Note: Descriptions are shown in the official language in which they were submitted.
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A~PROCESS FOR MANUFACTURE OF STABLE ORAL MULTIPLE UNITS
PHARMACEUTICAL COMPOSITION CONTAINING BENZIMIDAZOLES
Background:
Benzimidazolic compounds such as Omeprazole, Lansoprazole, Pantoprazole,
Pariprazole, Leminoprazole, and Rabeprazole are potent proton pump inhibitor
known
for inhibition of gastric acid secretion. They a re used i n t he therapeutics
of d iseases
related to gastric acidity in mammals, especially in humans, including gastric
and
duodenal ulcers, reflux oesophagitis, gastritis, duodenitis and Zollinger-
Ellison
syndrome.
Benzimidazole such as omeprazole, lansoprazole are sensitive to light, heat
and
moisture. They exhibit fast decomposition below pH 7.8 and has maximum
stability at
pH 11. Hence the oral dosage form containing benzimidazole needs to be p
rotected
from the acidic ingredient used to manufacture the dosage form a nd f rom the
a cidic
gastric fluid so that they reach intactly in the small intestine from where
they are
absorbed systemically. They also have very low aqueous solubility and the
solubility is
pH dependent. Various related art have addressed and have tried to overcome
the
issue of
~ Stabilizing benzimidazole and protecting benzimidazole from acidic
ingredients
acidic and physiological environment.
~ Releasing benzimidazole from enteric-coated pellet preferably more than 85%
w/w in pH 6.8 after 45 minutes with minimum acid degradation in 0.1 N HCI
after
2 hours.
~ Manufacturing pharmaceutical composition containing benzimidazole in single
equipment without involving use of organic solvents for making the process
operator and environment friendly.
U.S. Patent No. 4,786,505 describes extrusion spheronization process for
omeprazole
preparation wherein omeprazole core is prepared by granulating the mixture of
mannitol
powder with lactose anhydrous, hydroxypropylcellulose and microcrystalline
cellulose
with water containing alkaline compound and surfactant. Omeprazole is either
suspended in granulating liquid or added in above powder mixture. Separating
layer
that separates the omeprazole core and enteric layer contains alkaline pH
buffering
compounds and film coating polymer, which is deposited on the pellets,
followed by
deposition of enteric layer in coating pan or fluidized bed coater. Efficient
drying is
essential to reduce the water content of the final dosage form of not more
than 1.5
w/w, which is an absolute requirement for the stable formulation. The process
involves
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use of surfactant, disintegrating agent and filler in the composition, which
are in contact
with omeprazole thereby helping in the dissolution of omeprazole. The process
is a
batch process using multiple equipments, which makes it laborious and time
consuming.
U.S. Patent No. 5385739 describes microgranules dosage form containing
omeprazole.
Powder mixture of omeprazole, mannitol, disintegrating agent
carboxymethylstarch and
surfactant sodium lauryl sulfate is layered on neutral core of sugar and
starch in circular
turbine with inclined flat bottom. Further the core contains protective layer
consisting of
mannitol, sucrose and binding agent, which isolate the active agent from
external
enteric coating layer. Omeprazole and excipients used require additional
micronisation
steps to achieve particle size below 100 microns. Efficient drying is
essential to reduce
the moisture level of active layer to preferably less than 0.5 % to ensure
good stability.
The process also requires stringent temperature control for the granules to be
maintained between 32°C and 38°C.
U.S. Patent No. 6077541 describes process for manufacture of omeprazole
enteric-
coated pellets wherein the drug layer comprises of 20-70% w/w omeprazole.
Enteric
coating layer is directly applied to the drug layer. The process requires
additional step
of micronization of omeprazole. The process also requires alkaline agents,
surface-
active agents and binder, which along with micronised omeprazole is suspended
in
aqueous or non-aqueous solvents. This suspension containing omeprazole is
coated
on non-pariel sugar sphere in fluid bed coater.
EP 1108425 describes multiunit pharmaceutical preparation manufactured by
coating
aqueous suspension of substituted benzimidazole or its acceptable salts in the
micronized form onto inert core to obtain drug core. The invention requires
use of
surfactants and disaggregants in the layer-containing drug, which are mixed in
a
suitable proportion in order to allow disaggregation of the formulations and
dissolution
of the active ingredients. Drug core in turn is coated with an insulating
layer free from
alkaline agent of minimum thickness of 15-mu m, and finally with gastro
resistant layer
of minimum thickness of 30-mu m. The formulation has stringent requirement to
have
humidity less than 1.5% for good stability.
PCT Publication WO 9819668 describes delayed drug delivery system where
micronised omeprazole in aqueous suspension containing water soluble binder is
deposited on core containing alkaline material. The alkaline core structure is
obtained
by depositing powder blend of alkaline material and spheronizing /
disintegrating agent
on non-pariel seeds with the help of polymeric binding agent in fluid bed
granulator with
rotor insert. The drug core is further coated with non-enteric moisture
barrier followed
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by delayed release enteric barrier. The formulation releases only 60 - 80% of
omeprazole after 45 minutes in buffer of pH 6.8.
U.S. Patent No. 6207198 describes omeprazole composition where alkaline
reacting
substance is not present in the composition. It describes a process, which
involves
granulating omeprazole with inert nuclei or aqueous layering containing
suspended
omeprazole onto inert nuclei. The granules or the layered nuclei are
compressed to
form micro tablets, which are coated with intermediate layer followed by
enteric layer.
The composition makes use of disintegrants and surfactants in the intermediate
layer,
which is in immediate contact with a core containing omeprazole to improve the
dissolution of omeprazole. The process described is operator dependant and
makes
use of multiple equipments making it time laborious and consuming.
US Application 20010053387 describes Omeprazole composition where omeprazole
along with alkaline material is layered on non-pariel seeds in centrifugal
coater. These
drug cores are then coated with moisture barrier, which contains hydrophobic
material
(Polydimethylsiloxane) followed by enteric coating. The pellets are compressed
into
tablets or filled into hard gelatin capsules.
Thus the related art
~ Manufactures pharmaceutical composition containing less than 15% w/w
benzimidazole enabling low aqueous soluble benzimidazole to be distributed
over a wide surface area to obtain desired optimum dissolution.
~ Manufactures pharmaceutical composition containing high concentration of
benzimidazole specifically utilizing micronized benzimidazole or surfactant or
disintegrating agent or filler or their combination which are in contact with
benzimidazole for achieving optimum dissolution (pH 6.8 buffer release of more
than 85%w/w after 45 minutes).
~ Makes use of micronized benzimidazole, which becomes an additional step
before actual production takes place.
~ Has stringent requirement to have moisture content less than 1.5% w/w, which
is
essential for stable formulation thereby increasing the drying time and
processing time.
~ Makes use of multiple equipments thereby exposing the operator to potent
drug,
which may be hazardous, and increases the chances of cross contamination.
~ Has low batch yields thereby making the product expensive as it utilizes
suspension of micronized benzimidazole for deposition.
None of the related art teaches process for manufacture of a stable, oral,
multiple unit
pharmaceutical composition containing high concentration of benzimidazole upto
about
40%wlw without the use of micronized benzimidazole, disintegrating agent,
fillers and
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surfactant in contact with benzimidazole, having minimum acid degradation in
0.1 N HCI
after two hours and buffer release of more than 85% wlw in pH 6.8 after 45
minutes in a
single equipment fluid bed bottom spray processor and capable of being filled
in
smallest size (size 5) capsule for ease of administration and patient
acceptance.
Summary of the invention:
The o bject of the invention i s to provide a process for manufacture of a
stable, o ral,
multiple unit pharmaceutical composition containing high concentration of
benzimidazole upto about 40°!°w/w without the use of micronized
benzimidazole,
disintegrating agent, fillers and surfactants in contact with benzimidazole,
having
minimum acid degradation in 0.1 N HC1 after two h ours a nd pH 6.8 b uffer
release o f
more than 85% w/w after 45 minutes in a single equipment fluid bed bottom
spray
processor and capable of being filled in capsule size 5 to size 0 for ease of
administration and patient acceptance.
Further the object of t he invention i s t o p rovide a p rocess f or m
anufacture o f stable,
oral, multiple unit pharmaceutical composition containing high concentration
of
benzimidazole upto about 40%w/w which may be carried out continuously or in
batches
and is unaffected by high moisture content, which may be present in the
composition.
Further the object of the invention is to provide a process for manufacture of
a stable,
oral, multiple unit pharmaceutical composition containing high concentration
of
benzimidazole upto about 40%wlw capable of being filled in capsule size 5 for
the dose
of upto 40mg for omeprazole or upto 30mg for lansoprazole.
Further objects of the invention is to provide a process for manufacture of
alkaline
material treated non-pariel seeds suitable for deposition of alkaline
benzimidazole
dispersion containing dissolved b enzimidazole and t o w ithstand r igors a nd
attrition o f
fluid bed processor.
Further the object of the invention is to provide a process, which consists of
spraying
aqueous or hydroalcoholic solution of benzimidazole in alkali metal hydroxide
solution
on treated non-pariel seeds to obtain drug pellets, which are further coated
with sealant
polymer followed by enteric polymer in a single equipment to obtain
unagglomerated,
uniformly shaped and sized pellets.
Description:
This invention relates to process for manufacture of a stable, oral, multiple
unit
pharmaceutical composition containing high concentration of benzimidazole upto
about
40%w/w without the use of micronized benzimidazole, disintegrating agent and
fillers.
Surfactants in these compositions are part of enteric polymer system and are
not in
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contact with benzimidazole. Multiple unit pharmaceutical composition is m the
form
unagglomerated, a niformly s hape a nd sized enteric-coated pellets t hat are
processed
continuously or in batches in single equipment fluid bed bottom spray
processor. The
enteric-coated pellets obtained by the process of the invention are capable of
being
filled in smallest size capsule (size 5) for ease of administration and
patient acceptance.
The process is environmental friendly as it involves aqueous or hydroalcoholic
media.
Benzimidazole derivative is selected form omeprazole, lansoprazole,
rabeprazole,
pantoprazole, or their optically active isomer. For the purpose of this
invention
omeprazole i s selected as t he benzimidazole d erivative. T he process may b
a carried
out in batches or continuously in single equipment to give enteric-coated
pellets. The
invention involves sequential deposition of:
a) alkaline material layer on non-pariel seeds to obtain treated non-pariel
seeds
b) drug layer to obtain drug pellets
c) sealant polymer layer to obtain sealed pellets
d) enteric polymer layer to obtain enteric coated pellets
Enteric coated pellets containing benzimidazole has minimum acid degradation
after 2
hours in 0.1 N HCI and buffer release of not less than 85% after 45 minutes
when tested
in-vitro and is capable of being filled into size 5 to size 0 capsule.
This is distinct from the prior art as
~ It p rovides a process for manufacturing p harmaceutical composition
containing
high concentration of benzimidazole upto about 40%w/w without the use of
micronized b enzimidazole, d isintegrating a gent, fillers and surfactant in
contact
with benzimidazole, having minimum acid degradation in 0.1 N HCI after two
hours and pH 6.8 buffer release of more than 85% w/w after 45 minute.
~ The moisture content in the formulation is less than 5% wlw and preferably
less
than 3% w/w without having adverse effect on the stability of the formulation.
~ It does not make use of micronized benzimidazole thereby decreasing drug
micronization step in production and making the process more economical.
~ It makes use of single equipment thereby decreasing the chances of cross
contamination a nd I inviting t he exposure of p otent drug to t he operator
making
the process operator friendly.
~ It has high batch yields with minimum drug losses as it utilizes solution of
benzimidazole for deposition.
Following are the different stages of manufacturing, which involves sequential
deposition of following layers.
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Stage I: Treated Non-pariel Seeds
The first stage in the manufacture of pharmaceutical composition as enteric-
coated
pellets containing omeprazole is the d eposition o f alkaline material I aver
o n t he non-
pariel seeds. When aqueous alkaline dispersion containing dissolved omeprazole
was
sprayed on non-pariel seeds there was problem of breakages of non-pariel seeds
in
fluid bed bottom spray processor. It was surprisingly found that when non -
pariel
seeds were treated with alkaline material the problem of breakage was solved.
This
treatment to non-pariel seeds involves spraying alkaline material along with
binder on
non-pariel seeds to produce treated non-pariel seeds. Alternatively, treated
non-pariel
seeds may also be obtained by blending alkaline material with starch during
the
production of non-pariel seeds. This alkaline material treated non-pariel
seeds
produced are possessing high integrity and strength and can withstand the
further
process of manufacturing enteric-coated pellets containing benzimidazole
leading to
uniform Loading of benzimidazole thus resulting into high processing and batch
yields.
Treatment of non-pariel seeds is carried out in fluid bed bottom processor
wherein the
non-pariel seeds a re coated with mixture of water-soluble polymer, which is
selected
from the group of hydroxypropylmethylcellulose and alkaline material for e.g.
light
magnesium carbonate. The ratio of the polymer to alkaline material is about 1:
0.1 to
0.1: 1 and is preferably about 1: 0.5 to 0.5: 1. The total coating of this
mixture is 1 - 4
wlw of non-pariel seeds and the solid content of the spraying suspension is
about 5 - 15
w/w. The process is carried out in fluid bed processor with inlet air
temperature
between 60 - 90°C, outlet air temperature 40 - 55°C, atomization
air pressure 1.0 - 3.5
bars, fluidization flap open between 15 - 90% and continuous spray rate
between 1 -
300 ml / min. These treated non-pariel seeds are used for the production of
drug pellet
and subsequent stage.
Stage II: Drug Pellets
The next stage is the deposition of drug layer on treated non-pariel seeds to
obtain drug
pellets a r d rug c ore. It i nvolves deposition of suspension of dissolved
omeprazole on
treated non-pariel seeds. The solution of omeprazole is prepared by dissolving
omeprazole in aqueous solution of alkali metal hydroxide. The next step is the
preparation of binder solution wherein the binder is dispersed and dissolved
in water.
The drug solution is mixed with aqueous binder solution. Antitack agent is
added to
above solution. The suspension is filtered through appropriate mesh and is
sprayed on
treated non pariel seeds in fluid bed processor with inlet air temperature
between 60 -
90°C, outlet air temperature 40 - 55°C, atomization air pressure
1.0 - 3.5 bars,
fluidization flap open between 15 - 90% and continuous spray rate between 1 -
300 ml /
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min. Drug pellets are obtained after complete spraying of aqueous suspension
containing omeprazole in dissolved form. The drug pellets are dried in Fluid
bed bottom
spray processor to arrive moisture content of less than 5%w/w and preferably
less than
3%w/w. The yield of the process is about 98% w/w.
The content of omeprazole in the drug pellets is 5-60% w/w. The moisture
content of
the drug pellets is less than 5% w/w preferably less than 3% w/w. The particle
size of
the drug pellets ranges from about 600 - 2057 microns and preferably about 710
-
1680 microns. The particle size of treated non-pariel seeds size may be from
420-1405
microns and preferably from about 710-1204 microns.
The alkali metal hydroxide is selected from the group consisting of sodium
hydroxide,
potassium hydroxide, calcium hydroxide, magnesium hydroxide, ammonium
hydroxide
and their mixtures thereof and preferably is sodium hydroxide. The
concentration of
sodium h ydroxide in the drug pellets is about between 12 - 3 0 % w/w o f o
meprazole
and is preferably about 12 - 25% w/w.
The binder is selected from the group of water soluble binder which can
withstand high
pH, consisting of hydroxypropylmethylcellulose, hydroxypropylcellulose,
polyvinylpyrollidone, s odiumcarboxymethylcellulose, methylcellulose and their
mixtures
and is preferably hydroxypropylmethylcellulose alone or in combination with
polyvinylpyrollidone.
Hydroxypropylmethylcellulose used as a binder has a nominal viscosity of 5 -
100cps
and preferably about 5 - 15 cps measured on 2% wlw solution at 20°C.
The
concentration of the binder in drug pellets is about 10 - 40 % w/w of
omeprazole and is
preferably about 15 - 35 % wlw of omeprazole.
Antitack a gents i s s elected form t he group consisting of talc, colloidal
silicon dioxide,
glyceryl monostearate, glyceryl behenate and their mixtures, the preferable
choice
being talc with or without colloidal silicon dioxide and are used in the
concentration level
of about 7.5 - 25 % w/w of omeprazole.
The total solid content of the spraying suspension containing dissolved
omeprazole is
not more than 30 % w/w and is preferably about 15 - 20 % w/w.
The final pH of the spraying suspension is in the range of about 11-14.
The drug pellets after drying shows about 100% of drug release within about 10
minutes in pH 6.8 buffer when tested in-vitro using USP 24 type II dissolution
apparatus.
Stage III: Sealed pellets
The next stage is deposition of sealant polymer layer on drug pellets to
obtain sealed
layer. Seal coating suspension is prepared by dispersing and / or dissolving
sealant
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polymer in water. Antitack agent is added to the above solution. Suspension is
filtered
through appropriate mesh and is sprayed on drug pellets in fluid bed processor
to form
a seal coat, which prevents the contact of acidic enteric coating material
with drug
layer.
The coating parameters are same as per the drug pellets stage. The sealed
pellets are
dried for about 20 - 40 minutes to achieve the moisture level less than 5% and
preferably less than 3%wlw. The sealant polymer is selected from group
consisting of
hydroxypropylmethylcellulose, hydroxypropylcellulose, polyvinylpyrollidone,
sodium
carboxymethylcellulose, methylcellulose and their mixtures and is preferable
hydroxypropylmethylcellulose. The concentration of
hydroxypropylmethylcellulose is
about 10 to 150 % w/w of omeprazole.
Hydroxypropylmethylcellulose used as a sealant polymer has a nominal viscosity
of
about 3 - 100 cps and preferably about 5 - 15 cps measured on 2% w/w solution
at
20°C.
The solid content of the above seal coating suspension is between about 8 -
12% w/w.
The antitack agent is selected from the group consisting of talc, colloidal
silicon dioxide,
glyceryl monostearate, glyceryl behenate and their mixtures used in the
concentration
level of about 10 - 30 % w/w of the sealant polymer and preferably talc.
Optionally alkaline agent such as light magnesium carbonate may also be added
to
these seal coating suspension to improve the barrier property of the membrane.
The sealed pellets after drying shows about 100% of drug release within about
10
minutes in pH 6.8 buffer when tested in-vitro using USP 24 type II dissolution
apparatus.
Stage IV Enteric-Coated Pellets
The final s tage i n the p rocess f or m anufacture o f the p harmaceutical c
omposition as
enteric-coated pellets containing omeprazole is deposition of enteric layer on
sealed
pellets. Enteric coating suspension is prepared by dissolving neutralizing
agent in
water, w hich is s lowly added a nder s tirring to aqueous dispersion of
methacrylic acid
copolymer. This aqueous dispersion of methacrylic acid is ready to use
dispersion and
may contain upto about 3% w/w of surfactants of the total solid content
present in the
dispersion. Hence the surfactants are present in enteric polymer layer only
and in no
way comes in contact with omeprazole. This is in contrast to the formulations
and
processes in the related art as in U.S. Patent No. 4786505, U.S. Patent No.
5385739,
U.S. Patent No. 6077541, EP 1108425, U.S. Patent No. 6207198 where the
surfactant
in fairly large quantities (upto about 5%w/w of drug layer) is in contact with
drug.
Plasticizer, antitack and colorant are added to water to form a fine
suspension and this
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suspension is added to the above dispersion. The final enteric coat suspension
is then
filtered through appropriate mesh. The pH of enteric coat suspension is about
5.2 - 5.8.
The sealed pellets after drying are coated with above enteric coat suspension.
The
coating parameters are same as drug pellets stage. The enteric coat polymer is
methacrylic acid copolymer and is used in the concentration of about 12.5 - 30
% w/w
of sealed pellets.
The plasticizers are selected from the group consisting of polyethylene
glycol, triethyl
citrate, triacetin, tributyl citrate, castor oil, dibutyl sebacate, tween 80
and is used in the
concentration of about 10 - 25 % w/w of the enteric coat polymer and
preferably is
polyethylene glycol. The neutralizing agent is selected from the group
consisting of
sodium, potassium, calcium, magnesium, ammonium hydroxide and their mixtures
and
preferably is sodium hydroxide and is used in the concentration of about 1 - 2
% w/w of
enteric coat polymer. Any other agent that is capable of neutralizing the
acidic group of
methacrylic acid copolymer may also be used.
The antitack agent is selected from the group consisting of talc, colloidal
silicon dioxide,
glyceryl monostearate, glyceryl behenate and their mixtures used in the
concentration
level of about 10 - 30 % w/w of the polymer for enteric coating. The
preferable choice is
talc with or without colloidal silicon dioxide. The solid content of the final
enteric coating
suspension is in the range of about 15 - 25% w/w.
The amount of enteric polymer guarantees gastric resistance and allows the
dissolution
of omeprazole in proximal part of the small intestine. The final enteric-
coated product is
sieved through appropriate mesh and is capable of being encapsulated in hard
gelatin
capsules from size 5 to size 0. The entire manufacturing process is aqueous
and it
results in spherical, glossy pellets containing negligible amount of twins or
triplet. The
benzimidazole content in the final enteric-coated pellets is about upto 40%
w/w. The
yield of the final product is about in the range of 95 - 100% and usually
above 98%
w/w.
In one of the embodiments of the invention the process involving all the
stages that is
treated non-pariel seed stage, drug pellet stage, sealed pellets stage and
enteric-
coated pellets stage are carried out continuously in a single equipment fluid
bed
processor.
In another embodiment of the invention the process is a batch process, but all
the
stages that is treated non-pariel seed stage, drug pellet stage, sealed
pellets stage and
enteric-coated pellets stage are carried out in a single equipment fluid bed
processor,
where t he representative s ample a re sampled at the end of each stages that
is drug
pellet stage, sealed pellets stage and enteric-coated pellets stage for
analysis.
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Other equipments such as coating pan, tangential spray coater may also be used
for
manufacturing enteric-coated pellets containing benzimidazole using the above
process.
Examples:
The invention is further described by following sets of non - limiting
examples.
Enteric-coated pellets containing omeprazole involves following manufacturing
stages,
which are as follows. .
Stage I: Preparation of treated non-pariel seeds
Sr. No. Ingredients Quantity ( kg )
1. Non pariel seeds 18 - 20# 100
2. Hydroxypropylmethylcellulose 1.5
3. Magnesium Carbonate 1.5
4. Water 30
Hydroxypropylmethylcellulose (HPMC) is dispersed and dissolved in water.
Magnesium carbonate is added to this s olution to o btain a f ine s uspension,
which is
filtered t hrough a ppropriate m esh. T his suspension is s prayed on non-
pariel seeds in
fluid bed bottom spray processor to obtain treated non - pariel seeds, which
are used
for further process.
Hydroxypropylmethylcellulose and magnesium carbonate are used in the ratio of
1:0.5
to 0.5:1 and are used in the concentration level of 1 - 4% w/w of the non-
pariel seeds.
Examples 1: Omeprazole Enteric Coated Pellets
Sr. Quantity Quantity Quantity Quantity
Ingredients
No. (% w/w) (% wlw ) (% wlw ) (% w/w)
Stage II: Drug Pellets
1 Omeprazole 24.5 13.8 8.5 40.00
2 Treated Non-Pariel
32.3 56.5 61.9 15.00
Seeds
3 Sodium Hydroxide 3.2 1.8 1.1 5.26
4 Talc 3.7 2.1 1.3 3.00
HPMC E15 7.3 3.4 2.6 6.00
6 Water Qs Qs Qs Qs
Stage
III:
Sealed
Pellets
7.HPMC E5 4.3 4.7 4.9 4.35
8.Talc 0.4 0.5 0.5 0.47
9.Water Qs Qs Qs Qs
to
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Stage IV: Enteric Coated Pellets
Methacrylic acid
copolymer type C 17.3 12.4 13.7 18.5
(solid content)
Polyethylene Glycol
11. 1.7 1.2 1.4 1.9
6000
12.Talc 3.8 2.6 2.9 3.9
13.Titanium dioxide1.2 0.8 1.0 1.3
14.Sodium hydroxide0.3 0.2 0.2 0.32
15.Water Qs Qs Qs Qs
Particle size 18 - 16 -18 16 - 18 20 -
of 20 22
treated non - mesh mesh mesh mesh
pariel
seeds ASTM ASTM ASTM ASTM
Dose 20 mg 20 mg 20 mg 40 mg
Size of capsule
for
5 4 2 5
encapsulation
Stage II: Drug Pellets
Sodium hydroxide is dissolved in water followed by cooling to room
temperature.
Omeprazole is added to this solution. Separately disperse' and / or dissolve
hydroxypropylmethylcellulose E15 in water. Omeprazole solution is mixed with
hydroxypropylmethylcellulose solution. Talc is added to above solution and the
resulting
suspension is filtered through appropriate mesh. The above suspension is
sprayed on
treated non-pariel seeds in fluid bed bottom spray processor to obtain drug
pellets,
which are dried in the same equipment to moisture content of less than 5% w/w
an'd
preferably less than 3% wlw. The drug pellets after drying shows about 100% of
drug
release within about 10 minutes in pH 6.8 buffer when tested in-vitro using
USP 24 type
li dissolution apparatus.
Stage III: Sealed Pellets
Seal coating suspension is prepared by dispersing and / or dissolving
hydroxypropylmethylcellulose E5 in water. Talc is added to above solution. The
resulting suspension is filtered through appropriate mesh and is sprayed on
drug pellets
in fluid bed processor to form sealed pellets. These sealed pellets are dried
to moisture
content of less than 5% w/w and preferably less than 3% w/w. The sealed
pellets after
drying shows about 100% of drug release within about 10 minutes in pH 6.8
buffer
when tested in-vitro using USP 24 type II dissolution apparatus.
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Stage IV: Enteric Coated Pellets
Enteric coating suspension is prepared by dissolving sodium hydroxide in
water, which
is slowly added under stirring to aqueous dispersion of methacrylic acid
copolymer type
C. Polyethylene glycol 6000 is dissolved separately in water. To this solution
talc and
titanium dioxide is added to form a fine suspension and this suspension is
added to the
above dispersion. The final enteric coat suspension is then filtered through
appropriate
mesh. This suspension is sprayed on sealed pellets in fluid bed processor to
obtain
enteric-coated pellets containing omeprazole. These enteric-coated pellets are
then
dried to have moisture content of less than 5% w/w and preferably less than 3%
w/w.
The process of the invention results in the production of enteric-coated
pellets
containing omeprazole that does not require micronisation of omeprazole or any
additional excipients like disintegrating agents, fillers or surfactant in
contact with
omeprazole for improving the dissolution of omeprazole.
The enteric-coated pellets containing omeprazole thus obtained is tested in-
vitro for
acid resistance in 0.1 N HCI after 2 hours and buffer dissolution in pH 6.8
after 45 which
is described below. The acceptance criteria for these pellets are laid down in
the
specification below.
The pellets may receive an additional coat of an enteric layer if it does not
comply with
the specification for acid degradation as specified below.
The enteric-coated pellets containing omeprazole are filled in capsule of
varying sizes
that is from size 5 to size 0 depending on the final concentration of
omeprazole in
enteric-coated pellets.
Example 2: Lansoprazole enteric-coated pellets
Formulation for encapsulation in size 5 hard gelatin capsules.
Sr. No. Ingredients Quantity (%wlw)
Stage I : Drug Pellets
1. Lansoprazole 30.0
2. Treated Non- Pariel Seeds' 18 - 20
22.7
mesh ASTM
3. Sodium Hydroxide 7.5
4. Talc 3.0
5. Hydroxypropylmethylcellulose E15 6.0
6. Colloidal Silicon dioxide 0.5
7. Water QS
8. Isopropyl Alcohol QS
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Stage II : Sealed Pellets
9. Hydroxypropylmethylcellulose4.2
E5
10. Talc 0.4
11. Water Qs
Stage11 : Enteric Coated Pellets
1
12. Methacyrlic acid copolymer
type C
18.6
(solid content)
13. Polyethylene Glycol 6000 1.86
14. Talc 3.9
15. Colloidal Silicon dioxide 0.24
16. Titanium dioxide 0.85
17. Sodium hydroxide 0.25
18. Water Qs
Size of capsule for encapsulation'5'
Dose 30
mg
The p rocess f or t he m anufacture o f a nteric-coated p ellets c ontaining L
ansoprazole i s
same as described a hove except t hat Lansoprazole is dissolved in sodium
hydroxide
solution in water containing small quantity of isopropyl alcohol:
In-vitro dissolution studies of these pellets are carried out as described
below. The
acceptance criteria for these pellets are laid down in the specification
below.
The pellets may receive an additional coat of an enteric layer if it does not
comply with
the specification for acid degradation as specified below.
Dissolution Studies:
The pellets containing omeprazole or lansoprazole, which are manufactured, as
described in above examples are tested for acid resistance in 0.1 N HCI after
2 hours
and buffer dissolution in pH 6.8 after 45 minutes using USP 24 Type II
dissolution test
apparatus. The results obtained are as follows.
Time pH % Drug release Specification
NMT 15% degrades in 2
2 hours 0.1 N HCI 0 - 7
hours
45 minutes pH 6.8 buffer 90 -100 NLT 85%
These pellets which meets the requirements of the above mentioned
specification are
filled in capsule of different sizes containing unit dose of benzimidazole.
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The pellets containing upto about 40% wlw of omeprazole are capable of being
filled in
size 5 capsule for the dose of upto about 40mg of omeprazole. The enteric-
coated
pellets containing about 30% wlw of lansoprazole are capable of being filled
in size 5
capsule for the dose of upto about 30 mg of lansoprazole.
Stability:
The enteric-coated pellets containing about 20 mg omeprazole prepared as
described
in example above were encapsulated in size 5 hard gelatin capsules and
subjected to
accelerated stability condition at 40° C/75% RH and 25°C/60 %
RH. The stability results
are as follows.
Dissolution
Profile
Assay
PeriodCondition Acid Stage Buffer Stage
%wlw
(%wlw) (%w/w)
Initial- 98.5 1.0 99.85
1 Month25C/ 60%RH 99.9 0.24 98.68
1 Month40C/ 75%RH 100.05 0.0 99.04
3 Month25C/ 60%RH 97.25 1.5 98.45
3 Month40C/ 75tRH 99.7 0.31 97.56
6 Month25C/ 60%RH 98.45 0.1 101.1
6 Month40C/ 75%RH 96.15 0.0 92.59
The results presented above shows that enteric-coated pellets containing
omeprazole
of the present invention~are stable atleast for a period 2 years.
Bioequivalence Study:
A bioequivalence study was carried out in 12 healthy human volunteers using
Losec
RTM as reference. The results are as follows.
Pharmacokinetic parameters Test Reference
Cmax (pg/ml) (Avg. ~ std. dev.) 0.92 (~0.22) 0.88 (~0.17)
Tmax (hrs.) (Avg. ~ std. dev.) 3.67 (~0.47) 3.25 (~0.43)
AUC (0-24) p.g.hr/ml (Avg. ~ std. dev.) 6.70 (~1.39) 7.70 (~1.62)
Various modification and alteration may be made in the process and the product
without varying the spirit and scope of the invention. The process and the
product
described in the i nvention a re merely illustrative o f t he preferred
embodiments of the
invention and do not limit the scope of the invention.
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