Note : Les descriptions sont présentées dans la langue officielle dans laquelle elles ont été soumises.
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STABLE FORMULATION COMPRISING MOISTURE SENSITIVE DRUG/S AND
MANUFACTURING PROCEDURE THEREOF
FIELD OF THE INVENTION
The present invention relates to stable pharmaceutical compositions comprising
moisture sensitive drugs, in particular an angiotensin converting enzyme (ACE)
inhibitor,
such as Cilazapril, as the active ingredient and methods for preparing such
stable
pharmaceutical compositions.
BACKGROUND OF THE INVENTION
Cilazapril is apparently an angiotensin converting enzyme ("ACE") inhibitor,
which
enzyme inhibits the formation of angiotensin II from angiotensin I by
inhibiting the
angiotensin converting enzyme. Chemically, Cilazapril is reported to be
(1S,9S)-9-[(S)-1-
Ethoxycarbonyl-3-phenylpropylamino]-10-oxoperhydropyridazino[ 1,2-a] [
1,2]diazepine-l-
carboxylic acid and is understood to be disclosed in U.S. Patent No.
4,512,924. Cilazapril
has been prescribed in treating patients suffering from hypertension.
One of the requirements for an acceptable pharmaceutical composition is that
it must
be stable. A stable pharmaceutical composition does not exhibit substantial
decomposition of
the active pharmaceutical ingredient during the time between the manufacture
of the
composition and its use by a patient. Cilazapril and a number of other drugs
suffer from
instability problems because the active pharnlaceutical ingredient rapidly
degrades in the
presence of water/moisture. Such active pharmaceutical ingredients (drugs) can
therefore be
characterized as moisture-sensitive drugs.
It is known that, tablet blends may be dry mixed, dry-granulated or wet-
granulated
before tableting. The choice of the processing procedure, dry mixing, dry
granulation, wet
granulation, or some other granulation process, depends on the properties of
the drug an.d the
chosen excipients. Generally, a dry manufacturing process is thought to be
preferable for
moisture-sensitive drugs.
To improve the stability of moisture sensitive drugs, water scavenger
compounds may
be incorporated into a tablet matrix. One such a water scavenger compound is
the binder
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Copovidone (Plasdone S-6300), which binder is specifically recommended for
moisture
sensitive drugs. However, with very little success atteinpts were made to
formulate
Cilazapril tablets using this material in a dry granulation process. In such
Cilazapril tablets
degradation of the active pharmaceutical ingredient was apparent.
Wet-granulation processes have not been considered appropriate for moisture
sensitive drugs since the veiy nature of these processes can include the
presence of
water/moisture.
Surprisingly, we found that the best stability results can be achieved with a
composition or formulation comprising the moisture sensitive drug and a binder
such as
Copovidone, wherein the formulation/composition is prepared using a wet
granulation
process, comprising wetting and then drying the composition at an elevated
temperature.
SUMMARY OF THE INVENTION
The invention provides stable Cilazapril compositions and methods of their
preparation.
In one aspect the present invention provides a stable pharmaceutical
composition
comprising;
a) a moisture sensitive active pharmaceutical ingredient; and
b) at least one pharmaceutical excipient,
wherein the active pharmaceutical ingredient is wet granulated with a solution
of at least one
pharmaceutical excipient. Preferably, at least one excipient is a binder.
In another embodiment the present invention provides a method of preparing a
granular composition comprising a wet granulated moisture sensitive active
pharmaceutical
ingredient comprising the following steps of
a) providing a moisture sensitive active pharmaceutical ingredient;
b) mixing the moisture sensitive active pharmaceutical ingredient with at
least one
pharmaceutically acceptable excipient other than a binder, forming a mixture;
and
c) wet granulating the mixture with a solution of a binder excipient dissolved
in one
or more processing solvents thus forming a granulate.
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The present invention also provides a method of treating a patient suffering
from a
disease comprising administering to a patient in need thereof a
therapeutically effective
amount of a stable pharmaceutical composition comprising a moisture sensitive
active
pharmaceutical ingredient, preferably Cilazapril, and at least one
pharmaceutical excipient,
wherein the active pharmaceutical ingredient is wet granulated with a solution
of the at least
one pharmaceutical excipient.
BRIEF DESCRIPTION OF THE FIGURES
Figure 1. Shows a comparison of the degradation at 55 C during stability test
of various
Cilazapril tablets packed in aluminum cold-form blister, according to the
invention, with a dry granulated tablet and a commercially available tablet.
The increase of Cilazaprilat, a major Cilazapril degradation product, was
determined.
Figure 2. Shows the stability behavior of Cilazapril tablets when comparing
aqueous
and ethanol based granulation processes.
Figure 3. Shows the stability behavior of Cilazapril tablets when comparing a
Polyvinyl
Alcohol based tablet coating (Opadry II (85 Series) and a Hydroxypropyl
Methylcellulose based tablet coating.
DETAILED DESCRIPTION OF THE INVENTION
As used herein the term moisture sensitive active pharmaceutical ingredient
refers to
an active pharmaceutical ingredient which rapidly degrades in the presence of
water/
moisture.
In one aspect, the present invention provides a stable pharmaceutical
composition
comprising a moisture sensitive active pharmaceutical ingredient, exemplified
by Cilazapril,
and at least one pharmaceutically acceptable excipient, wherein at least one
pharmaceutically
acceptable excipient is a binder. Preferably, the pharmaceutical composition
comprises at
least two phannaceutically acceptable excipients.
In one embodiment of the present invention there is provided a stable
phannaceutical
composition comprising; a) a moisture sensitive active pharmaceutical
ingredient; and b) at
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least one pharmaceutical excipient, wherein the active pharmaceutical
ingredient is wet
granulated with a solution of at least one pharmaceutical excipient.
Preferably, the moisture
sensitive active pharmaceutical ingredient is Cilazapril and at least one
pharmaceutical
excipient is a binder.
Preferably the amount of the moisture sensitive active pharmaceutical
ingredient in
the composition is about 0.1% to about 25%, more preferably of about 0.5% to
about 15%, of
the total weight of the composition. A most preferred amount of the active
pharmaceutical
ingredient in the composition is about 0.6% to about 2.7% of the total weight
of the
composition.
In another aspect, the present invention provides a stable pharmaceutical
composition
comprising a moisture sensitive active pharmaceutical ingredient and at least
one
pharmaceutically acceptable excipient, wherein the formulation contains not
more than 3%
(w/w of the initial amount of the active pharmaceutical ingredient) of a
degradation product
after storage in a package with moisture sensitive barrier properties whicli
are at least as
efficient as aluminum-aluminum cold form blisters. Preferably, the
concentration of the
degradation product in the stable pharmaceutical composition of the present
invention after
storage as described above is not more than 2%. More preferably, the
concentration of the
degradation product in the stable pharmaceutical composition of the present
invention after
storage as described above is not more than 1%. Storage may comprise storage
at a
temperature of 55 C for 14 days and storage at a temperature of 40 C and 75%
relative
humidity for three months. The degradation product may be detected by HPLC
analysis.
Preferably, the moisture sensitive active pharmaceutical ingredient is
Cilazapril and the
degradation product is its major degradation product Cilazaprilat.
A stable pharmaceutical composition of the present invention therefore
provides a
pharmaceutical composition of a moisture sensitive active pharmaceutical
ingredient,
preferably Cilazapril, characterized by comprising not more than 3%,
preferably not more
than 2%, most preferably not more than 1%, by weight per weight of said
pharmaceutical
ingredient, of its major degradation Cilazaprilat product upon storage.
Preferably, the stable pharmaceutical composition of the present invention
comprises
at least about 4% of a binder by total weight of the composition. Preferably,
the
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pharmaceutical composition comprises from about 4% to about 20%, more
preferably from
about 5% to about 10% of a binder by total weight of the composition. The
binder comprises
for example, one or more of, a cellulose derivative, a polyvinyl pyrrolidone
(PVP) and its
derivatives, a polyvinylacetate (PVA) or a polyvinyl alcohol. Examples of
suitable cellulose
derivatives as a binder in the present invention are Hydroxypropylmethyl
cellulose (HPMC)
or Hydroxypropyl cellulose (HPC). More preferably, the binder is the
Copovidone,
exemplified by Plasdone S-630 (Copovidone), which is a synthetic, 60:40,
linear, random
copolymer of N-vinyl-2-pyrrolidone and vinyl acetate, and which has a reduced
hydrophilicity and a reduced polymer glass transition temperature (Tg) in
comparison to a
polyvinyl pyrrolidone (PVP) homopolymer.
The stable phannaceutical compositions comprising a moisture sensitive active
pharmaceutical ingredient of the present invention may further contain
excipients such as
tablet and capsule fillers and diluents (such as microcrystalline cellulose,
lactose, starch and
tri-basic calcium phosphate), disintegrants (such as starch, croscarmellose
sodium,
crospovidone and sodium starch glycolate), and glidants (such as colloidal
silicon dioxide
and talc), lubricants (such as magnesium stearate, sodium lauryl sulfate,
stearic acid and
sodium stearyl fumarate).
More particularly, suitable diluents and fillers for use in the pharmaceutical
composition of the present invention include microcrystalline cellulose (e.g.
Avicel ),
lactose, starch, pregelatinized starch, calcium carbonate, calcium sulfate,
sugar, dextrates,
dextrin, dextrose, dibasic calcium phosphate dihydrate, tribasic calcium
phosphate,
magnesium carbonate, magnesium oxide, maltodextrin, mannitol, powdered
cellulose,
sodium chloride, sorbitol and talc.
Solid pharmaceutical compositions of the present invention that are compacted
into a
dosage form, such as a tablet, may include the addition of a disintegrant to
the composition.
Disintegrants include croscarmellose sodium (e.g. Ac Di Sol , Primellose ),
crospovidone
(e.g. Kollidon , Polyplasdone ), microcrystalline cellulose, polacrilin
potassium, powdered
cellulose, pregelatinized starch, sodium starch glycolate (e.g. Explotab ,
Primoljele) and
starch.
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Glidants can be added to improve the flowability of a solid composition before
compaction and to improve the accuracy of dosing especially during compaction
and capsule
filling. Excipients that may function as glidants include colloidal silicon
dioxide, magnesium
trisilicate, powdered cellulose, and talc.
A lubricant can be added to the composition to reduce adhesion and/or ease the
release of the product from e.g. the dye. Lubricants include magnesium
stearate, calcium
stearate, glyceryl monostearate, glyceryl palmitostearate, hydrogenated castor
oil,
hydrogenated vegetable oil, mineral oil, polyethylene glycol, sodium lauryl
sulfate, sodium
stearyl fumarate, stearic acid, talc and zinc stearate.
Other excipients that may be incorporated into the formulation include
preservatives,
surfactants, antioxidants, or any other excipient commonly used in the
pharmaceutical
industry.
In a preferred embodiment of the present invention, the stable formulation
comprises
in addition to Cilazapril, copovidone, lactose monohydrate, sodium starch
glycolate, talc
extra fine and sodium stearyl fumarate.
The solid compositions of the present invention include powders, granulates,
aggregates and compacted compositions. The dosages include dosages suitable
for oral,
buccal, and rectal administration. Although the most suitable administration
in any given case
will depend on the nature and severity of the condition being treated, the
most preferred route
of the present invention is oral. The dosages may be conveniently presented in
unit dosage
form and prepared by any of the methods well known in the pharmaceutical arts.
The pharmaceutical composition of the present invention may be prepared in any
dosage form such as a compressed granulate in the form of a tablet for
example. Also,
unco2npressed granulates and powder mixes that are obtained by the method of
the present
invention in the pre-compression steps can be simply provided in a dosage form
of a capsule
or sachet. Therefore, dosage forms of the pharmaceutical composition of the
present
invention include solid dosage forms like tablets, powders, capsules, sachets,
etc. The dosage
form of the present invention may also be a capsule containing the
composition, preferably a
powdered or granulated solid composition of the invention, within either a
hard or soft shell.
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The shell may be made from gelatin and optionally contain a plasticizer such
as glycerin and
sorbitol, and an opacifying agent or colorant.
Once a moisture sensitive active pharmaceutical ingredient, preferably
Cilazapril,
solid composition is prepared in accordance witli the present invention, it is
preferably
formulated into pharmaceutical formulations such as conventional dosage forms,
including
tablets and capsules. Tablets are a preferred dosage form. In addition, the
tablets may be
coated with an optional cosmetic tablet coating. More preferably this cosmetic
coat has
"moisture barrier" properties. This moisture barrier property provides
protection against
environmental moisture for sensitive cores, enhances product stability, and
improves shelf
life. Preferably, the cosmetic coating is a tablet coating based on polyvinyl
alcohol. More
preferably, the cosmetic coating comprises polyvinyl alcohol, talc and
polyethylene glycol
(PEG). Most preferably, the cosmetic coating further comprises an opacifier
and/or a
colorant, e.g. titanium dioxide and/or iron oxide.
As shown in figure 3, a comparison is made between the stability of a tablet
coated
with Opadry II 85F (a coating with moisture barrier properties) and a tablet
coated with a
HPMC based coat. The comnlercially available series of powder mixes for
coating
suspension sold as the Opadry II 85F series, available from Colorcon, which
are based on
Polyvinyl alcohol, are examples of such cosmetic coat. In addition to
Polyvinyl Alcohol, this
Opadry series of products comprise Talc, PEG 3350, Titanium Dioxide and
pigments.
Preferably, the tablets of the present invention comprise a cosmetic coat of
about 2% to about
6% of the tablet weight, more preferably of about 2.5% to about 4.5% of the
tablet weight,
most preferably of about 3% to about 3.5% of the tablet weight.
In another embodiment the present invention provides a method of preparing a
granular composition comprising a wet granulated moisture sensitive active
pharmaceutical
ingredient, preferably Cilazapril, comprising the following steps of
a) providing a moisture sensitive active pharmaceutical ingredient;
b) mixing the moisture sensitive active pharmaceutical ingredient with at
least one
pharmaceutically acceptable excipient, preferably other than a binder, forming
a mixture; and
c) wet granulating the mixture with a solution of a binder in a processing
solvent,
forming a granulate.
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In preparing a pharmaceutical composition of the present invention a typical
granulation process involves mixing the active ingredient and possibly
excipients in a mixer.
The binder is dissolved in the solvent used for granulating although a further
portion of
binder or another binder may be one of the excipients added in the dry mix
state. The
granulating solvent, solution or suspension is added to the dry powders in the
mixer and
mixed until the desired characteristics are achieved. This usually produces a
granule that will
be of suitable characteristics for producing tablets with adequate hardness,
dissolution,
content uniformity, and other physical characteristics. After the wet
granulation step, the
product is most often dried and then milled after drying, to obtain a major
percentage of the
product within a desired size range. Preferably, the product after wet
granulation is dried
until the loss on drying (LOD) is not more than about 1.5%, more preferably
not more than
about 1.1%. Preferably, the product is milled or sized through an 1 mm screen,
more
preferably through a 0.8 mm screen.
Preferably, the stable pharmaceutical composition of the present invention is
prepared
by wet granulation with a suitable solvent/processing solvent. A suitable
solvent/processing
solvent is able to dissolve the selected binder. Preferably, the
solvent/processing solvent is
capable of dissolving the binder to reach a concentration of at least about
10% W/W. More
preferably, the solvent/processing solvent is selected from the group
consisting of ethanol,
isopropyl alcohol, water, and combinations thereof. Preferably, the stable
formulation
prepared by wet granulation comprises at least 4%, preferably about 4% to
about 20%, more
preferably about 5% to about 10%, of a binder by weight of the formulation.
Preferably, the
binder comprises at least Copovidone and more preferably, the binder is
applied as a solution
in ethanol or water. A preferred solution of the binder in ethanol or water
comprises about
25% to about 55% (w/w) binder, preferably Copovidone, more preferably about
30% to about
50% (w/w) binder, preferably Copovidone.
Surprisingly, it was determined that the choice of processing solvent used in
wet
granulation impacts the stability of the final product differently depending
on the
dose/amount of Cilazapril in the final product. Thus, for compositions
comprising 1 mg of
Cilazapril it was determined that a granulation processing solvent comprising
predominantly
ethanol, such as ethanol (95%), produces more stable pharmaceutical
compositions than the
same process wherein the processing solvent predoininantly comprises water.
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In contrast, with respect to pharmaceutical compositions comprising 5 mg of
Cilazapril, it was determined that a granulation processing solvent comprising
predominantly
water (aqueous granulation) produces a more stable phatmaceutical composition
than the
same process wherein the processing solvent predominantly comprises ethanol
(95%).
This effect may be characterized as related to the concentration of the
moisture
sensitive active phannaceutical ingredient in the dried granulate. Therefore,
dried granulates
comprising about 0.6% of the active pharmaceutical ingredient are
preferentially prepared by
wet granulation with an alcoholic granulation processing solvent, whereas
dried granulates
comprising about 2.7% of the active pharmaceutical ingredient are
preferentially prepared by
wet granulation with an aqueous granulation processing solvent. Granulates
with intermediate
concentrations of the active pharmaceutical ingredient display an intermediate
effect.
Therefore, final pharmaceutical compositions of the present invention
comprising not
more than about 1.7 % of the moisture sensitive active ingredient in the dried
granulate are
preferably prepared by wet granulation with an alcoholic granulation process
solvent.
Preferably, wet granulation with an alcoholic processing solvent is used for
such
compositions comprising not more than about 0.6% of the moisture sensitive
active
ingredient in the dried granulate. Pharmaceutical compositions comprising more
than about
1.7% of the moisture sensitive active ingredient in the dried granulate are
preferably prepared
by wet granulation with water (an aqueous granulation) as the granulation
processing solvent.
Preferably, wet granulation with an aqueous processing solvent is used for
such compositions
comprising not less than about 2.7% of the moisture sensitive active
ingredient in the dried
granulate. The preferred moisture sensitive active pharnaceutical ingredient
being
Cilazapril.
The method of the present invention may further comprise steps in preparing a
tablet
of the pharmaceutical composition of the present invention. In preparing such
tablet the
method further comprises the steps of
d) mixing the granulate with one or more excipients forming a final blend;
e) pressing the final blend into a tablet; and
f) optionally coating the tablet with a cosmetic coat. Preferably, the
cosmetic coat has
moisture barrier properties. Examples of such cosmetic coatings are tablet
coatings based on
polyvinyl alcohol.
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The optional cosmetic coating of the tablet preferably comprises preparing a
suspension
comprising about 10% to about 25%, preferably about 12% to about 15%, more
preferably
about 12% to about 13%, of a powder mixture for cosmetic coating, and applying
the
suspension on the tablet. The cosmetic coating suspension is preferably
prepared such that the
tablet comprises about 2% to about 6%, preferably 2.5% to about 4.5%, of a
tablet cosmetic
coat. The tablet cosmetic coat in the present invention preferably has
"moisture barrier"
properties. The commercially available series of powder mixes for coating
suspension sold as
the Opadry II 85F series, available from Colorcon, which are based on
Polyvinyl alcohol, are
examples of such cosmetic coat.
Capsules comprising either a hard or soft shell and containing the composition
of the
present invention may be prepared. The shell may be made from gelatin and
optionally contain
a plasticizer such as glycerin and sorbitol, and an opacifying agent or
colorant. A capsule
filling of the present invention may comprise the granulates that were
described with reference
to tableting, a final blend of a granulate composition of the present
invention mixed woth one
or more excipients, however they are not subjected to a final tableting step.
Further, such
capsules may be prepared by any of the methods well known in the
pharmaceutical arts.
Further, in a preferred embodiment, the present invention provides a method
for
preparing a stable pharmaceutical composition comprising:
a) mixing cilazapril, lactose, talc and sodium starch glycolate;
b) adding a solution of copovidone to the mixture obtained from step a) to
fornz a
granulate;
c) drying and then milling the granulate;
d) combining the milled granulate with further sodium starch glycolate and
mixing; and
e) adding sodium stearyl glycolate to the blend obtained from step iv) and
mixing to
obtain a final blend.
In a more preferred embodiment, the pharmaceutical composition is a 1 mg
tablet and
step b) is performed using a granulation solution comprising ethanol. In an
alternative
preferred embodiment, the pharmaceutical composition is a 5 mg tablet and step
b) is
performed using an aqueous granulation solution.
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The present invention also provides a method of treating a patient suffering
from a
disease comprising administering to a patient in need thereof a
therapeutically effective amount
of a pharmaceutical composition comprising a moisture sensitive active
pharmaceutical
ingredient, preferably Cilazapril, and at least one pharmaceutical excipient,
wherein the active
pharmaceutical ingredient is wet granulated with a solution of the at least
one pharmaceutical
excipient. Preferably, the disease is hypertension.
The following examples are presented in order to further illustrate the
invention. These
examples should not be construed in any manner to limit the invention.
EXAMPLES
Example 1.
1 mg tablets, dry granulation, *-5% (w/w) binder (Comparative example)
(* % of the binder calculated per tablet core)
In a polyethylene bag 8.4 g Cilazapril Monohydrate, 1360g Lactose Monohydrate,
64g Talc Extra Fine and 80g Copovidone were mixed. The blend was screened
through a
0.71 mm screen, transferred to a twin-shelled (Y-cone) dry blender and mixed
for 25 minutes.
To this mixture 16g of screened Sodium Stearyl Fumarate was added and all the
materials
were mixed in a Y-cone blender for 5 minutes.
The blend was pressed into slugs on a rotary tablet press and the slugs were
milled to
a granulate in an oscillating granulator through 0.8 mm screen. The obtained
granulate was
combined with 64g screened Sodium Starch Glycolate (type A) and mixed in a Y-
cone
bleiider for 10 minutes. To the granulate mixture 8g screened Sodium Stearyl
Fumarate was
added and all materials were mixed in a Y-cone blender for 5 minutes.
Tablets were pressed in a rotary tablet press. Subsequently, a part of the
tablets cores
were coated with:
a)Opadry II 85F22055 (Yellow), which comprises polyvinyl alcohol, talc, PEG
3350, titanium dioxide and iron oxide, as a 13% aqueous suspension, using an
Glatt
film coater, to obtain approximately a 2.7 % w/w coating. The tablets were
then
packaged in aluminum blisters covered with aluminum foil, (cold - forin
Aluminum
blisters).
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Another part of the tablets cores were coated with:
b) Opadry 02G222555 (Yellow), which comprises Hydroxypropyl Methylcellulose
(HPMC), talc, PEG, titanium dioxide and iron oxide, as a 11% aqueous
suspension,
using an Glatt film coater, to obtain approximately a 2.2 % w/w coating. The
tablets
were then packaged in aluminum blisters covered with aluminum foil, (cold -
form
Aluminum blisters)
Packaged tablets were either stored at 55 C or at 40 C and 75% relative
humidity
(RH). The presence of the main degradation product, Cilazaprilat, was
determined using the
HPLC method. In figure 1 the presence of this main degradation product of
Cilazapril after
such storage is shown. Also, figure 3 compares the degradation of Cilazapril
tablets, as a
function of the presence of this main degradation product after storage, of
tablets coated with
a cosmetic coating of Opadry II 85 F22055 with tablets having a cosmetic coat
of Opadry
02G222555 (HPMC based).
Example 2.
1 mg tablets, wet Lyranulation, -5 /a (w/w) binder
2.1 g Cilazapril Monohydrate, 333.9 g Lactose Monohydrate, 16g Talc Extra Fine
and
16g Sodium Starch Glycolate (type A) were mixed for 1 minute in a high shear
mixer. 70 g of
a 28.6% (w/w) solution of Copovidone (binder) in Alcohol (95%) was added and
mixed in
the high shear mixer for 2.5 minutes. 10 g of Alcohol (95%) was added and
mixed for 1
minute. The obtained granulate was dried using a fluid bed dryer until the
Loss On Dry
(LOD) of the dried granulate (as measured by Mettler HR73 at 80 C, level 5)
was not more
than (NMT) 1.1 %. The granulate was milled or "sized" in an oscillating
granulator through
0.8 mm screen.
The milled granulate was combined with 8g Sodium Starch Glycolate -type A
(disintegrant) and mixed in a Y-cone blender for 10 minutes. 4g screened
Sodium Stearyl
Fumarate (lubricant) was added to the blend and mixed for 5 minutes to obtain
a final blend.
Tablets were pressed from the final blend in a rotary tablet press. The
tablets were
coated with a commercially available tablet coating powder blend Opadry II
85F22055
(Yellow) as a 12% aqueous suspension, using a Glatt film coater, to obtain
approximately a
3% w/w coating.
The tablets were packaged in aluminum blister covered with aluminum foil.
Packaged
tablets were stored at 55 C. The presence of the main degradation product,
Cilazaprilat, was
determined using HPLC method.
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Example 3.
1 mg tablets, wet granulation, -9% (w/w) binder
20.1 g Cilazapril Monohydrate, 3099.1 g Lactose Monohydrate, 160g Talc Extra
Fine
and 160g Sodium Starch Glycolate (type A) were mixed for 2 minutes in a high
shear mixer;.
790 g of a 45.57% (w/w) solution of Copovidone in Alcohol (95%) was added and
mixed in a
high shear mixer for 5 minutes. The obtained granulate was dried using a fluid
bed dryer until
the Loss On Dry (LOD) of the dried granulate was not more than (NMT) 1.1 % as
tested at
80 C. The dried granulate was milled in a hammer mill through a 0.84 mm
screen.
The milled granulate was combined with 160g screened Sodium Starch Glycolate
(type A) and mixed in a Y-cone blender for 10 minutes. 40g screened Sodium
Stearyl
Fumarate was added to the blend and mixed in a Y-cone blender for 5 minutes to
obtain a
final blend.
Tablets were pressed from the final blend in a rotary tablet press. The
tablets were
coated with Opadry II 85F22055 Yellow as a 13% aqueous suspension, using an
O'HARA
film coater, to obtain approximately a 3.5% w/w coating.
The tablets were packaged in aluminum blister covered with aluminum foil.
Packaged tablets were stored either at 55 C or at 40 C and 75% RH. The
presence of the
main degradation product, Cilazaprilat, was determined using the HPLC method.
Example 4.
1 mg tablets, wet granulation, -10% (w/w) binder
2.1 g Cilazapril Monohydrate, 305.9 g Lactose Monohydrate, 16g Talc Extra Fine
and
16g Sodium Starch Glycolate (type A) were mixed for 1 minute in a high shear
mixer. 105 g
of a 38.1 % (w/w) solution of Copovidone in Alcohol (95%) was added and mixed
in a high
shear mixer for 1 minute. The granulate obtained was dried using a fluid bed
dryer until the
Loss On Dry (LOD) of the dried granulate was not more than (NMT) 1.1 % as
tested at 80 C.
The dried granulate was milled in an oscillating granulator through a 0.8 mm
screen.
The milled granulate was combined with 16g Sodium Starch Glycolate (type A)
and
mixed in a Y-cone blender for 10 minutes. 4g screened Sodium Stearyl Fumarate
was added
to the blend and mixed in a Y-cone blender for 5 minutes to obtain a final
blend.
Tablets were pressed on a rotary tablet press. The tablets were coated with
Opadry
II 85F22055 Yellow as a 12% aqueous suspension, using a Glatt film coater, to
obtain
approximately a 3% w/w coating.
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The tablets were packaged in aluminum blister covered with aluminum foil.
Packaged tablets were stored at 55 C. The presence of the main degradation
product,
Cilazaprilat, was determined using an HPLC method.
Example 5. (R- 02636)
mg tablets, wet aqueous granulation, -5% (w/w) binder
The following components were mixed for 1 minute in a high shear mixer; 10.4 g
Cilazapril Monohydrate, 318g Lactose Monohydrate, 16g Talc Extra Fine and 16 g
Sodium
Starch Glycolate (type A). 50 g of a 40% (w/w) aqueous solution of Copovidone
was added
and mixed in the high shear mixer for 5 minutes. The granulate achieved was
dried using a
fluid bed dryer until the Loss On Dry (LOD) of the dried granulate was not
more than (NMT)
1.1 % as tested at 80 o C. the dried granulate was milled in an oscillating
granulator through
0.8 mm screen.
The milled granulate was combined with 16g of screened Sodium Starch Glycolate
(type A) and mixed in a Y-cone blender for 10 minutes. To the resultant blend
4g of screened
Sodiiun Stearyl Fumarate was added and mixed in a Y-cone blender for 5 minutes
to achieve
a final blend.
The tablets were pressed in a rotary tablet press. The tablets were packaged
in
aluminum blisters covered with aluminum foil. Packaged tablets were stored at
either 55 C
or at 40 C and 75% RH. The presence of the main degradation product,
Cilazaprilat, was
determined using an HPLC method.
Example 6.
Stability comparisons of various Cilazapril pharmaceutical compositions.
The stability of pharmaceutical compositions according to the present
invention were
compared with the stability of a dry granulated comparative example of a
Cilazapril tablet
and with a commercialized product. The samples of the commercialized product
were
Vascace 1 mg tablets, produced by F. Hoffinann-La Roche Ltd, Basel,
Switzerland. Table 1
shows the formulations of these pharmaceutical compositions with the exception
of the
commercialized product which was obtained as a finished product.
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Table 1. Comparison of formulations and manufacturing methods.
*Exam le 1 Example 2 Example 3 Example 4 Example 5
1 mg tablets, 1 mg tablets, 1 mg tablets, 1 mg tablets, 5 mg tablets
Dry Wet Wet Wet Wet
granulation, granulation, granulation, granulation, granulation,
5% binder 5% binder 9% binder 10% binder 5% binder
Ingredient Content, % of the total tablet weight
Cilazapril Monohydrate 0.51 0.51 0.50 0.51 2.61
Lactose Monohydrate 82.50 81.05 74.86 74.25 79.39
Talc Extra Fine 3.88 3.88 3.86 3.88 4.00
Sodium Starch Glycolate 3.88 5.83 7.73 7.77 8.00
Copovidone 4.85 4.85 8.70 9.71 5.00
Sodium Stearyl Fumarate 1.46 0.97 0.97 0.97 1.00
Opadry 11851722055 2.91 2.91 3.38 2.91 N/A
Yellow
Granulation process N/A Alcohol Alcohol Alcohol Water
solvent
* comparative example
Stability was measured by determining the presence of the major Cilazapril
degradation product Cilazaprilat in the pharmaceutical composition after
storage. An HPLC
test method was applied to determine the quantity of the degradation products
of Cilazapril.
The mobile phase was a mixture of triethylamine buffer, tetrahydrofuran and
acetonitrile. The
detector was a UV spectrophotometer set at 214 nm.
Figure 1 shows stability test results comparing degradation after storage at
55 C for
14 days of various Cilazapril tablets, prepared according to the invention by
wet granulation
process, with the (control) tablets prepared by dry granulatio and
commercially available
tablets. All tested tablets were packed in aluminum blisters. The commercially
available
product is also packed in aluminium blister. The presence of increasing levels
of Cilazaprilat
over time was determined. Further, test results for degradation of some of
these formulations
under standard stress conditions are shown in Table 2.
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Table 2. Degradation under standard "stress" conditions (40 C and 75% RH), of
Cilazapril displayed as function of different formulations and manufacturing
methods.
Description 1 mg tablets, 1 mg tablets, Wet 5 mg tablets, Wet 1 mg tablets,
*Dry granulation, granulation** granulation*** Vascace ,
5% binder (ethanol) (aqueous) Lot: B2017
9 % binder 5 % binder
Major degradation
product,
Cilazaprilat, 0.4 0.2 0.2 0.6
Time "Zero".
% per labeled
claim of Cilazapril
Major degradation
product,
Cilazaprilat,
storage period 8.7 0.8 0.8 2.4
3 months.
% per labeled
claim of Cilazapril
~ Comparative example (example 1)
Example 3
*** Example 5
Example 7.
1 mg tablets, wet granulation, -9% (w/w) binder (% of the binder calculated
per
tablet core), (batch No: K-33603, as shown in table 3).
In a high shear mixer the following components were mixed for 2 minutes; 20.9
g
Cilazapril Monohydrate, 3099.1 g Lactose Monohydrate, 160 g Talc Extra Fine
and 160g
Sodium Starch Glycolate (type A). 770 g of a 46.8% (w/w) solution of
Copovidone in
Alcohol (95%) was added and mixed in a high shear mixer for 5 minutes. The
granulate
obtained was dried using a fluid bed dryer. The LOD of the dried granulate was
not more
than (NMT) 1.1% as tested by Mettler HR73 at 80 C, level 5. The dried
granulate was milled
in a hammer mill through a 0.84 mm screen.
The milled granulate was combined with 160g screened Sodium Starch Glycolate
(type A) and mixed in a Y-cone blender for 15 minutes. 40g screened Sodium
Stearyl
Fumarate was added to the blend and the materials mixed in a Y-cone blender
for 5 minutes
to obtain a final blend.
Tablets were pressed in a rotary tablet press. The tablets were coated with
Opadryo II
85F22055 Yellow as a 13% aqueous suspension, using an O'HARA film coater, to
obtain
approximately a 3.5% w/w coating.
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The tablets were packaged in aluminum blisters covered with aluminum foil.
Packaged tablets were stored at 40 C and 75% RH. The presence of the main
degradation
product, Cilazaprilat, was determined using the HPLC method described above.
Example 8.
2.5 mg tablets, wet 2ranulation, *-9% (w/w) binder
*(% of the binder calculated per tablet core), (batch K-33604, as is shown in
table 3).
The following components were mixed for 2 minutes in a high shear mixer; 52.2
g
Cilazapril Monohydrate, 3068g Lactose Monohydrate, 160.00 g Talc Extra Fine
and 160.00 g
Sodium Starch Glycolate (type A). Added 770 g of a 46.8% (w/w) solution of
Copovidone in
Alcohol (95%) and mixed in a high shear mixer for 5 minutes. The obtained
granulate was
dried using a fluid bed dryer (LOD of the dried granulate was not more than
(NMT) 1.1 % as
tested by a Mettler HR73 at 80 C, and milled in a hammer mill through 0.84 mm
screen.
The milled granulate was combined with 160.00 g screened Sodium Starch
Glycolate
(type A) and mixed in a Y-cone blender for 15 minutes. To the mix 40.00 g
screened Sodium
Stearyl Fumarate was added and the materials mixed in a Y-cone blender for 5
minutes.
The tablets were pressed in a rotary tablet press. The tablets were coated
with
Opadry II 85F24033 Pink as a 13% aqueous suspension, using O'HARA film
coater, to
obtain approximately a 3.5% w/w coating.
The tablets were packaged in aluminum blisters covered with aluminum foil.
Packaged tablets were stored at 40 C and 75% RH. The presence of the main
degradation
product, Cilazaprilat, was determined using the HPLC method as described.
Example 9.
m2 tablets, wet granulation, -9% (w/w) binder
(% of the binder calculated per tablet core), (batch K-33749, as is shown in
table 3).
The following components were mixed for 2 minutes in a high shear mixer; 522 g
Cilazapril Monohydrate, 30678 g Lactose Monohydrate, 1600g Talc Extra Fine and
1600g
Sodium Starch Glycolate (type A). 6600g of a 54.55% (w/w) solution of
Copovidone in
Alcohol (95%) was added and mixed in the high shear mixer for 3.5 minutes. The
granulate
obtained was dried using a fluidized bed dryer until the LOD of the dried
granulate was not
more than (NMT) 1.1% as tested by a Mettler HR73 at 80 C, level 5. The dried
granulate was
milled in a hammer mill through a 0.84 mm screen.
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The milled granulate was combined with 1600 g screened Sodium Starch Glycolate
(type A) and mixed in a Y-cone blender for 15 minutes. 400 g screened Sodium
Stearyl
Fumarate was added to the blend and the materials mixed in a Y-cone blender
for 5 minutes
to obtain a final blend.
The tablets were pressed from the final blend in a rotary tablet press. The
tablets were
coated with Opadry II 85F25401 Red as a 13% aqueous suspension, using an
O'HARA film
coater, to obtain approximately a 3.5% w/w coating.
The tablets were packaged in aluminum blister covered with aluminum foil.
Packaged tablets were stored at 40 C and 75% RH. The presence of the main
degradation
product, Cilazaprilat, was determined using the HPLC method as described.
Table 3. Compositions of Cilazapril tablets, formulated by wet granulation
process.
Ethanol (95%) was used as a process solvent.
Example 7 Example 8 Example 9
1 mg tablets, 2.5 mg tablets, 5 mg tablets,
K-33603 K-33604 K-33749
Ingredient % Content, of the total tablet weight
Cilazapril Monohydrate 0.50 1.26 1.26
Lactose Monohydrate 74.86 74.10 74.10
Talc Extra Fine 3.86 3.86 3.86
Sodium Starch Glycolate 7.73 7.73 7.73
Copovidone 8.70 8.70 8.70
Sodium Stearyl Fumarate 0.97 0.97 0.97
Opadry II 85F22055 Yellow 3.38
Opadry II 85F24033 Pink 3.38
Opadry II 85F25401 Red 3.38
*Ethano195% (process solvent) 10.3 10.3 9.9
*Removed during the drying process
Example 10.
Batch R-02474 -1 mg tablets, wet aqueous granulation, -7.5% (w/w) binder, (as
shown in table 4).
In a high shear mixer were mixed for 1 minute; 2.09 g Cilazapril Monohydrate,
315.91 g Lactose Monohydrate, 16.00 g Talc Extra Fine and 16.00 g Sodium
Starch
Glycolate (type A). 65 g of a 46.2% (w/w) aqueous solution of Copovidone was
added and
mixed in a higll shear mixer for 4 minutes. The obtained granulate was dried
using a fluid bed
dryer (LOD of the dried granulate was not more than (NMT) 1.1 % as tested by a
Mettler
HR73 at 80 C, level 5) and milled in an oscillating granulator through 0.8 mm
screen.
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The milled granulate (359.34 g) was combined with 15.13 g screened Sodium
Starch
Glycolate (type A) and mixed in a Y-cone blender for 15 minutes. To the mix
3.78 g screened
Sodium Stearyl Fumarate was added and the materials were mixed in a Y-cone
blender for 5
minutes.
The tablets were pressed in a single punch tablet press. The tablets were
packaged in
aluminum blister covered with aluminum foil. Packaged tablets were stored
either at 55 C or
at 40 C and 75% RH. The presence of the main degradation product,
Cilazaprilat, was
determined using the HPLC method.
Table 4. Compositions of Cilazapril tablets, formulated by wet granulation
process.
Water was used as a process solvent.
1 mg tablets, R-02474 5 mg tablets, R-02636
Ingredient % Content, of the total tablet weight
Cilazapril Monohydrate 0.52 2.61
Lactose Monohydrate 78.98 79.39
Talc Extra Fine 4.00 4.00
Sodium Starch Glycolate 8.00 8.00
Copovidone 7.50 5.00
Sodium Stearyl Fumarate 1.00 1.00
*Water (process solvent) 8.75 7.50
*Removed during the drying process
Example 11.
Stability comparisons of various Cilazapril pharmaceutical compositions.
The stability of pharmaceutical compositions according to the present
invention
prepared with either ethanol (95%) or water as the processing solvent were
compared. In
addition, the stability of commercially available products was determined
under the same
testing conditions. The samples of the commercially available product were
Vascace
tablets, produced by F. Hoffinann-La Roche Ltd, Basel, Switzerland. As is
shown in table 5
comparable formulations of Cilazapril processed predominantly using ethanol,
which only
differ with respect to the content of Cilazapril in mg/tablet have very
different degradation
profiles, such that the lmg tablets are the most stable and the 5mg the least
stable.
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Table 5. Monitoring results of Cilazapril tablets, placed under standard
stress
conditions (40 C & 75% RH), in comparison to a commercially available
product. Packaging - aluminuin blister.
Test samples VascaceTM
Batch K-33603 K-33604 K-33749 #B2022 #B2141 #B2117
Strength l mg 2.5 mg 5 mg l mg 2.5 mg 5 mg
Major degradation product, Cilazaprilat
Test Interval % er labeled claim of Cilaza ril
Time "0" 0.2 0.2 0.2 0.9 0.5 0.4
1 Month 0.3 0.8 1.2 2.0 1.4 0.8
2 Months 0.4 1.1 2.0 2.5 1.7 1.0
3 Months 0.8 2.2 2.7 3.5 2.3 1.3
6 Months 1.6 4.2 4.8 5.1 3.4 1.8
In contrast, table 6 shows that comparable formulations of Cilazapril
processed
predominantly using water as processing solvent which only differ with respect
to the content
of Cilazapril in mg/tablet have the opposite degradation characteristics, such
that the 5mg
tablets are the most stable and the lmg the least stable.
Table 6. Monitoring results of Cilazapril tablets, placed under standard
stress
conditions (40 C & 75% RH).
Packaging - blister aluminium.
Batch R-02474 R-02636
Strength 1 mg 5 mg
Test Interval Cilazaprilat, % per labeled claim of
Cilazapril
Time "0" 1.0 0.2
3 Months 2.9 0.8
