Note: Descriptions are shown in the official language in which they were submitted.
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BENZIMIDAZOLE PHARMACEUTICAL COMPOSITION AND PROCESS OF PREPARATION
The present invention relates to a pharmaceutical composition and to
a process of preparation thereof, and more particularly to a pharmaceutical
composition containing a benzimidazole.
Benzimidazole derivatives, such as omeprazole, lansoprazole and
timoprazole, etc., are known potent proton pump inhibitors with powerful
inhibitory action against the secretion of gastric acid (Lancet, Nov. 27,
1982, pages
1223 - 1224). They are used in the treatment of Zollinger-Ellison syndrome and
stress related oesophagitis ulceration. The derivatives are well known and are
described, for example, in EP-A-0005129.
It has been found that these benzimidazole derivatives, and in
particular omeprazole, are susceprible to degradation in acid and neutral
media and
it is known to protect oral dosage forms by provision of an enteric coating.
In this
way, the active material is protected from acidic gastric juices until it
reaches the
site of desired release, e.g. the small intestine. Because certain enteric
coatings
can themselves be, or contain, acidic materials it is also often required to
protect
the benzimidazole from the acidity of the enteric coatings. For example, it is
known to formulate the benzimidazole with an alkaline material before applying
the enteric coating; it is also known to provide an intermediate coating
between
the benzimidazole and the enteric coating, generally the intermediate coating
is
selected so as to be substantially water soluble.
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EP-A-0247983 describes an oral pharmaceutical preparation of
omeprazole which is composed of a core material in the form of small beads or
tablets containing omeprazole together with an alkaline reacting compound, the
core material having one or more inert reacting subcoating layers thereon. The
alkaline reacting compounds can be chosen among but are not restricted to
substances such as the sodium, potassium, calcium, magnesium and aluminium
salts of phosphoric acid, carbonic acid, citric acid or other suitable weak
inorganic
or organic acids; substances normally used in antacid preparations such as
aluminium, calcium and magnesium hydroxides; magnesium oxide or composite
substances, such as A1203.6MgO.C02.12H20, (Mg6A12(OH),6C03.4H20),
MgO.A1203.2SiOZ.nHzO or similar compounds; organic pH-buffering substances
such as trihydroxymethylaminomethane or other similar, pharmaceutically
acceptable pH-buffering substances. The specification further states that if
an
alkaline reacting salt of omeprazole such as the sodium, potassium, magnesium,
calcium or ammonium salt of omeprazole (which are described in EP-A-0124495)
is used, this can be in place of or in addition to the allcaline reacting
compound.
TW289733 describes a process of preparing pellets containing
omeprazole. The process comprises spraying a solution comprising omeprazole,
excipient, ethanol, water, ammonia and binder on an inert core; granulating;
spraying an intermediate coating solution comprising excipient, ethanol,
water,
ammonia and binder on the granules; and providing a final outer coating.
US4786505 describes pharmaceutical preparations containing
omeprazole in an alkali environment as the core material, one or more inert
subcoating layers which are water soluble and an outer enteric coating.
There is however provided by the present invention pharmaceutical
compositions, and processes of preparing the same, wherein an active
ingredient
comprising a benzimidazole can be protected from surrounding acidic media, and
the compositions offer further advantages over the prior art by exhibiting
extended
shelf life.
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According to the present invention, there is provided a
pharmaceutical composition which is a solid pellet comprising an inert core, a
benzimidazole in or on the core, a moisture resistant coating around the core,
the
moisture resistant coating comprising at least one hydrophobic material, and
an
enteric coating around the moisture resistant coating.
There is further provided by the present invention a process of
preparing a composition substantially as described above, which process
comprises ,
providing an inert core having a benzimidazole therein or thereon, applying a
moisture resistant coating around the core, the moisture resistant coating
comprising at least one hydrophobic material, and applying an enteric coating
around the moisture resistant coating.
Preferably, the benzimidazole in or on the core is present in an
alkaline environment, and more particularly the benzimidazole is present as an
intimate mixture with at least one alkali. Suitably, the alkali is ammonia or
a
solution of ammonia or ammonium carbonate. A process according to the present
invention therefore preferably further comprises formulating the benzimidazole
in
an alkaline environment substantially as herein described.
It is generally preferred that an alkali employed in the present
invention comprises an aqueous solution of ammonia (i.e. ammonium hydroxide)
or ammonium carbonate, although it is of course also possible to use liquid
ammonia or ammonia gas. In such cases, the benzimidazole may be formulated
under an ammonia atmosphere, for example, and the gas may be absorbed, such as
by dissolution in any aqueous material present.
In accordance with the invention, the pH of the benzimidazole-
containing part of any formulation is preferably from above 7 to 10, and is
more
preferably in the range 8 to 9. Advantageously, an ammonia solution is used,
the
solution preferably containing from 20 to 40wt% ammonia, more preferably about
30 wt% ammonia.
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The invention is applicable to pharmaceutically active
benzimidazole derivatives. Particularly useful such derivatives are the alkali
metal
salts of the benzimidazole. Examples of specific useful derivatives are
omeprazole, lansoprazole, timoprazole, pariprazole and pantoprazole, in
particular
omeprazole.
The purpose of the moisture resistant coating employed in the
present invention is to resist moisture absorption by the pharmaceutical
composition, thereby extending shelf life. Suitably, the hydrophobic material
of
the coating is present in sufficient amount to ensure that the coating
substantially
repels water therefrom. The hydrophobic material can be solid or liquid, and
is
desirably selected from the group consisting of a polyalkylsiloxane, castor
oil,
mineral oil, isopropyl myristate, stearic acid, cetyl alcohol or the like.
Preferably,
the hydrophobic material comprises a polyalkylsiloxane, and it is particularly
preferred that the hydrophobic material comprises polydimethylsiloxane.
The moisture resistant coating may ful-ther comprise at least one
binding agent. The binding agent may be hydrophobic or hydrophilic. In the
latter
case, the binding agent is incorporated in the moisture resistant coating in
an
amount which ensures that the water repellent properties of the latter (as
provided
by the hydrophobic maternal substantially as described above), are
substantially
unaffected by the hydrophilic nature of the binding agent. The binding agent
is
preferably selected from the group consisting of a sugar, polyvinyl-
pyrrolidone,
shellac and gums, such as xanthan gum, or the like. It is especially preferred
that
the binding agent comprises a sugar, such as sucrose or the like.
Advantageously, a binding agent is employed in the moisture
resistant coating when the hydrophobic material is a liquid. A preferred
moisture
resistant coating comprises an emulsion of a polyalkylsiloxane (especially
polydimethylsiloxane) or an admixture thereof, with the binding agent.
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The moisture resistant coating may contain one or more other
conventional additives that typically aid in the process of adhesion onto the
inert
core.
The moisture resistant coating may also be useful in benzimidazole
pharmaceutical compositions that do not have an alkaline binder. The moisture
resistant coating can be typically applied by spraying, using conventional
equipment. In addition to the moisture resistant coating applied directly to
the
inert core substantially as hereinbefore described, a further moisture
resistant
coating can be provided over the enteric coating.
A wide variety of convenrional enteric coatings may be employed in
the present invention, including for example: cellulose acetate phthalate;
hydroxypropyl methyl cellulose phthalate (HPMCP); hydroxypropyl cellulose
acetyl succinate; polyvinyl acetate phthalate; copolymerised methacrylic
acid/methacrylic acid methyl esters, such as Eudragit L 12-5, Eudragit L 100
55 or
Eudragit S 100; and mixtures thereof. The enteric coating may contain
conventional plasticisers, pigments and/or dispersants, including for example
polyethylene glycols, triacetin, triethyl citrate, and Citroflex, dibutyl
sebacate.
The enteric coating can be applied in any suitable manner, for
example in the form of an aqueous dispersion in water, or other dispersing
medium, or in the form of a solution. It is preferred that a dispersion or
solution of
the enteric coating is treated with an alkali in order to neutralise at least
part of any
free acid content. The alkali may be, for example, a carbonate or hydroxide of
sodium, potassium, magnesium or calcium.
According to a first embodiment of the present invention, the
benzimidazole is present in the inert core. Suitably, the inert core of the
pharmaceutical composition comprises a plurality of compressed granules of the
benzimidazole. This embodiment is particularly useful when it is desired to
provide the pharmaceutical composition in tablet form, and there is further
provided by the present invention a tablet which comprises a pharmaceutical
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composition substantially as herein described, wherein the inert core is
formed
from a plurality of granules comprising the benzimidazole, which granules are
compressed together to form the core.
According to the first embodiment of the present invention, the
moisture resistant coating is applied around the inert core, then the enteric
coating
is suitably provided around the moisture resistant coating on the inert core.
According to a second embodiment of the present invention, the
benzimidazole is present on the inert core. The second embodiment of the
present
invention is particularly applicable for the inclusion of a plurality of
pellets
substantially as herein before described in a capsule. The inert cores of the
pellets
may typically be non-pareils, and suitably provided in the form of sugar beads
or
sugar/starch beads. According to the second embodiment of the present
invention
there is therefore provided a capsule which comprises a capsule shell
containing a
plurality of pellets substantially as herein before described.
According to the second embodiment of the present invention, the
moisture resistant coating is applied around the inert core of each of the
pellets to
be provided in a capsule, and the enteric coating is suitably provided around
the
moisture resistant coating on each of the inert cores.
Pharmaceutical compositions according to the present invention may
comprise one or more additives. Examples of particularly useful additives
include
a solubiliser to aid solubilisation of the pharmaceutically active ingredient,
and a
lubricant to aid flow of the active ingredient during manufacture. The
solubiliser
may be, for example, a sugar, which is preferably in pulverised form. An
example
of a suitable sugar is sucrose. The lubricant may be, for example, starch
and/or
talcum. It will be appreciated that the pharmaceutical compositions of the
invention may contain any one or more other additives conventionally used in
the
formulation of pharmaceutical compositions.
The pharmaceutical compositions of the invention may be used to
treat conditions in the same manner as the prior known benzimidazole
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compositions. The pharmaceutical compositions may be formulated for oral,
topical, parenteral or rectal administration. Oral administration is
preferred.
The pharmaceutical compositions may take the form of, for example,
a tablet or peltab (e.g. comprising a plurality of granules comprising a
benzimidazole, together with conventional excipients, such as disintegrants
and
binders, compressed into a tablet) or a capsule (e.g. containing a plurality
of
individual pellets comprising a benzimidazole disposed within the capsule
shell).
Furthermore, the pharmaceutical composition may include conventional
excipients.
Tablets to be employed in compositions of the invention can be
made, for example, by using equipment known as a marumerizer (which is also
called a spheronizer). In such cases, core ingredients, including the
benzimidazole, can be extruded into the marumerizer, and converted into
substantially spherical granules by a high speed rotating disk. Subsequently,
the
granules may be compressed by conventional means in order to form a solid
core,
and subsequently coated with a moisture resistant coating and an enteric
coating as
herein before described.
When, alternatively, the pellets comprise benzimidazole loaded onto
a plurality of inert cores suitable for inclusion in a capsule, the
benzimidazole can
be supplied as a spray, for example. The benzimidazole may be mixed with one
or
more additives before being loaded on the inert cores. As described above, the
additives may include, for example, a solubiliser and/or a lubricant. The
inert
cores can be loaded with the benzimidazole (together with any additives), and
sprayed with a binder, in a centrifugal coating apparatus.
The following Intermediate Examples and Examples illustrate the
invention. In each case, the active drug was omeprazole unless indicated
otherwise. Whilst sucrose (sugar) is the illustrated binding agent, other
binding
agents such as polyvinylpyrrolidone, shellac or xanthan gum, may be used
instead.
Intermediate Example I
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A plurality of part~.cles containing the active drug were prepared
from the following materials:
Non-pareil seeds 95.00 mg
Active drug 20.00 mg
Sucrose 32.00 mg
Corn starch 32.00 mg
Talcum 10.00 mg
HPMC 1.00 mg
90.00 mg
Water: as required.
Particles were also made of the above materials with the addition of
30% by weight ammonia solution in an amount to provide a pH of 8.0-9Ø
Initially, the active drug, the sucrose, the corn starch and the talcum
were blended thoroughly to yield a dusting powder. The non-pareil seeds were
loaded into a centrigual coater and then coated with the dusting powder while
spraying the HPMC (hydroxypropyl methyl cellulose) solution, with the ammonia
solution when used. This resulted in the production of a plurality of discrete
particles containing the active ingredient. The particles so obtained were
dried
using conventional tray dryers/fluid bed dryers to an outlet temp. of 45
° C.
Intermediate Example 2
A plurality of particles containing the active drug were prepared as
follows:
Non-pareil seeds 95.00 mg
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Active drug 20.00 mg
Sucrose _ , 32.00 mg
Corn starch 32.00 mg
Talcum 10.00 mg
HPMC I.00 mg
190.00 mg
Water: as required.
Particles were also made of the above materials with the addition of
3.00 mg ammonium carbonate.
Initially, the active drug, the sucrose, the corn starch, the ammonium
carbonate (when present) and the talcum were blended thoroughly to yield a
dusting powder. The non-pareil seeds were loaded into the centrifugal coater
and
then coated with the dusting powder while spraying the HPMC (hydroxypropyl
methyl cellulose) solution. This resulted in the production of a plurality of
discrete particles containing the active ingredient. The particles so obtained
were
dried using conventional tray dryers/fluid bed dryers to an outlet temp. of
45°C.
Intermediate Example 3
A plurality of particles containing the active drug were prepared
from the following materials:
Non-pareil seeds 108.00 mg
Active drug 20.00 mg
Sucrose 35.90 mg
Corn starch 21.10 mg
Talcum 2.00 mg
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HPC-L Klucel _ 1.00 mg
186.00 mg
Water: as required.
Particles were also made of the above materials but with the addition
of 3.00 mg ammonium carbonate.
Initially, the active drug, the sucrose, the corn starch, the ammonium
carbonate (when present) and the talcum were blended thoroughly to yield a
dusting powder. The non-pareil seeds were loaded into the centrifugal coater
and
then coated with the dusting powder while spraying the HPC-L Klucel
{hydroxypropyl cellulose) solution. This resulted in the production of a
plurality
of discrete particles containing the active ingredient. The particles so
obtained
were dried using conventional tray dryers/fluid bed dryers to an outlet temp.
of
45°C.
Intermediate Example 4
A plurality of tablet cores containing an active drug were prepared
from the following materials:
Sucrose 80.00 mg
Corn Starch 86.00 mg
Active drug 20.00 mg
Talcum 1.00 mg
Magnesium stearate 1.00 mg
Gelatine 2.00 mg
190.00 mg
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Water: as required
Particles were also made of the above materials but with the addition
of 30% by weight solution of ammonia to give a pH of 8.0-9Ø
Initially the active drug was blended with the sucrose and the corn
starch in a suitable mixer. The blend containing the active drug was then
granulated with a solution of the gelatine binder (with the ammonia when
present).
The granules were dried using conventional means, then lubricated with the
talcum
and magnesium stearate. Finally, the granules were compressed into a suitable
shape for a tablet core using conventional compression equipment.
Intermediate Example 5
Employing the same procedure of Intermediate Example 4, tablet
cores were also made of the following composition:
Sucrose 45.00 mg
Dicalcium phosphate 75.00 mg
Corn starch 45.00 mg
Active drug 20.00 mg
Talcum 1.00 mg
Magnesium stearate 2.00 mg
Gelatine 2.00 mg
190.00 mg
Water: as required
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Particles were also made of the above materials but with the
addition of 30% by weight solupon of ammonia to a pH of 8.0-9Ø
Intermediate Example 6
A plurality of tablet cores containing an active drug were prepared
from the following materials:
Sucrose 80.00 mg
Corn Starch 86.00 mg
Active drug 20.00 mg
Talcum 1.00 mg
Magnesium stearate 1.00 mg
Gelatine 2.00 mg
190.00 mg
Water: as required
Particles were also made of the above materials but also including
3.00 mg ammonium carbonate.
Initially the active drug was blended with the sucrose, corn starch
and the ammonium carbonate (when present) in a suitable mixer. The blend
containing the active drug was then granulated with a solution of the gelatine
binder. The granules were dried using conventional means, then lubricated with
the talcum and magnesium stearate. Finally, the granules were compressed into
a
suitable shape for a tablet core using conventional compression equipment.
Intermediate Example 7
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A plurality of tablet cores containing an active drug were prepared
from the following materials:
. Active drug 20.00 mg
Mannitol 115.50 mg
Polyvinylpyrrolidone K30 4.00 mg
Crospovidone 7.00 mg
Magnesium stearate 3.00 mg
Talcum 1.50 mg
Polyethylene Glycol 2.00 mg
6000
153.00 mg
Water: as required
Particles were also made of the above materials but also including
2.00 mg ammonium carbonate.
The active drug was blended with the mannitol, and then granulated
with a solution of PVP-K30 containing ammonium carbonate (when present). The
granules were dried using conventional means, then lubricated with the talcum,
magnesium stearate, PEG 6000 and Crospovidone. Finally, the granules were
compressed into a suitable shape for a tablet core using conventional
compression
equipment.
Intermediate Example 8
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A plurality of tablet cores containing an active drug were prepared
from the following materials: -
Active drug 20.00 mg
Mannitol 115.50 mg
Polyvinylpyrrolidone K30 4.00 mg
Crospovidone 7.00 mg
Magnesium stearate 3.00 mg
Talcum 1.50 mg
Polyethylene Glycol 2.00 mg
6000
153.00 mg
Water: as required
Particles were also made of the above materials but including 30%
by weight ammonia solution to a pH of 8.0-9Ø
The active drug was blended with the mannitol. It was then
granulated with the ammonia solution (when present). The granules were dried
using conventional means, then lubricated with the talcum, magnesium stearate,
PEG 6000 and Crospovidone. Finally, the granules were compressed into a
suitable shape for a tablet core using conventional compression equipment.
Intermediate Example 9
190.00 mg of the particles of the composition formed in Intermediate
Example 1 were treated with 3.00 mg of polydimethylsiloxane, and as much water
as necessary. The coating was carned out using a conventional coating pan.
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Instead, it could have been carried out using a fluidised bed coater. This
produced
a moisture resistant coating around the particles of the composition of
Intermediate
Example 1.
Intermediate Example 10
190.00 mg of the particles of the composition formed in Intermediate
Example 1 were also treated with 20.00 mg of an emulsion of 4.27 mg of
polydimethylsiloxane, and 15.73 mg sucrose along with other conventional
coating
additives. The coating was carried out using a conventional coating pan.
Instead,
it could have been carried out using a fluidised bed coater. This produced a
moisture resistant coating around the particles of the composition of
Intermediate
Example 1.
Intermediate Example I1
193.00 mg of the particles of the composition formed in Intermediate
Example 2 were also treated with 20.00 mg of an emulsion of 4.27 mg of
polydimethylsiloxane, and 15.73 mg sucrose along with other conventional
coating
additives. The coating was carried out using a conventional coating pan.
Instead,
it could have been carried out using a fluidised bed coater. This produced a
moisture resistant coating around the particles of the composition of
Intermediate
Example 2.
Intermediate Example 12
189.00 mg of the particles of the composition formed in Intermediate
Example 3 were treated with 3.00 mg of polydimethylsiloxane, and as much water
as necessary. The coating was carried out using a conventional coating pan.
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Instead, it could have been carried out using a fluidised bed coater. This
produced
a moisture resistant coating around the particles of the composition of
Intermediate
Example 3.
Intermediate Example 13
189.00 mg of the particles of the composition formed in Intermediate
Example 3 were also treated with 20.00 mg of an emulsion of 4.27 mg of
polydimethylsiloxane, and 15.73 mg sucrose along with other conventional
coating
additives. The coating was carried out using a conventional coating pan.
Instead,
it could have been carried out using a fluidised bed coater. This produced a
moisture resistant coating around the particles of the composition of
Intermediate
Example 3.
Intermediate Example 14
Intermediate Example 9 was repeated, using an amount of 30% by
wt. ammonia solution, in addition to the polydimethylsiloxane. This produced a
moisture resistant coating around the particles of the composition of
Intermediate
Example 1.
intermediate Example 15
The 190.00 mg particles formed in Intermediate Example 4 were
coated with 3.00 mg polydimethylsiloxane to produce a moisture resistant
coating
around each particle.
Intermediate Example 16
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The 190.00 mg particles formed in Intermediate Example S were
coated with 3.00 mg polydimethylsiloxane to produce a moisture resistant
coating
around each particle.
Intermediate Example 17
The 190.00 mg particles formed in Intermediate Example 4 were also
treated with 20.00 mg of an emulsion of 4.27 mg of polydimethylsiloxane, and
15.73 mg sucrose along with other conventional coating additives to produce a
moisture resistant coating around each particle.
Intermediate Example 18
The 190.00 mg particles formed in Intermediate Example 5 were also
treated with 20.00 mg of an emulsion of 4.27 mg of polydimethylsiloxane, and
15.73 mg sucrose along with other conventional coating additives to produce a
moisture resistant coating around each particle.
Intermediate Example 19
The 193.00 mg particles formed in Intermediate Example 6 were
coated with 3.00 mg polydimethylsiloxane to produce a moisture resistant
coating
around each particle.
Intermediate Example 20
The 193.00 mg particles formed in Intermediate Example 6 were also
treated with 20.00 mg of an emulsion of 4.27 mg of polydimethylsiloxane, and
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15.73 mg sucrose along with other conventional coating additives to produce a
moisture resistant coating around each particle.
Intermediate Example 21
The 190.00 mg particles formed in Intermediate Example 4 were
coated with polydimethylsiloxane, and an amount of 30% by wt. ammonia
solution, to produce a moisture resistant coating around each particle.
Intermediate Example 22
The 190.00 mg particles formed in Intermediate Example 5
were coated with polydimethylsiloxane, and an amount of 30% by wt. ammonia
solution, to produce a moisture resistant coating around each particle.
Intermediate Example 23
A plurality of particles containing the active drug were prepared
from the following materials:
Non-pared seeds 108.00 mg
Active drug 20.00 mg
HPMC 10.00 mg
Polyvinylpyrrolidone 4.00 mg
Talcum 2.50 mg
Water As required
Total 144.50 mg
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Initially, the polyvinylpyrrolidone and HPMC were dissolved in
water, to obtain a clear solution. To this solution were added the active drug
and
talcum, in that order, and dispersed well. This drug suspension was sprayed
onto
the non-pared seeds using a fluidised bed coater to obtain drug-loaded cores.
These cores were then given a moisture resistant coating in the same way as
described in Intermediate Example 9 or 10. Also, an addition of 30% by weight
ammonia solution can be used as in Intermediate Example 14.
Intermediate Example 24
A plurality of particles containing the active drug were made from
the following materials:
Non-pareil seeds 95.00 mg
Active drug 20.00 mg
Sucrose 30.00 mg
Corn Starch 30.00 mg
Talcum 10.00 mg
Polyvinylpyrrolidone 4.00 mg
HPMC 1:00 mg
Water As required
Total 190.00 mg
Particles were also made of the above materials with the addition of
30% by weight solution of ammonia to pH 8.0-9Ø
The procedure used was as in Intermediate Example I, the PVP
being included in the dusting powder.
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Intermediate Example 25
A plurality of particles containing the active drug were prepared
from the following materials:
Non-pareil seeds 108.00 mg
Active drug 20.00 mg
Sucrose 35.90 mg
Corn Starch 21.10 mg
Talcum 2.00 mg
Polyvinylpyrrolidone 4.00 mg
HPC-L Klucel I .00 mg
Water As required
Total 192.00 mg
Particles were also made of the above materials with the addition of
30% by weight solution of ammonia to pH 8.0-9Ø
The procedure used was as in Intermediate Example 1, the PVP
being included in the dusting powder.
Intermediate Example 26
The compositions obtained in Intermediate Examples 1 - 8 and 23,
24, 25 were treated with 11.00 mg of a mixture comprising of 2.85 mg of an
emulsion of polydimethylsiloxane with 9.00 mg of a binding agent as described
earlier (Sucrose/Polyvinylpyrrolidone/Shellac/Xanthan Gum), along with 1 mg of
talc. The coating was carried out using a fluidised bed coater. Alternately,
it
could have been carried out using a conventional coating pan. This produced a
moisture resistant coating around each composition of the respective examples.
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Example 1
In this Example, the particles formed in Intermediate Examples 9 to
14 were provided with an enteric coating to yield compositions according to
the
. present invention. Some were coated with cellulose acetate phthalate, some
with
HPMCP and some with Eudragit L 100 55. In each case, 500.00 g of the particles
were each coated with 55.00 g of the respective enteric coating polymer. The
enteric coating polymer was deposited using a conventional coating process.
Example 2
In this Example, the particles formed in Intermediate Examples 15 to
22 were each coated with an enteric coating polymer to yield tablet
compositions
according to the present invention. Some were coated with cellulose acetate
phthalate, some with HPMCP and some with Euragdit L 100 55. In each case, the
enteric coating polymer was deposited using a conventional process for
coating.
Example 3
500.00 g of the enteric coated particles from Example 1 were coated
with 3.00 mg per unit dosage form of a moisture resistant coating of
polydimethylsiloxane. The moisture resistant coating was sprayed onto the
particles.
Example 4
500.00 g of the enteric coated particles from Example 1 were coated
with 20.00 mg of an emulsion containing 4.27 mg of polydimethylsiloxane, and
15.73 mg sucrose per unit dosage form to give a moisture resistant coating.
The
moisture resistant coating was sprayed onto the particles.
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Example 5
500.00 g of the enteric coated tablets from Example 2 were each
coated with 3.00 mg per unit dosage form of a moisture resistant coating of
polydimethylsiloxane. The moisture resistant coating was sprayed onto the
tablets.
Example 6
500.00 g of the enteric coated tablets from Example 2 were each
coated with 20.00 mg of an emulsion containing 4.27 mg of
polydimethylsiloxane,
and 15.73 mg sucrose per unit dosage form to give a moisture resistant
coating.
The moisture resistant coating was sprayed onto the tablets.
Example 7
The enteric coated particles of Examples 1 and 2 were respectively
employed in the following formulae:
Particles 193.00 mg
Microcrystalline 20.00 mg
Cellulose
Starch 50.00 mg
Talcum 1.00 mg
Particles 189.00 mg
Microcrystalline 20.00 mg
Cellulose
Starch 50.00 mg _.
Talcum 1.00 mg
CA 02290824 1999-11-19
WO 98/52564 PCT/GB98/01465
-23-
The particles were intimately mixed with the other ingredients in a suitable
mixer.
The resultant blend was made into peltabs which were subsequently respectively
provided with a moisture resistant and an enteric coating as follows.
Moisture Resistant Coatings
3.00 mg polydimethylsiloxane (optionally with 30% ammonia
solution) to produce a moisture resistant coating around each particle; or
20.00 mg of an emulsion of 4.27 mg of polydimethylsiloxane, and
15.73 mg sucrose, along with other conventional coating additives to produce a
moisture resistant coating around each particle.
Enteric Coatings
Enteric coatings included cellulose acetate phthalate, HPMCP and Euragdit L
100
55.
It will appreciated that modifications may be made to the invention
described above.
