Note: Descriptions are shown in the official language in which they were submitted.
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MULTIPLE UNIT TABLET COMPOSITIONS OF BENZIMIDAZOLE
COMPOUNDS
Field of the Invention
The present invention relates to multiple unit tablet compositions of
benzimidazole
compounds and process of preparation thereof. The compositions are useful
against
various gastrointestinal disorders.
Backuound of the Invention
Benzimidazole compounds such as omeprazole, lansoprazole, pantoprazole,
rabeprazole or single enantiomers thereof are strong inhibitors of proton pump
and thus
are widely used as therapeutic agents for stomach ulcer, duodenal ulcer,
gastro esophageal
reflux disorders etc. by inhibiting gastric acid secretion.
The single isomers of corresponding benzimidazole compounds are reported to be
more useful in therapy compared to the racemic benzimidazole compounds. U.S.
Patent
No. 5,877,192 describes the use of the (-)-enantiomer of omeprazole
(esomeprazole), or a
pharmaceutically acceptable salt thereof, in the treatment of gastric acid
related diseases.
Because of the instability of benzimidazole compounds under neutral and acidic
environment, moisture, heat, organic solvents and to some degree by light,
numerous
approaches have been tried to form a stable pharmaceutical formulation
comprising a
benzimidazole compound. Most oral benzimidazole preparations are enteric-
coated, due to
the rapid degradation of the drug in the acidic conditions of the stomach.
This is most
commonly achieved by formulating multiple unit formulations i.e. enteric-
coated granules
within capsules, enteric-coated granules compressed into tablets etc., and
single unit
enteric-coated tablets.
The pharmacokinetics of the two formulations differ considerably. The multiple
unit formulation (capsules or tablets) is usually emptied gradually from the
stomach into
the intestine. In contrast to this, the single unit tablet will enter the
intestine and dissolve
as one unit. Further, the enteric- coated pellets of the multiple unit
formulations disperse
readily in contact with fluid, and are therefore suitable for patients with
swallowing
difficulties (can be dispersed in water or juice and the contents taken orally
by the patient)
or for patients with feeding tubes. Among the multiple unit formulations,
tablets offer the
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advantage of good mechanical stability and being more tamper-resistant than
capsules,
which is an important consideration in OTC settings.
U.S. Patent Nos. 4,786,505 and 4,853,230 teach compositions of benzimidazole
compounds having an alkaline core, separating layer and enteric coating.
When preparing multiple unit tablets, the application of compression forces to
the
tablet mixture comprising enteric-coated particles present a problem with
respect to the
strength of the coating and specifically the requirement to maintain the
gastro-resistance
and the integrity of the tablet and of the enteric- coated units after
tableting.
It is known that the film-forming agents generally used to coat particles
cannot
under normal conditions absorb the mechanical stresses applied during
tableting. Films
composed of only enteric polymers or copolymers have very mediocre mechanical
properties, such that they do not withstand tableting. The application of
these compression
forces can result in the appearance of cracks in the enteric coating film or
by the splitting
thereof, resulting in the partial or complete loss of the properties of the
film coating.
The prior art provides solutions such as for example modifying the composition
of
the enteric coating films, so as to substantially improve its mechanical
characteristics with
regard to tableting properties, i.e. to withstand the application of
compression forces.
Improvements in gastro-resistance and less film damage can also be achieved by
using
excipients that deform plastically during tableting. Alternative solutions
consist of
diluting/mixing the enteric-coated particles with auxiliary substances, which
substances
can absorb the physical stresses during tableting.
The document "Drugs made in Germany", 37(2) p. 53 (1994) teaches combination
of Eudragit . L30D and Eudragit . NE30D to produce multiparticulate tablets
comprising the enteric coated particles.
European Patent No. 0 723 436 B 1 teaches an oral pharmaceutical multiple unit
tableted dosage form comprising tablet excipients and individually enteric
coating layered
units of a core material containing active substance in the form of omeprazole
or one of its
single enantiomers, the core material being covered with one or more layer(s),
of which at
least one is an enteric coating layer, characterized in that the enteric
coating layer
comprises a plasticizer in the amount of 20 - 50% by weight of the enteric
coating layer
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polymer. This patent teaches that the enteric coating layer contains
pharmaceutically
acceptable plasticizers to obtain the desired mechanical properties, such as
flexibility and
hardness of the enteric coating layers. The amount of the plasticizer is
optimized for each
enteric coating layer formula, in relation to selected enteric coating layer
polymer, selected
plasticizer and the applied amount of said polymer, in such a way that the
mechanical
properties, i.e. flexibility and hardness of the enteric coating layer are
adjusted so that the
acid resistance of the pellets covered with enteric coating layer does not
decrease
significantly during the compression of pellets into tablets.
European Patent No. 0 723 437 B 1 teaches an oral pharmaceutical multiple unit
tableted dosage form of an acid labile H+K+-ATPase inhibitor or one of its
single
enantiomers, the core material being covered with one or more layer(s) of
which at least
one is an enteric coating layer, characterized in that the enteric coating
layer has a
thickness of at least 10 m and said layer comprises a plasticizer in an
amount of 15 - 50
% by weight of the enteric coating layer polymer.
European Patent Application No. 0 723 777 Al teaches a tablet containing
enteric
granules prepared by tabletting a mixture of enteric granules with at least
one member
selected from the group consisting of synthetic hydrotalcite, dried aluminium
hydroxide
gel, a coprecipitate of aluminium hydroxide with sodium hydrogencarbonate,
aluminium
magnesium hydroxide, synthetic aluminium silicate and dihydroxyaluminium
aminoacetate. The enteric-coated granules include a plasticizer, preferably
added during
formulation of the coating to be coated on the granules, at 15-40% w/w, and
preferably 30-
40 % w/w with respect to the total amount of the enteric coating.
PCT Application No. WO 02/19991 teaches a multiparticulate dosage form,
produced from particles compressed with conventional binding agents. Said
particles
contain a pharmaceutical active ingredient and are covered with a gastric
juice resistant
coating consisting of a methacrylate copolymer and more than 15 and up to 50
wt % of the
plasticizer propylene glycol in relation to the methacrylate copolymer.
U.S. Patent Application No. 2006/0018964 discloses a multiparticulate tablet
comprising a pharmaceutically active substance in the form of enteric-coated
particles, and
a mixture of tableting excipients, wherein the mixture of excipients
comprises: a first
diluent selected from the group consisting of xylitol, maltitol, and mixtures
thereof,
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wherein the first diluent is in a directly compressible form; a disintegrating
agent; a
lubricant; and at least one other diluent, and wherein the ratio of a) the
first diluent to b)
the other diluent(s) is less than 5/95 (weight/weight). The enteric coating
composition can
also comprise a plasticizer. The plasticizer is usually used in a total
proportion of at most
40%, preferably between 10% and 30%, expressed by weight with respect to the
dry
weight of polymer. However, the examples disclosed in this patent application
state that
the enteric coated microgranules are manufactured according to the teaching of
the prior
art WO 96/01623 (PCT application corresponding to EP 0 723 436 BI).
However, there is still a need for development of new enteric coating layered
multiple unit preparations with good mechanical and chemical stability. We
have
surprisingly found that multiple unit tablets of benzimidazole compounds
having desired
mechanical properties and good acid resistance can be prepared by using a
plasticizer in
the enteric coating layer in an amount lower than that disclosed in the prior
art.
Summary of the Invention
Multiple unit tablet compositions of benzimidazole compounds are disclosed.
According to one embodiment the multiple unit tablet composition comprises: a)
one or more tablet excipients, and b) a multiple of enteric coating layered
core units
containing a benzimidazole compound, wherein each core unit is covered with an
enteric
coating layer comprising a plasticizer in an amount of less than 15% by weight
of the
enteric coating layer polymer.
According to another embodiment the multiple unit tablet composition
comprises:
a) one or more tablet excipients, and b) a multiple of enteric coating layered
core units
containing a benzimidazole compound, wherein each core unit is covered with an
enteric
coating layer comprising a plasticizer in an amount ranging from 8% to 14% by
weight of
the enteric coating layer polymer.
According to still another embodiment the multiple unit tablet composition
comprises: a) one or more tablet excipients, and b) a multiple of enteric
coating layered
core units containing a benzimidazole compound, wherein each core unit is
covered with
an enteric coating layer comprising a plasticizer in an amount of less than
15% by weight
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of the enteric coating layer polymer and the enteric coating layer is further
covered by an
over-coating layer.
According to further embodiment the multiple unit tablet composition
comprises:
a) one or more tablet excipients, and b) a multiple of enteric coating layered
core units
5 containing a benzimidazole compound, wherein each core unit is covered with
an enteric
coating layer comprising a plasticizer in an amount ranging from 8% to 14% by
weight of
the enteric coating layer polymer and the enteric coating layer is further
covered by an
over-coating layer comprising a plasticizer in an amount ranging from 0-30% by
weight of
the enteric coating layer polymer.
According to further embodiment the process of preparation of multiple unit
tablet
composition of the present invention is disclosed.
Detailed Description of the Invention
The term benzimidazole compound used herein refers to any of the compounds
belonging to the category of benzimidazole used for gastrointestinal disorders
and may be
selected from omeprazole, lansoprazole, rabeprazole, pantoprazole,
leminoprazole and
pariprazole, including their single enantiomers, pharmaceutically accepted
salts, solvates
and mixtures. For example, the benzimidazole compound may be esomeprazole in
the
form of a pharmaceutically acceptable alkaline salt such as esomeprazole
calcium or
esomeprazole magnesium. The benzimidazole compound may be either in the
crystalline
or amorphous form.
The core may be in the form of pellets, granules or beads. The core may be
acidic,
alkaline or neutral depending on the type of formulation. The core may contain
one or
more pharmaceutically acceptable excipients selected from the group consisting
of inert
carriers, binders, diluents, disintegrants, lubricants/glidants,
solubilizers/wetting agents
and mixtures thereof. The inert carrier may be coated with the benzimidazole
compound
and one or more of the binders, diluents, disintegrants, lubricants/glidants,
solubilizers/wetting agents and mixtures thereof.
The inert carrier may comprise starch, microcrystalline cellulose or sugar
sphere
such as nonpareil sugar seeds.
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Generally the diluents may be selected from one or more of sugars like
dextrose,
glucose, lactose; sugar alcohols like sorbitol, xylitol, mannitol; cellulose
derivatives like
powdered cellulose, microcrystalline cellulose; starches like corn starch,
pregelatinized
starch, maize starch and mixtures thereof.
Generally the binders are selected from one or more of cellulose derivatives
like
hydroxypropylmethyl cellulose, hydroxypropyl cellulose, methylcellulose; gums
like
xanthan gum, gum acacia, tragacanth; water-soluble vinylpyrrolidone polymers
like
polyvinylpyrrolidone, copolymer of vinylpyrrolidone and vinyl acetate; sugars
like
sorbitol, mannitol and mixtures thereof.
Generally the disintegrants are selected from one or more of sodium starch
glycolate, croscarmellose sodium, crospovidone, cornstarch and mixtures
thereof.
The solubilizers/wetting agents may be selected from one or more of sodium
lauryl
sulphate, polysorbate 80 and mixtures thereof. The lubricant/glidants may be
selected
from one or more of magnesium stearate, talc, sodium stearyl fumarate,
colloidal silicon
dioxide and mixtures thereof.
The core may be coated with a separating layer prior to the enteric coating
layer.
The separating layer is made up of substantially water-soluble material, which
is capable
of dissolving or forming a gel in contact with water. Such material may
include
substantially water-soluble polymer and/or substantially water-soluble
excipients. The
substantially water-soluble excipients may be selected from glucose, lactose,
mannitol,
sorbitol, sucrose, dextrose and mixtures thereof. The substantially water-
soluble polymers
may be selected from hydroxypropylmethylcellulose, hydroxypropyl cellulose,
polyvinylpyrrolidone, sodium alginate, sodium carboxymethyl cellulose,
copolymer of
vinylpyrrolidone and vinyl acetate.
An enteric coating layer is applied onto the core coated with the separating
layer
by using suitable coating techniques. The enteric coating layer may include
polymers such
as cellulose acetate phthalate, hydroxypropylmethyl cellulose phthalate,
polyvinyl acetate
phthalate, carboxymethylethylcellulose, methacrylic acid copolymers, for
example,
compounds known under the trademarks of Eudragit NE30D, Eudragit L, Eudragit
S,
Eudragit L 100 55 or mixtures thereof. The enteric coating layer contains
plasticizers and
may also include inert excipients such as talc, titanium dioxide, colloidal
silicon dioxide,
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hydroxypropyl methylcellulose and crospovidone. The plasticizer is used in an
amount of
less than 15% by weight of the enteric coating layer polymer. For example, the
amount of
the plasticizer may range from 8% to 14% by weight of the enteric coating
layer polymer.
For example, the amount of plasticizer is 13% by weight of the enteric coating
layer
polymer. These amounts of the plasticizer in the enteric coating layer provide
the desired
mechanical properties, such as flexibility and hardness of the enteric coating
layers. The
acid resistance of the core covered with enteric coating layer does not
decrease
significantly during the compression of core into tablets. The plasticizers
may be selected
from one or more of triacetin, citric acid esters, phthalic acid esters,
dibutyl sebacate, cetyl
alcohol, polyethylene glycols, polysorbates and mixtures thereof.
The core covered with enteric coating layer may further be covered with one or
more over-coating layers. The materials for over-coating layers are
pharmaceutically
acceptable compounds such as sugar, polyethylene glycol, polyvinylpyrrolidone,
polyvinyl
alcohol, polyvinyl acetate, hydroxypropyl cellulose, methylcellulose,
ethylcellulose,
hydroxypropyl methylcellulose and carboxymethylcellulose sodium, used alone or
in
mixtures. Additives such as plasticizers, colorants, pigments, fillers, anti-
tacking and anti-
static agents, such as magnesium stearate, titanium dioxide and talc may also
be included
into the over-coating layer. The over coating layer may contain plasticizers
in an amount
ranging from 0-30 % by weight of the enteric coating layer polymer. For
example, the
amount of the plasticizer may range from 5-20 % by weight of the enteric
coating layer
polymer. Said over-coating layer may further prevent potential agglomeration
of enteric
coating layered core, protect the enteric coating layer towards cracking
during the
compaction process and enhance the tableting process.
The separating layer, enteric coating layer and the over-coating layer can be
applied to the core by coating or layering procedures in suitable equipments
such as
coating pan, coating granulator or in a fluidized bed apparatus using water
and/or organic
solvents for the layering process.
The multiple enteric-coating layered core units are mixed with one or more
tablet
excipients and compressed into a multiple unit tablet dosage form. The enteric
coating
layered core units, with or without an over-coating layer, are mixed with
tablet excipients
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such as fillers, binders, disintegrants, lubricants and other pharmaceutically
acceptable
additives and compressed into tablets.
Generally the fillers may be selected from one or more of sugars like
dextrose,
glucose, lactose; sugar alcohols like sorbitol, xylitol, mannitol; cellulose
derivatives like
powdered cellulose, microcrystalline cellulose; starches like corn starch,
pregelatinized
starch, maize starch and mixtures thereof.
Generally the binders are selected from one or more of cellulose derivatives
like
hydroxypropylmethyl cellulose, hydroxypropyl cellulose, methylcellulose; gums
like
xanthan gum, gum acacia, tragacanth; water-soluble vinylpyrrolidone polymers
like
polyvinylpyrrolidone, copolymer of vinylpyrrolidone and vinyl acetate; sugars
like
sorbitol, mannitol and mixtures thereof.
Generally the disintegrants are selected from one or more of sodium starch
glycolate, croscarmellose sodium, crospovidone, cornstarch and mixtures
thereof.
The lubricant/glidants may be selected from one or more of magnesium stearate,
talc, sodium stearyl fumarate, colloidal silicon dioxide and mixtures thereof.
According to one embodiment the process for the preparation of the multiple
unit
tablet composition comprises the steps of:
a) preparing a multiple of core units comprising the benzimidazole compound
and
one or more pharmaceutically acceptable excipients.
b) coating the core of step (a) with a separating layer,
c) covering the core of step (b) with an enteric coating layer comprising a
plasticizer in an amount of less than 15% by weight of the enteric coating
layer
polymer,
d) mixing the multiple of enteric coating layered core units of step (c) with
one or
more tablet excipients, and
e) compressing the mixture of step (d) into tablets.
According to another embodiment the process for the preparation of the
multiple
unit tablet composition comprises the steps of:
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a) preparing a multiple of core units comprising the benzimidazole compound
and
one or more pharmaceutically acceptable excipients.
b) coating the core of step (a) with a separating layer,
c) covering the core of step (b) with an enteric coating layer comprising a
plasticizer in an amount of less than 15% by weight of the enteric coating
layer
polymer,
d) covering the enteric coating layered core units of step (c) with an over-
coating
layer,
e) mixing the multiple of over coating layered core units of step (d) with one
or
more tablet excipients, and
f) compressing the mixture of step (e) into tablets.
The compressed tablet is optionally coated with a non-functional film coating
to
obtain a smooth surface of the tablet and further enhance the stability of the
tablet during
packaging and transport.
The following non-limiting examples describe the various embodiments:
Example 1
Qty (mg/unit)
Ingredients Strength (40mg) Strength (20mg)
40 mg 20 mg
Sugar spheres 60 30
Drug Layer
Esomeprazole Magnesium eqv. to 44.5 22.25
Esomeprazole
Hydroxypropylcellulose 16.0 8.0
Crospovidone 5.0 2.5
Purified water q. s. q.s.
Total 125.5 62.75
Separating layer
Polyvinyl pyrrolidone 14.5 7.25
Polyethylene G1yco1400 1.0 0.5
Talc 4.0 2.0
Purified water/Isopropyl alcohol q. s. q.s.
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Total 145.0 72.5
Enteric Coating layer
Hydroxypropylmethyl cellulose phthalate 98.77 49.39
HPMCP (HP-55S)
Hydroxypropylmethyl cellulose phthalate 42.33 21.17
HPMCP HP-50
Diethyl phthalate 18.4 9.2
Acetone q.s. q.s.
Purified water q.s. q.s.
Total 304.5 152.25
Overcoating layer
Hydroxypropylcellulose 6.0 3.0
Polyethylene glycol (PEG 6000) 9.0 4.5
Isopropyl alcohol/Dichloromethane q. s. q.s.
Total 319.5 159.75
Compression
Crospovidone 58 29
Cellulose microcrystalline PH 101 502.5 251.25
Cellulose microcrystalline PH 112 211 105.5
Polyvinylpyrrolidone/Hydroxypropylcellulose 105 52.5
Sodium stearyl Fumarate 4.0 2.0
Total 1200 600
Film Coating
Opadry pink 30 15
Isopropyl alcohol q.s. q.s.
Dichloromethane q.s. q.s.
Process of preparation:
Drug Layering
1. Sugar spheres were sifted through # 36 BSS and # 60 BSS and the fraction
retained
between # 36-60 BSS was collected.
5 2. Hydroxypropylcellulose and Crospovidone was sifted through # 30 BSS
followed
by dispersing in purified water under mechanical stirring to obtain a
dispersion.
3. Esomeprazole Magnesium was sifted through # 30 BSS followed by dispersing
in
step 2 dispersion.
4. The sugar spheres of step 1 were loaded into Wurster coater and coated with
the
10 dispersion of step 3 to obtain drug layered beads.
5. The beads obtained in step 4 were dried at product temperature of 35 5 C
for 15-
30 minutes.
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Separating layer
6. Polyvinylpyrrolidone was sifted through # 30 BSS and dissolved in purified
water/Isopropyl alcohol followed by addition of polyethylene glycol (PEG 400)
in
the solution.
7. Talc was sifted through # 30 BSS and dispersed in solution of step 6.
8. The drug-layered beads of step 5 were coated with the dispersion of step 7
to
obtain separating layer coated beads.
9. The beads were dried at product temperature of 35 5 C for 15-30 minutes.
Enteric Coating
10. Diethylpthalate was dissolved in acetone followed by
hydroxypropylmethylcellulose phthalate under continuous stirring.
11. Purified water was added in the dispersion of step 10 under stirring.
12. The separating layer coated beads of step 9 was coated with dispersion of
step 11
to obtain enteric-coated beads.
13. The beads obtained in step 12 were dried at product temperature of 35 5
C for
12 hrs in vacuum tray drier.
Overcoating
14. Hydroxypropylcellulose was sifted through # 30 BSS and dissolved in
Isopropyl
alcohol/Dichloromethane followed by addition of Polyethylene glycol (PEG 400)
in the solution to obtain a dispersion.
15. The enteric-coated beads of step 13 were coated with the dispersion of
step 14 to
obtain overcoated coated beads.
16. The beads were dried at product temperature of 35 5 C for 15-30
minutes.
Compression
17. The overcoated beads of step 16 were sifted through # 22 BSS.
18. Microcrystalline cellulose, polyvinylpyrrolidone/Hydroxypropylcellulose-L
and
crospovidone was sifted through # 30 BSS.
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19. The material of step 17 & 18 were blended in a blender.
20. Sodium stearyl fumarate was sifted through # 30 BSS and added to the
material of
step 19 and blended further.
21. The material of step 20 was compressed using approved tooling.
Film Coating
22. Opadry pink was dispersed in isopropyl alcohol/dichloromethane.
23. The tablets of step 21 were coated with the dispersion of step 22.
Example 2
Qty (mg/unit)
Ingredients Strength (40mg)
40 mg
Sugar spheres (#40-60) 60
Drug Layer
Esomeprazole Magnesium eqv. to Esomeprazole 45.44
Hydroxypropylcellulose 16.0
Crospovidone 8.0
Purified water q. s.
Total 131.44
Separating layer
Polyvinyl pyrrolidone 8.5
Polyethylene G1yco1400 0.8
Talc 14.5
Purified water/Isopropyl alcohol q. s.
Total 155.24
Enteric Coating layer
Methacrylic acid copolymer (Eudragit L100D 55) 121
Hydroxypropylmethyl cellulose phthalate HPMCP 30
Triethyl citrate 19.63
Talc 15.8
Acetone q.s.
Purified water q.s.
Total 341.67
Overcoating layer
Hydroxypropylcellulose 5.6
Polyethylene glycol (PEG 6000) 8.4
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Isopropyl alcohol/Dichloromethane q. s.
Total 355.67
Compression
Crospovidone 60
Cellulose microcrystalline PH 101 478
Cellulose microcrystalline PH 112 189
Hydroxypropylcellulose 110
Sodium stearyl Fumarate 18
Total 1200
Film Coating
Opadry pink 27
Isopropyl alcohol q.s.
Dichloromethane q. s.
Drug Layering
1. Sugar spheres were sifted through # 36 BSS and # 60 BSS and the fraction
retained
between # 36-60 BSS was collected.
2. Hydroxypropylcellulose and Crospovidone was sifted through # 30 BSS
followed
by dispersing in purified water under mechanical stirring to obtain a
dispersion.
3. Esomeprazole Magnesium was sifted through # 30 BSS followed by dispersing
in
step 2 dispersion.
4. The sugar spheres of step 1 were loaded into Wurster coater and coated with
the
dispersion of step 3 to obtain drug-layered beads.
5. The beads obtained in step 4 were dried at product temperature of 35 5 C
for
15-30 minutes.
Separating layer
6. Polyvinylpyrrolidone was sifted through # 30 BSS and dissolved in purified
water/Isopropyl alcohol followed by addition of Polyethylene glycol (PEG 400)
in
the solution.
7. Talc was sifted through # 30 BSS and dispersed in solution of step 6.
8. The drug-layered beads of step 5 were coated with the dispersion of step 7
to
obtain separating layer coated beads.
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9. The beads obtained in step 8 were dried at product temperature of 35 5 C
for
15-30 minutes.
Enteric Coating
10. Triethylcitrate was dissolved in acetone followed by
hydroxypropylmethylcellulose phthalate and Eudragit L 100D 55 under continuous
stirring.
11. Purified water was added in the dispersion of step 10 under stirring to
obtain a
dispersion.
12. The separating layer coated beads of step 9 were coated with dispersion of
step 11
to obtain enteric-coated beads.
13. The beads obtained in step 12 were dried at product temperature of 35 5
C for
12 hrs in vacuum tray drier.
Overcoating
14. Hydroxypropylcellulose was sifted through # 30 BSS and dissolved in
Isopropyl
alcohol/Dichloromethane followed by addition of Polyethylene glycol (PEG 400)
in the solution.
15. The enteric-coated beads of step 13 were coated with the dispersion of
step 14 to
obtain overcoated coated beads.
16. The beads obtained in step 15 were dried at product temperature of 35 5
C for
15-30 minutes.
Compression
17. The overcoated beads of step 16 were sifted through # 18 BSS.
18. Microcrystalline cellulose, L- Hydroxypropylcellulose and crospovidone was
sifted through # 30 BSS.
19. The material of step 17 & 18 were blended in a blender.
20. Sodium stearyl fumarate was sifted through # 30 BSS and added to the
material of
step 19 and blended further.
21. The material of step 20 was compressed using approved tooling.
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Film Coating
22. Opadry pink was dispersed in isopropyl alcohol/dichloromethane.
23. The tablets of step 21 were coated with the dispersion of step 22.
5 Acid resistance test of the multiple unit tablet was performed in 0.1N HC1
at 75
rpm paddle for 120min (at initial time point and after 3 months storage at
accelerated
conditions). The result is given in the following table 1 below:
Table 1: Acid resistance test of Example 2
Initial After 3M storage
at 40 C/75% RH
Acid resistance (%) 101 96
Dissolution of the multiple unit tablet was carried out in 0.1N HC1 (300m1) at
75rpm paddle for 2hrs followed by pH 6.8 (700m1) at 75rpm paddle for 45
minutes (at
initial time point and after 3 months storage at accelerated conditions). The
result for
Example 2 is given in Table 2 given below:
Table 2: Dissolution test of Example 2
Initial After 3M storage at
40 C/75% RH
% Drug release
100 98
Further, it was observed that the multiple unit tablet dosage form according
to the
present invention has good stability. The assay values and the amount of
impurities (at
initial time point and after 3 months storage at accelerated conditions) for
Example 2 is
provided in Table 3 below:
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Table 3: Stability data for Example 2
Initial 3M (40 / 75 % RH)
Assay (%) 98 94.5
Impurity 1 0.077 0.130
Impurity 2 0.018 0.015
Impurity 3 0.145 0.157
Impurity 4 0.047 0.100
Impurity 5 0.062 0.197
Totallmpurity 0.753 1.481
The above results show that composition of the present invention is stable
even
after storage for 3 months at 40 C and 75% RH.
Example 3
Qty (mg/unit)
S. No Ingredients Strength (40mg)
40 mg
Sugar spheres 60
A Drug Layer
Esomeprazole calcium eqv. to Esomeprazole 45.44
Hydroxypropylcellulose 16.0
Crospovidone 8.0
Purified water q. s.
Total 131.44
B Separating layer
Polyvinyl pyrrolidone 8.5
Polyethylene G1yco1400 0.8
Talc 14.5
Purified water/Isopropyl alcohol q. s.
Total 155.24
C Enteric Coating layer
Hydroxypropylmethyl cellulose phthalate 119
HPMCP (HP-55)
Hydroxypropylmethyl cellulose phthalate 29.66
HPMCP HP-50
Diethyl phthalate 19.1
Talc 3
Acetone q.s.
Purified water q.s.
Total 326
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D Overcoating layer
Hydroxypropylcellulose 5.6
Polyethylene glycol (PEG 6000) 8.4
Isopropyl alcohol/Dichloromethane q. s.
Total 341.23
E Compression
Crospovidone 60
Cellulose microcrystalline PH 101 478
Cellulose microcrystalline PH 112 189
Hydroxypropylcellulose (L-HPC) 110
Sodium stearyl Fumarate 18
Total 1200
F Film Coating
Opadry pink 27
Isopropyl alcohol q.s.
Dichloromethane q.s.
Process of preparation:
Drug Layering
1. Sugar spheres were sifted through # 36 BSS and # 60 BSS and the fraction
retained
between # 36-60 BSS was collected.
2. Hydroxypropylcellulose (HPC-L) and Crospovidone was sifted through # 30 BSS
followed by dispersing in purified water under mechanical stirring.
3. Esomeprazole calcium was sifted through # 30 BSS followed by dispersing in
step
2 dispersion.
4. The sugar spheres of step 1 were loaded into Wurster coater and coated with
the
dispersion of step 3 to obtain drug-layered beads.
5. The beads obtained in step 4 were dried at product temperature of 35 5 C
for
15-30 minutes.
Separating layer
6. Polyvinylpyrrolidone was sifted through # 30 BSS and dissolved in purified
water/Isopropyl alcohol followed by addition of Polyethylene glycol (PEG 400)
in
the solution.
7. Talc was sifted through # 30 BSS and dispersed in solution of step 6 to
obtain a
dispersion.
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8. The drug-layered beads of step 5 were coated with the dispersion of step 7
to
obtain separating layer coated beads.
9. The beads were dried at product temperature of 35 5 C for 15-30 minutes.
Enteric Coating
10. Diethyl phthalate was dissolved in acetone followed by
hydroxypropylmethylcellulose phthalate under continuous stirring.
11. Purified water was added in the dispersion of step 10 under stirring to
obtain a
dispersion.
12. The separating layer coated beads of step 9 was coated with dispersion of
step 11
to obtain enteric-coated beads.
13. The beads were dried at product temperature of 35 5 C for 12 hrs in
vacuum
tray drier.
Over coating
14. Hydroxypropylcellulose was sifted through # 30 BSS and dissolved in
Isopropyl
alcohol/Dichloromethane followed by addition of Polyethylene glycol (PEG 400)
in the solution to obtain a dispersion.
15. The enteric-coated beads of step 13 were coated with the dispersion of
step 14 to
obtain overcoated coated beads.
16. The beads were dried at product temperature of 35 5 C for 15-30
minutes.
Compression
17. The overcoated beads of step 16 were sifted through # 18 BSS.
18. Microcrystalline cellulose, L- hydroxypropylcellulose and crospovidone was
sifted
through # 30 BSS.
19. The material of step 17 & 18 were blended in a blender.
20. Sodium stearyl fumarate was sifted through # 30 BSS and added to the
material of
step 19 and blended further.
21. The material of step 20 was compressed using approved tooling.
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Film Coating
22. Opadry pink was dispersed in isopropyl alcohol/dichloromethane.
23. The tablets of step 21 were coated with the dispersion of step 22.
Example 4
Qty (mg/unit)
S. No Ingredients Strength (40mg)
40 mg
Sugar spheres 60
A Drug Layer
Esomeprazole magnesium e v. to Esomeprazole 44.5
Hydroxypropylcellulose 18.0
Crospovidone 8.0
Purified water q. s.
Total 130.5
B Separating layer
Polyvinyl pyrrolidone 15.0
Polyethylene G1yco1400 1.0
Talc 3.2
Purified water/Isopropyl alcohol q. s.
Total 150.0
C Enteric Coating layer
Eudragit L30D55 96.51
Triethyl citrate 12.53
Talc 23.67
Acetone q.s.
Purified water q.s.
Total 282.72
D Overcoating layer
Hydroxypropylmethylcellulose (HPMC-E5) 12.0
Polyethylene glycol (PEG 6000) 16.0
Isopropyl alcohol/Dichloromethane q.s.
Total 310.72
E Compression
Crospovidone 58
Cellulose microcrystalline PH 101 511.28
Cellulose microcrystalline PH 112 211
Polyvinylpyrrolidone /Hydroxypropylcellulose / low 105
substituted hydroxypropylcellulose (L-HPC)
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Sodium stearyl Fumarate 4.0
Total 1200
F Film Coating
Opadry pink 30
Isopropyl alcohol q.s.
Dichloromethane q. s.
Process of preparation:
Drug Layering
1. Sugar spheres were sifted through # 36 BSS and # 60 BSS and the fraction
retained
between # 36-60 BSS was collected.
5 2. Hydroxypropylcellulose and Crospovidone was sifted through # 30 BSS
followed
by dispersing in purified water under mechanical stirring.
3. Esomeprazole magnesium was sifted through # 30 BSS followed by dispersing
in
step 2 dispersion.
4. The sugar spheres of step 1 were loaded into Wurster coater and coated with
the
10 dispersion of step 3 to obtain drug-layered beads.
5. The beads obtained in step 4 were dried at product temperature of 35 5 C
for
15-30 minutes.
Separating layer
6. Polyvinylpyrrolidone was sifted through # 30 BSS and dissolved in purified
15 water/Isopropyl alcohol followed by addition of Polyethylene glycol (PEG
400) in
the solution.
7. Talc was sifted through # 30 BSS and dispersed in solution of step 6 to
obtain a
dispersion.
8. The drug-layered beads of step 5 were coated with the dispersion of step 7
to
20 obtain separating layer coated beads.
9. The beads were dried at product temperature of 35 5 C for 15-30 minutes.
Enteric Coating
10. Triethylcitrate was dissolved in purified water followed by addition of
talc under
continuous stirring.
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11. Eudragit dispersion was added to step 10 under continuous stirring.
12. The separating layer coated beads of step 9 were coated with dispersion of
step 11
to obtain enteric-coated beads.
13. The beads obtained in step 12 were dried at product temperature of 35 5
C for
12 hrs in vacuum tray drier.
Overcoating
14. Hydroxypropylmethylcellulose (HPMC-E5) was sifted through # 30 BSS and
dissolved in Isopropyl alcohol/Dichloromethane followed by addition of
Polyethylene glycol (PEG 400) in the solution.
15. The enteric-coated beads of step 13 were coated with the dispersion of
step 14 to
obtain overcoated coated beads.
16. The beads obtained in step 15 were dried at product temperature of 35 5
C for
15-30 minutes.
Compression
17. The overcoated beads of step 16 were sifted through # 18 BSS.
18. Microcrystalline cellulose, Polyvinylpyrrolidone /Hydroxypropylcellulose /
low
substituted hydroxypropylcellulose (L-HPC) and crospovidone were sifted
through
# 30 BSS.
19. The material of step 17 & 18 were blended in a blender.
20. Sodium stearyl fumarate was sifted through # 30 BSS and added to the
material of
step 19 and blended further.
21. The material of step 20 was compressed using approved tooling.
Film Coating
22. Opadry pink was dispersed in isopropyl alcohol/dichloromethane.
23. The tablets of step 21 were coated with the dispersion of step 22.
