Note: Descriptions are shown in the official language in which they were submitted.
' CA 02218054 1997-10-10
1
SOLID COMPOSITIONS CONTAINING POLYETHYLENE OXIDE AND AN
ACTIVE INGREDIENT
The present invention relates to novel solid
compositions, notably pharmaceutical compositions,
containing polyethylene oxide and an active ingredient,
and to methods for their preparation.
Certain medicaments need to be formulated in so-
called delayed-release or sustained release form.
Polyethylene oxide referred to as PEO below is
moreover known as a component of medicaments in tablet
form designed to be administered by oral route. This
compound is marketed by the Union Carbide Corporation
under the commercial name Polyox~. The use of PEO for
formulating medicaments has furthermore been the subject
matter of many earlier patents.
EP-A-0 277 092, in the name of Ciba-Geigy relates to
a composition comprising a casing in a material that is
porous to water but not to the active ingredient,
surrounding a central core consisting of a mixture of a
substance that is weakly soluble in water, and a
hydrophilic swelling material, said material consisting
of a mixture of PEO and a vinyl pyrrolidone/vinyl acetate
polymer. The composition in that patent is an example of
current compositions in which a core which swells when
exposed to water is surrounded by a water-porous
material, release of the active ingredient being delayed
or sustained as a result of the time necessary to expand
the core, and for diffusion to take place through the
casing following the penetration of water.
The abstract of the US-A-4,404,183 and US-A-4,
343,789 discloses two embodiments of a sustained release
composition. In the first embodiment, the composition
contains PEO, the active ingredient in an amorphous form,
and a basic component. In the second embodiment, the
active ingredient is nicardipine in an amorphous state,
it being possible to omit the basic component.
It '.1= In n n ~ _'.775I nS=.UC7f' ~ L uuubri I ~JW _ I/34
' CA 02218054 1997-10-10
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Actually, the compositions according to the prior art
are complex, require specific active ingredients or are
provided in a specific form. Moreover, the results
achieved are not always very good.
The present invention provides a simple composition
which is suitable for use with a multiplicity of active
ingredients, and has a remarkabledelaying or sustaining
effect.
Thus, the present invention provides a solid
composition comprising, by weight based on the total
weight of the composition:
(a) from 1 to 700 of an active ingredient which is
not in an amorphous form;
(b) from 10 to 950 of polyethylene oxide;
(c) the balance consisting of conventional additives,
excluding basic components.
The expression "solid composition" means that the
composition is in a tablet or mini-tablet form, these in
their turn being able to be encapsulated using for
example the conventional hard gelatin.
The expression "active ingredient" should be
understood in its normal sense and, generally speaking,
covers medicaments for treatment of the human or animal
body as well as an association of one or several such
medicaments. Active ingredients that are either
hydrophilic or lipophilic are envisaged.
The expression "not in amorphous form" should be
understood in its conventional meaning. Various sources
give a definition of this term "amorphous" as meaning
non-crystalline, lacking the lattice structure
characterizing the crystalline state. The following
references, which provide a definition of the term
amorphous (or the opposite thereof) are, in a on-limiting
manner . Hawley's, Condensed Chemical Dictionary, 12th
Edition, p. 71; Handbook of Chemistry and Physics, 65th
Edition, F-67; The Theory and Practice of Industrial
Pharmacy, 1970, pp. 253-255; Remington's Pharmaceutical
Sciences, 14th Edition, p. 182; General Chemistry 1992,
~e ~t_.mnr, m,msms~ mor _ ~ ~~z~~~~ > »n _ v2v _
CA 02218054 1997-10-10
3
pp.314-315; Encyclopedia of Pharmaceutical Technology,
vol I, pp. 12-13.
The expression "excluding basic compounds" should be
understood as excluding the presence of a compound or a
group of compounds that confer a basic nature on the
composition, in other words a pH greater than 7, when the
composition is diluted in water at a rate of lOg per
litre of water. In particular, this term should be taken
as excluding the presence of one or several basic
components) such as described in column 1, lines 38 to
62 of US-A-4,404,183 if no acid compound is counteracting
the effect of said basic compound, or if the basic
compound is present in a relatively large amount.
According to one preferred embodiment, the
composition according to the invention, comprises:
(a) from 5 to 450 of an active ingredient;
(b) from 25 to 70% polyethylene oxide
(c) the balance consisting of conventional additives,
excluding basic components.
According to one preferred embodiment of the
composition according to the invention, the active
ingredient is a hydrophilic or lipophilic active
ingredient, advantageously a hydrophilic ingredient.
According to another preferred embodiment of the
composition according to the invention, the active
ingredient is selected from the group comprising
acyclovir, nifedipine, nicardipine, captopril, verapamil,
diltiazem, oxybutynine, valacyclovir, glipizide,
felodipine, isosorbide, carbidopa, levodopa,
pentoxiphylline, and their pharmaceutically acceptable
salts.
According to one alternative embodiment, in the
composition according to the invention, the polyethylene
oxide has a molecular weight which varies from 50,000 to
8,000,000, and preferably from 100,000 to 3,000,000. The
required molecular weight for the PEO can be obtained by
mixing PEO of differing molecular weights, that are
available commercially.
H'111J1111'.1=J'cl 151.1117(.' _ G <.ct«lpre 1917 - T/2G
CA 02218054 1997-10-10
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According to a further embodiment, in the composition
according to the invention, the balance consisting of
conventional additives comprises microcrystalline
cellulose, lactose, ascorbic acid, pigments, plastifying
agents, lubricants and so on. Obviously, other
conventional additives known to those skilled in the art
can be employed.
According to one embodiment of the invention, in a
composition, the balance consisting of conventional
additives comprises magnesium stearate and/or glycerol
behenate and/or sodium stearyl fumarate, which is
employed as a lubricant ensuring better compression of
the composition when provided in tablet form, for
example.
According to one or alternative embodiment, the
composition is additionally coated. Surface coating is
employed for the purposes of improving appearance making
the drug more readily acceptable to the patient, or for
dimensionally stabilising the compressed tablet. The
coating can be a conventional coating suitable for
enteral use. It is obtained using any conventional
technique employing conventional ingredients. A surface
coating can for example be obtained using a quick-
dissolving film. It should be noted that the coating
according to this invention is fundamentally different
from the coating used in EP-A-0,277,092 as one does not
encounter, in the invention, the dichotomy (water-
swellable core)/(water-porous coating), and moreover, the
coating in the invention dissolves and/or disintegrates
whereas the coating in EP-A-0,277,092 does not dissolve.
The present solid compositions are suitable for the
administration of medicaments. Thus, the invention also
relates to pharmaceutical compositions deriving therefrom
as well as to compositions thereof for use as
medicaments.
The present composition can be obtained by any
conventional method known to those skilled in the art
such as, for example direct compression after simply
H:1124!)1711=47S77.S=.UOC'-G Vc(oLrc 1917-4/2G
CA 02218054 1997-10-10
w
mixing the dry ingredients, moist or wet granulation
involving the use of a granulation liquid, and dry
granulation involving a densification phase for the dry
mixture.
5 However, use is preferably made of a process
comprising the steps of:
( i ) mixing in the dry state and for a sufficient
time, the active ingredient, polyethylene oxide and
optionally, one or several additives;
(ii) optionally adding solvent when this is used,
followed by mixing for a sufficient period of time;
(iii) granulation by passage through a suitable
sieve;
(iv) ~ drying the granules thus formed for a
sufficient period of time;
(v) optionally adding one of more additives, with
mixing in the dry state for a sufficient time and
passage through a suitable sieve;
(vi) optionally adding one or several additives
and mixing in the dry state for a sufficient period
of time;
(vii) compressing the mixture obtained from the
preceding steps to obtain the desired compressed
tablet; and
(viii) optionally coating said compressed tablet_
The solvent employed, when use is made of a solvent,
is preferably an alcohol. The solvent is eliminated by
drying at one point or another in the process, and is
substantially not encountered in the final composition.
The choice of mixing times, apparatus used, sieve
mesh, and other operating conditions are within the
province of the normal knowledge of those skilled in the
art.
The invention will now be described in more detail,
with reference to Fig. 1 which shows percentage in-vitro
release of an active ingredient as a function of time for
the solid compositions of examples 1 and 2.
~e.v=.~omn ~.am ~sz.UOC . a ~~z~~~~ 1997 _ snv
CA 02218054 1997-10-10
6
x
Without wishing to be bound by any theory, the
applicant believes that the PEO, in the formulation,
forms a hydrogel from contact with water. This hydrogel
dissolves more or less rapidly as a function of the
molecular weight of the PEO employed. Choosing the
molecular weight of the PEO, in combination with a
suitable choice of the weight concentrations of the
active ingredient, of PEO, and of additives enables
release of the active ingredient to be controlled.
Moreover, the present composition exhibits
particularly surprising results. In a hydrophilic
matrix, when the concentration of the hydrophilic active
ingredient increases, one would expect that the rate of
release of the active ingredient would increase. The
present composition exhibits the opposite effect, in the
case, for example, of acyclovir as active ingredient.
This is clearly shown in Fig. l, which gives in-vitro
dissolution of the compositions of examples 1 and 2. The
composition of example 1 has a lower concentration of the
active ingredient (200 mg medicament in a 905 mg tablet)
and shows a faster- in-vitro release of the drug as
compared to the formulation of example 2 which has a
higher concentration of the active ingredient (400 mg of
medicament in a 905 mg tablet). This result is
particularly surprising.
The examples below are provided as examples
illustrating the invention and should not be considered
as limiting its scope . In the examples, the amount of
solvent employed is given in brackets, it being
understood that the solvent is substantially absent in
the final composition.
Example 1
The following composition was prepared:
Acyclovir - 200.0 mg
PEO (M4~T = 100 000 ) 700 . 0 mg
Magnesium stearate 5.0 mg
Industrial alcohol (260.0 mg)
I2 \I=alili\I=~i7G1 ~S=.U()(' . p m4nre 1997 _ G/2(,
CA 02218054 2001-09-27
7
The acyclovir and PEO are weighed and added to a
mixer kneader. Mixing in the dry state is performed for
minutes. Alcohol is added to the mixture and followed
by mixing by 5 minutes. GranL.lation is achieved by
5 passing through a sieve of 1.6 mm mesh. The granules are
dried and are passed through a 0.8 mm mesh sieve. After
weighing, the magnesium stearate is added and mixing in
the dry state is performed during 2 minutes. Tabla_ts are
obtained by compression using a Frogerais MR 15 machine.
Example 2
The following composition is prepared:
Acyclovir 400.0 mg
PEO (MW = 100 000) 500.0 mg
Magnesium stearate 5.0 mg
Industrial alcohol (260.0 mg)
The acyclovir and PEO are weighed and added in a
mixer kneader. Mixing in the dry state is performed for
5 minutes. Alcohol is added to the mixture and followed
by mixing by 5 minutes. Granulation is achie~red by
passing through a sieve of 1.6 mm mesh. The granu7.es are
dried and are passed through a 0.~3 mm mesh sieve. After
weighing, the magnesium stearate is added and mixing in
the dry state is performed during 2 minutes. Tablets are
obtained by compression using a :rotary Frogerais MR 15*
type machine.
Example 3:
The following composition was prepared:
Nifedipine 60.0 mc~
Microcristalline cellulose 100.0 mg
PEO (MW = 3 000 000) 336.0 mg
Colloidal silicon dioxide 2.5 mg
Magnesium stearate 2.5 mg
Industrial alcohol (150.0 mg)
The nifedipine, microcrystalline cellulose (ava.ilable
from the company FMC under the commercial name Avicel PH
lOl~S and the PEO are weighed and added to a mixer
kneader. They are mixed in the dry state for 5 minutes
and the alcohol is added to the mixture with further
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CA 02218054 2001-09-27
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mixing for 5 minutes. Granulation is performed by
passage through a 1.8 mm mesh sieve. The granules are
dried. The colloidal silicon dioxide (available from
Degussa under the commercial name Aerosil 200) is weighed
and added and mixing is carried out in the dry state for
5 minutes followed by passage through a 0.6 mm mesh
sieve. The magnesium stearate is weighed and added with
mixing in the dry state for 2 minutes. The tablets are
obtained by compression in a rotary Frogerais MR 15 type
machine.
Example 4:
Core
Nifedipine 60.0 mg
Microcristalline cellulose 100.0 mg
PEO (MW = 3 000 000) ~ 336.0 mg
Colloidal silicon dioxide 2.5 mg
Magnesium stearate 2.5 mg
Industrial alcohol (150.0 mg)
Coating:
Iron oxide 2.0 mg
Titanium dioxide 1.0 mg
Methylcellulose 12.0 mg
Industrial alcohol (150.0 mg)
The nifedipine, microcrystalli:ne cellulose (available
from the company FMC under the commercial name Avi.cel PH
101'0 and the PEO are weighed and added to a mixer
kneader. They are mixed in the d.ry state for S minutes
and the alcohol is added to the mixture with further
mixing for 5 minutes. Granulation is performed by
passage through a 1.6 mm mesh siE_ve. The granules are
dried. The colloidal silicon dioxide (available from
Degussa under the commercial name .Aerosil 20~*)is weighed
and added and mixing is carried out in the dry state for
10 minutes followed by passage through a 0.8 mm mesh
3S sieve. The magnesium stearate is weighed and added with
mixing in the dry state for 2 minutes. The tablets are
obtained by compression in a rotary Frogerais MR 15*type
machine.
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CA 02218054 2001-09-27
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Following tr:i s, t~~e mechylcel.lulose (availabl.e frcm
_ciorccn under she commercial name Methocel*)is dissolved
in the alcohol. The iron oxide and titanium diox_Lde are
added to tre solution, followed by homogenization in an
Ultra Turrax* apparatus for 10 minutes. The tablets are
coated by spraying this suspension in a perforated pan
coating apparatus of the "Glatt coater" type.
Example 5:
The following composition is prepared:
Core:
Nicardipine.HCl 60.0 mg
Microcrystalline cellulose 77.0 mg
PEO (MW = 2 000 000) 270.0 mg
Magnesium stearate 3.0 mc~
Industrial alcohol (150.0 mg)
Coat inct
Iron oxide 2.0 mc~
Titanium dioxide 1.0 mg
Methylcellulose 12.0 mg
2o Industrial alcohol (150.0 mg)
The nicardipine.HCl, microcrystalline cellulose
(Avicel PH 101*) and PEO are weighed and added to a
kneader. Mixing in the dry state: is carried out for 5
minutes. The alcohol is added to the mixture with
further kneading for 5 minutes. Granulation is carried
out by passage through a 1.6 mm meah sieve. The granules
are dried and passed through a 0.8 mm mesh sieve. The
magnesium stearate is weighed and added followed by dry
mixing for 2 minutes. The tablets are obtained by
compression in a rotary Frogerais MR 15*type machine
Following this, the methylce.llulose (Methocel*) is
dissolved in the alcohol. The iron oxide and titanium
oxide are added to the solution followed by
homogenization in an Ultra Turrax* apparatus for 10
minutes. ~ The tablets are coated by spraying this
suspension in a Glatt coater type coating apparatus.
ExamQle 6
The following composition is prepared:
* Trade-marks
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CA 02218054 2001-09-27
Core:
Captop,ril 50.0 mg
Microcrystalline cellulose 100.0 mg
PEO (MW = 2 500 000) 300.0 mg
S Ascorbic ar_i d (powder) 100 . 0 mg
Magnesium stearate 3.0 mg
Coating:
Titanium dioxide 1.0 mg
Methylcellulose 10.0 mg
10 Industrial alcohol (150.0 mg)
The captopril, microcristalline cellulose (Avicel
200*), ascorbic acid and PEO are weighed and added to a
mixer kneader. Dry mixing is carried out during 5
_- minutes, followed by a passage through 1.6 mm mesh sieve.
The magnesium stearate is weighed and added with mixing
in the dry state for 2 minutes. The tablets are obtained
by compression in a rotary Frogerais MR 15*type machine.
Next, the methylcellulose (Me:thocel*) is dissolved in
the alcohol. The titanium dioxide is added to the
solution followed by homogenization in an Ultra Turrax*
apparatus for 10 minutes. The tablets are spray coated
with this suspension in a Glat:t coater type coating
apparatus.
Example 7
2S The following composition is prepared:
Verapamil . HC1 240 . 0 rng
Lactose 100.0 rng
PEO (MW = 1 000 000) 200.0 mg
Magnesium stearate 5,0 mg
Industrial alcohol (200.0 rng)
The Verapamil.HCl, lactose (available from the
company HMS under reference 80 mesh) and the PEO are
weighed and added to a mixer kneader followed by mixing
in the dry state for S minutes. The alcohol is added to
3S the mixture with further kne<~ding for S minutes.
Granulation is achieved by passage through a 1.6 mm mesh
sieve. The granules are dried and passed through a 0.8
mm sieve. The magnesium stearate is weighed and added,
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CA 02218054 2001-09-27
11
with mixing in the dry state for 2 minutes . -The tablets
are obtained by compression in a rotary Frogerais MR 15*
type machine.
Example 8
The following composition is prepared:
Diltiazem HC1 180.0 mg
Lactose 100.0 mg
PEO (MW = 1 500 000) 160.0 mg
Magnesium stearate 3.0 mg
Industrial alcohol (150.0 mg)
The diltiazem.HCl, lactose (HMS, 80 mesh) and PEO are
weighed and added to a mixer kneader. Mixing is carried
out in the dry state for 5 minutes. The alcohol is added
to the mixture with mixing for 5 minutes. Granulation is
achieved by passage through a 1.6 mm mesh sieve. The
granules are dried and passed through a 0.8 mm mesh
sieve. The magnesium stearate is weighed and added,
followed by mixing in the dry state for 2 minutes. The
tablets are obtained by compression in a rotary Frogerais
MR 15*type machine.
Example 9.
The following composition is prepared:
Oxybutynine.HCl 15.0 mg
Microcrystalline cellulose 75.0 mc~
PEO (MW = 1 000 000) 120.0 mg
Colloidal silicon dioxide 1.5 mg
Magnesium stearate 1.5 mq
Industrial alcohol (110.0 mg) _
The oxybutynine.HCl, microcrystalline cellulose
(Avicel PH 101*) and PEO are weighed and added to a mixer
kneader. Mixing in the dry state is performed for 5
minutes. The alcohol is added to the mixture with
further mixing for 5 minutes. Granulation is achieved by
passage through a 1.6 mm mesh sieve. The granules are
dried. The colloidal silicon dioxide (Aerosil 200) is
weighed and added followed by mixing in the dry state for
10 minutes and passage through a 0.8 mm mesh sieve. The
magnesium stearate is weighed and added, with mixing in
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CA 02218054 2001-09-27
12
the dry state for 2 minutes. The tablets are.-obtained
by
compression in a rotary Frogerais MR 15* type
machine.
Example 10:
The following composition was prepared:
S Core:
Nifedipine 60.0 mg
Microcristalline cellulose 100.0 mg
PEO (MW = 3 000 000) 336,0 rng
Colloidal silicon dioxide 2.5 mg
Magnesium stearate 2.5 mg
Industrial alcohol (150.0 mg)
Coating 1:
Ammonio methacrylate copolymer type A 160.0 mg
Hydroxy propyl methyl cellulose 20.0 mg
Water 30.0 g
Industrial alcohol (150.0 mg)
CoatincL2:
Iron oxide ~ 2.0 mg
Titanium dioxide 1.0 mg
Methylcellulose 12.0 mg
Industrial alcohol (150.0 mg)
The method of preparing the core is to that
identical
described in Example 4.
Coating 1 is prepared as follows.
The hydroxy propyl methyl is weighed
and
dissolved in the water/alcohol The amminio
methacrylate copolymer (USP XXIII, 12.5 % solid vailable
a
from Rohm Pharma, German under the commerci al name
Eudragit RL:*) is weighed and adde d followed mixing.,
by
Coating is done in a Glatt coater
type apparatus.
The method for preparing coating 2 and
the
application of the coating to the tablet
obtained from
the previous step are identical to those described
in
Example 4.
Example 11:
The following composition is prepared:
Valacyclovir_ 200.0 mg
PEO (MW = 3U0 000) 700.0 mg
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CA 02218054 2001-09-27
t
13
Magnesium stearate 5.-0 mg
Industrial alcohol (260.0 mg
The valacyclovir and PEO are weighed and added in a
mixer kneader. Mixing in the dry state is performed for
S S minutes. Alcohol is added to the: mixture, followed by
mixing by 5 minutes. Granulation is achieved by passing
through a sieve of 1.6 mm mesh. The granules are dried
and are passed through a 0.8 mm mesh sieve. After
weighing, magnesium stearate is added and mixing in the
l0 dry state is performed during 2 minutes. Tablets are
obtained by compression using a 1~rogerais MR 15* type
machine.
According to the general process disclosed in the
previous examples, the following compositions are
15 prepared, where the active ingredient is a crystalline
powder.
Example 12:
The following composition ways prepared:
Core:
20 Glipizide ~ 10.0 mg
PEO 220.0 mg
Microcristalline cellulose 55.0 mg
Hydroxy propyl methyl cellulose 20.0 mg
Lactose 50.0 mg
25 Sodium stearyl fumarate 1.7 mg
Coatina:
Methacrylic acid copolymer 10.0 mg
Polyethylene glycol 2.0 mg
Talc 2.5 mg
30 Silicon dioxide 4.5 mg
Example 13:
The following composition wa.s prepared:
Core:
Glipizide 10.0 mg
3S PEO 220.0 mg
Microcristalline cellulose 55.0 mg
Hydroxy propyl methyl cellulose 20.0 mg
Lactose 50.0 mg
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' CA 02218054 1997-10-10
14
Sodium stearyl fumarate 1.7 mg
Coating:
Ammonio methacrylate copolymer 10.0 mg
Triethyl citrate 3.0 mg
Polyethylene glycol 1.0 mg
Hydroxypropylmethylcellulose 7.0 mg
Example 14:
The following composition was prepared:
Core:
Glipizide 10.0 mg
PEO 220.0 mg
Microcristalline cellulose 55_0 mg
Hydroxy propyl methyl cellulose 20.0 mg
Lactose 50.0 mg
Sodium stearyl fumarate 1.7 mg
Coatincr
Ammonio methacrylate copolymer 10.0 mg
Lactose 10.0 mg
Silicon dioxide 4.0 mg
Example 15:
The following composition was prepared:
Core:
Glipizide 10.0 mg
PEO 220.0 mg
Microcristalline cellulose 55.0 mg
Hydroxy propyl methyl cellulose 20.0 mg
Lactose 50.0 mg
Sodium stearyl fumarate 1.7 mg
Coating:
30o polyacrylate dispersion 15.0 mg
Silicon dioxide 6.0 mg
Talc 2.0 mg
Hydroxypropylmethylcellulose 6.0 mg
Example 16:
The following composition was prepared:
Core:
Felodipine 10.0 mg
PEO _ 220.0 mg
12 '.I ?411(1\I?J7G1 n.11-DC7C' . (, mlubre 1997 _ 7-1~=b
CA 02218054 1997-10-10
Microcristalline cellulose 55.0 mg
Hydroxy propyl methyl cellulose 20.0 mg
Sodium stearyl fumarate 1.5 mg
Coating:
5 Methacrylic acid copolymer 10.0 mg
Polyethylene glycol 2.0 mg
Talc 2.5 mg
Silicon dioxide 4.5 mg
Examt~le 17:
10 The following composition was prepared:
Core:
Felodipine 10.0 mg
PEO 220.0 mg
Microcristalline cellulose 55.0 mg
15 Hydroxy propyl methyl cellulose 20.0 mg
Sodium stearyl fumarate 1.5 mg
Coatincf
Ammonio methacrylate copolymer 10.0 mg
Triethyl citrate 3.0 mg
Polyethylene glycol 1.0 mg
Hydroxypropylmethylc~llulose 7.0 mg
Example 18:
The following composition was prepared:
Core:
Felodipine 10.0 mg
PEO 220.0 mg
Microcristalline cellulose 55.0 mg
Hydroxy propyl methyl cellulose 20.0 mg
Sodium stearyl fumarate 1.5 mg
3 Coatinct
0
Ammonio methacrylate copolymer 10.0 mg
Lactose 10.0 mg
Silicon dioxide 4.0 mg
Example 19:
The following composition was prepared:
Core : .
Felodipine 10.0 mg
PEO 220.0 mg
R:\1240(1\12475[ V2.DOC - G octuLre 1997 - I5/2G
CA 02218054 1997-10-10
16
Microcristalline cellulose 55.0 mg
Hydroxy propyl methyl cellulose 20.0 mg
Sodium stearyl fumarate l.5 mg
Coating:
30o polyacrylate dispersion 15.0 mg
Silicon dioxide 6.0 mg
Talc 2.0 mg
Hydroxypropylmethylcellulose 6.0 mg
Example 20:
The following composition was prepared:
Core:
Isosorbide mononitrate 60.0 mg
PEO 100.0 mg
Microcristalline cellulose 25.0 mg
low substituted Hydroxypropylcellulose mg
5.0
Glycerol behenate 1_9 mg
Coating:
Methacrylic acid copolymer 10.0 mg
Polyethylene glycol 2.0 mg
Talc 2.5 mg
Silicon dioxide 4.5 mg
Example 21:
The following composition was prepared:
Core:
Isosorbide mononitrate 60.0 mg
PEO 100.0 mg
Microcristalline cellulose 25.0 mg
low substituted Hydroxypropylcell ulose 5.0 mg
Glycerol behenate 1.9 mg
3 Coatinct
0
Ammonio methacrylate copolymer 5.0 mg
Triethyl citrate 1.5 mg
Polyethylene glycol 0.5 mg
Hydroxypropylmethylcellulose 3.5 mg
Example 22:
The following composition was prepared:
Core:
Isosorbide mononitrate 60.0 mg
R \1 ~J~L7\12J7W ~S2.DC7C' - v mGObrc 1 on7 . L(J=v
' CA 02218054 1997-10-10
17
PEO 100.0 mg
MicrocYistalline cellulose 25_0 mg
low substituted Hydroxypropylcellulose 5.0 mg
Glycerol behenate 1.9 mg
Coatinct
Ammonio methacrylate copolymer 5.0 mg
Lactose 5.0 mg
Silicon dioxide 2.0 mg
Example 23:
The following composition was prepared:
Core:
Isosorbide mononitrate 60.0 mg
PEO 100.0 mg
Microcristalline cellulose 25.0 mg
low substituted Hydroxypropylcellulose 5.0 mg
Glycerol behenate 1.9 mg
Coatirig:
30o polyacrylate dispersion 7.5 mg
Silicon dioxide 3.0 mg
Talc 3.0 mg
Hydroxypropylmethylcellulose 3.0 mg
Example 24:
The following composition was prepared:
Core:
Carbidopa 25.0 mg
Levodopa 100.0 mg
Microcristalline cellulose 20.0 mg
Povidone 4.0 mg
Low substituted Hydroxypropylcellulose 8.0 mg
PEO 20.0 mg
Sodium stearyl fumarate 1.7 mg
Coatin:cr
Methacrylic acid copolymer 50.0 mg
Polyethylene glycol 1.0 mg
Talc 1.25 mg
Silicon dioxide 2.25 mg
Example 25:
The following composition was prepa red:
Itw.l?.Itlf1\I=-l7Sl IS_ 1)()C' ~ G mcmbm 1997 - 17/_v
' CA 02218054 1997-10-10
18
Core:
Carbidopa 25.0 mg
Levodopa 100.0 mg
Microcristalline cellulose 20.0 mg
Povidone 4.0 mg
Low substituted Hydroxypropylcellulose 8.0 mg
PEO 20.0 mg
Sodium stearyl fumarate 1.7 mg
Coating:
Ammonio methacrylate copolymer 5.0 mg
Triethyl citrate 1_5 mg
Polyethylene glycol 0.5 mg
Hydroxypropylmethylcellulose 3_5 mg
Example 26:
The following composition was prepared:
Core:
Carbidopa 25.0 mg
Levodopa 100.0 mg
Microcristalline cellulose 20.0 mg
Povidone 4.0 mg
Low substituted Hydroxypropylcellulose 8.0 -mg
PEO 20.0 mg
Sodium stearyl fumarate 1.7 mg
Coating:
Ammonio methacrylate copolymer 5.0 mg
Lactose 5.0 mg
Silicon dioxide 2.0 mg
Example 27:
The following composition was prepared:
Core:
Carbidopa 25.0 mg
Levodopa 100.0 mg
Microcristalline cellulose 20.0 mg
Povidone 4.0 mg
Low substituted Hydroxypropylcellulose 8.0 mg
PEO 20.0 mg
Sodium stearyl fumarate 1.7 mg
Coating:
li \I=~1(11111=~I7Cl IS=.DOC' . (, meliobre 1997 _ 18/16
' CA 02218054 1997-10-10
19
30o polyacrylate dispersion 7.5 mg
Silicon dioxide 3.0 mg
Talc 1.0 mg
Hydroxypropylmethylcellulose 3.0 mg
Example 28:
The following composition was prepared:
Core:
Pentoxiphylline 400.0 mg
PEO 150.0 mg
Povidone 30.0 mg
Glycerol behenate 6.0 mg
Coating:
Methacrylic acid copolymer 20.0 mg
Polyethylene glycol 4.0 mg
Talc 5.0 mg
Silicon dioxide 9.0 mg
Example 29:
The following composition was prepared:
Core:
Pentoxiphylline 400.0 mg
PEO 150.0 mg
Povidone 30.0 mg
Glycerol behenate 6.0 mg
Coating:
Ammonio methacrylate copolymer 20.0 mg
Triethyl citrate 6.0 mg
Polyethylene glycol 2.0 mg
Hydroxypropylmethylcellulose 14_0 mg
Examt~le 30:
The following composition was prepared:
Core:
Pentoxiphylline 400.0 mg
PEO 150.0 mg
Povidone 30.0 mg
Glycerol behenate 6.0 mg
Coatincr
Ammonio methacrylate copolymer 20.0 mg
Lactose 20.0 mg
R \12~1(tIt\I=~175I1S=.DOC - G ~ctubrc 1997 _ I9/2G
' CA 02218054 1997-10-10
Silicon dioxide - 8.0 mg
Example 31:
The following composition was prepared:
Core:
5 Pentoxiphylline 400.0 mg
PEO 150.0 mg
Povidone - 30.0 mg
Glycerol behenate 6.0 mg
Coating:
l0 30o po.lyacrylate dispersion 30.0 mg
Silicon dioxide 12.0 mg
Talc 4.0 mg
Hydroxypropylmethylcellulose 12.0 mg
Example 32:
15 The following composition was prepared:
Core:
Nicardipine 30.0 mg
PEO 150.0 mg
Microcristalline cellulose 30.0 mg
20 Povidone 5.0 mg
Magnesium stearate 2.0 mg
Coating:
Methacrylic acid copolymer 6.0 mg
Polyethylene glycol 1.2 mg
Talc _ 1.5 mg
Silicon dioxide 2.7 mg
Example 33:
The following composition was prepared:
Core:
Nicardipine 30.0 mg
PEO 150.0 mg
Microcristalline cellulose 30.0 mg
Povidone 5-.0 mg
Magnesium stearate 2.0 mg
Coating:
Ammonio methacrylate copolymer 6.0 mg
Triethyl citrate l.g mg
Polyethylene glycol 0.6 mg
IL \I2~lllln.l=i7S~i5-.DOC-G UCIUI7fC 1997 -20/26 -
' CA 02218054 1997-10-10
21
Hydroxypropylmethylcellulose 4_2 mg
Example 34:
The following composition was prepared:
Core:
Nicardipine 30_0 mg
PEO 150.0 mg
Microcristalline cellulose 30.0 mg
Povidone 5.0 mg
Magnesium stearate 2.0 mg
Coating:
Ammonio methacrylate copolymer 6.0 mg
Lactose 6.0 mg
Silicon dioxide 2.4 mg
Example 35:
The following composition was prepared:
Core:
Nicardipine 30.0 mg
PEO 150.0 mg
Microcristalline cellulose 30.0 mg
Povidone 5.0 mg
Magnesium stearate 2.0 mg
Coating:
30o po~lyacrylate dispersion 9.0 mg
Silicon dioxide 3.6 mg
Talc 1.2 mg
Hydroxypropylmethylcellulose 3.6 mg
R~\124UWI=.J7W'S_-DU<'-6uctubre 1997-21/26
