating formulation) (% w/w):
Polyvinyl acetate 70%
Polyvinylpyrrolidone 30%
Coating level of the
subcoating formulation: 5% w/w based on total
mass of pellets.
Formulation layer of one or more pH-dependent water-
soluble polymers (topcoating formulation) (% w/w):
Methacrylic acid-ethyl acrylate copolymer 100%
Coating level of the topcoating
formulation (% w/w) :
CA 02617280 2008-01-30
WO 2007/017219 PCT/EP2006/007783
- 18 -
0% (Fig. 6a) ; 2.5% (Fig. 6b) ; 5% (Fig. 6c) based
on total mass of pellets.
Microcrystalline cellulose and active ingredient are
sieved and mixed in a Turbula mixer for 10 minutes.
Sieved potassium chloride is added and mixed in the
Turbula mixer for a further 10 minutes.
The dry Yowder mixture is mixed with the required
amount of binder solution (water) in a high-speed
mixer. The resulting moist granules are subsequently
extruded through a 1 mm screen in an extruder.
The produced extrudate is rounded in portions in a
spheronizer at 400 rpm. The pellets are subsequently
dried in a GPCGl fluidized bed granulator at 60 C.
After sieving, the pellet fraction from 0.8 mm to
1.25 mm diameter was used for further production.
The matrix pellet cores are equilibrated at 50 C in a
GPCG1 fluidized bed granulator with Wurster insert for
10 minutes. Then a 15% (w/w) polyvinyl acetate
dispersion which comprises the water-soluble pore
former polyvinylpyrrolidone is applied at an inlet air
temperature of 50 C.
After intermediate drying for 10 min, the
pH-dependently soluble methacrylic acid-ethyl acrylate
copolymer (15% w/w) is sprayed on at an inlet air
temperature of 50 C.
After the pollTmer has been applied, the coated matrix
pellets are equilibrated at 40 C for 24 h.
Example 3: Production of coated matrix pellets with
pH-dependent water-soluble polymer layer with osmagent
(NaCl) in the core (Fig. 7a-c)
CA 02617280 2008-01-30
WO 2007/017219 PCT/EP2006/007783
- 19 -
Core formulation (% w/w):
Active ingredient (piperazineurea) 60%
Osmotically active substance (NaCl) 15%
Microcrystalline cellulose 25%
Formulation layer of one or more water-insoluble
polymers (subcoating formulation) (% w/w):
Polyvinyl acetate 70%
Polyvinylpyrrolidone 30%
Coating level of the
subcoating formulation: 5% w/w based on total
mass of pellets.
Formulation layer of one or more pH-dependent water-
soluble polymers (topcoating formulation):
Methacrylic acid-ethyl acrylate copolymer 100%
Coating level of the topcoating
formulation (% w/w) :
0% (Fig. 7a) ; 3% (Fig. 7b) ; 4% (Fig. 7c) based on
total mass of pellets.
Microcrystalline cellulose and active ingredient are
sieved and mixed in a Turbula mixer for 10 minutes.
Sieved sodium chloride is added and mixed in the
Turbula mixer for a further 10 minutes.
The dry powder mixture is mixed with the required
amount of binder solution (water) in a high-speed
mixer. The resulting moist granules are subsequently
extruded through a 1 mm screen in an extruder.
The produced extrudate is rounded in portions in a
spheronizer at 400 rpm. The pellets are subsequently
dried in a GPCG1 fluidized bed granulator at 60 C.
After sieving, the pellet fraction from 0.8 mm to
1.25 mm diameter was used for further production.
The matrix pellet cores are equilibrated at 50 C in a
CA 02617280 2008-01-30
WO 2007/017219 PCT/EP2006/007783
- 20 -
GPCG1 fluidized bed granulator with Wurster insert for
minutes. Then a 15% (w/w) polyvinyl acetate
dispersion which comprises the water-soluble pore
former polyvinylpyrrolidone is applied at an inlet air
5 temperature of 50 C.
After intermediate drying for 10 min, the
pH-dependently soluble methacrylic acid-ethyl acrylate
copolymer (15% w/w) is sprayed on at an inlet air
10 temperature of 50 C.
After the polymer has been applied, the coated matrix
pellets are equilibrated at 40 C for 24 h.
