U.S. patent application number 10/804255 was filed with the patent office on 2004-09-09 for omeprazole formulation.
Invention is credited to Chen, Chih-Ming, Chou, Joseph, Kositprapa, Unchalee.
Application Number | 20040175427 10/804255 |
Document ID | / |
Family ID | 32230706 |
Filed Date | 2004-09-09 |
United States Patent
Application |
20040175427 |
Kind Code |
A1 |
Chen, Chih-Ming ; et
al. |
September 9, 2004 |
Omeprazole formulation
Abstract
A stable pharmaceutical composition of omeprazole for oral
administration which consists essentially of: (a) a core of
Omeprazole or a pharmaceutically equivalent salt, a filler and an
alkaline material selected from the group consisting of lysing and
arginine; and (b) a single layer of coating on said core which
comprises a layer of an enteric coating agent which is applied from
an organic solvent based system.
Inventors: |
Chen, Chih-Ming; (Davie,
FL) ; Chou, Joseph; (Manassas, VA) ;
Kositprapa, Unchalee; (Ft. Lauderdale, FL) |
Correspondence
Address: |
Martin P. Endres, Esq.
HEDMAN & COSTIGAN, P.C.
1185 Avenue of the Americas
New York
NY
10036
US
|
Family ID: |
32230706 |
Appl. No.: |
10/804255 |
Filed: |
March 19, 2004 |
Related U.S. Patent Documents
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Application
Number |
Filing Date |
Patent Number |
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10804255 |
Mar 19, 2004 |
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09763831 |
Jul 11, 2001 |
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6733778 |
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09763831 |
Jul 11, 2001 |
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PCT/US99/19847 |
Aug 27, 1999 |
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09763831 |
Jul 11, 2001 |
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09143167 |
Aug 28, 1998 |
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6174548 |
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Current U.S.
Class: |
424/471 |
Current CPC
Class: |
A61K 9/5078 20130101;
A61K 9/1617 20130101; A61K 9/2013 20130101; A61K 31/4439 20130101;
A61K 9/2886 20130101; A61K 9/1635 20130101; A61K 9/2846 20130101;
A61K 9/284 20130101; A61K 9/2077 20130101; A61K 9/2866 20130101;
A61K 9/1652 20130101; A61K 9/2081 20130101 |
Class at
Publication: |
424/471 |
International
Class: |
A61K 009/24; A61K
009/28 |
Claims
1. A stable pharmaceutical composition of omeprazole for oral
administration which consists essentially of: (a) a core of
Omeprazole or a pharmaceutically equivalent salt, a filler and an
alkaline material selected from the group consisting of lysine and
arginine; and (b) a single layer of coating on said core which
comprises a layer of an enteric coating agent applied from an
organic solvent based system.
2. A pharmaceutical composition of omeprazole as defined in claim 1
wherein said core is further comprised essentially of a surface
active agent, and a binder and said pharmaceutical composition is
formed into a compressed tablet.
3. A pharmaceutical composition as defined in claim 1 wherein said
core is further comprised essentially of a an inert core component,
a surface active agent and a binder and said pharmaceutical
composition is pelleted.
4. A pharmaceutical composition of omeprazole as defined in claim 2
wherein the acid resistant component is selected from the group
consisting of cellulose acetate phthalate, hydroxypropylmethyl
cellulose phthalate, polyvinyl acetate phthalate,
carboxymethylethylcellulose, co-polymerized methacrylic
acid/methacrylic acid methyl esters.
5. A pharmaceutical composition of omeprazole as defined in claim 3
wherein the acid resistant component is selected from the group
consisting of cellulose acetate phthalate, hydroxypropylmethyl
cellulose phthalate, polyvinyl acetate phthalate,
carboxymethylethylcellulose, co-polymerized methacrylic
acid/methacrylic acid methyl esters.
6. A pharmaceutical composition of omeprazole as defined in claim 1
wherein the enteric coating agent also includes an inert processing
aid.
7. A pharmaceutical composition of omeprazole as defined in claim 1
wherein the enteric coating agent around the core includes from 5
to 55wt % by weight of the coating of an inert processing aid.
8. A pharmaceutical composition of omeprazole as defined in claim 1
which includes a sodium lauryl sulfate as the surface active
agent.
9. A pharmaceutical dosage formulation which consists essentially
of: (a) a tablet core comprising omeprazole, a binder, an alkaline
agent selected from the group consisting of arginine or lysine, a
filler; and (b) an enteric coating agent around said core, said
enteric coating comprising hydroxypropylmethyl cellulose phthalate
and talc.
10. A pharmaceutical composition as defined in claim 3 wherein the
core contains a non-pariel sugar seed.
11. A pelleted pharmaceutical dosage formulation which consists
essentially of: (a) a core comprising a non-pariel sugar seed
coated with drug layer composition comprising omeprazole, a binder,
an alkaline agent selected from the list consisting of arginine and
-lysine, a filler and a surface active agent; and (b) an enteric
coating agent around said core, said enteric coating comprising
hydroxypropylmethyl cellulose phthalate and talc which is applied
from an organic solvent based system.
Description
BACKGROUND OF THE INVENTION
[0001] The present invention relates to a stable formulation of
omeprazole. It is well known that omeprazole is sensitive to acidic
conditions and after contact with an acid, omeprazole will degrade
and will not function in its intended manner. Initially, alkaline
materials were added to a core of omeprazole and later an enteric
coating was applied over the core to prevent the omeprazole from
contacting the acidic pH conditions of the stomach. This approach
is satisfactory if the product is administered within a short time
after it is manufactured but if the product is stored under ambient
conditions, the acidic residue of the enteric coating appears to
degrade the omeprazole before it is administered to a patient. To
solve this problem, the prior art has used a separate layer of a
coating agent to coat a pellet core which contains omeprazole and
an alkaline material which is thereafter coated with the enteric
coating. This technique is described in U.S. Pat. No. 4,786,505. In
addition WO 96/24338 discloses the use of an in situ formed
interlayer that is based on the reaction of an aqueous enteric
coating material with an alkaline material in the core.
[0002] This dual layer coating technique requires the application
of two separate functional coating operations which increases the
length of the manufacturing process and the cost of the product.
The applicants have surprisingly discovered a coating system which
avoids the need to use a coating layer to separate the omeprazole
core from the enteric coating layer in an omeprazole dosage form.
The separate coating system is based on the combined use of an
enteric coating agent which is applied to a pelletized core or a
granular core of omeprazole as a suspension in a suitable
solvent.
[0003] The applicants have also surprisingly discovered that
arginine or lysine can be used as a pH stabilizing agent.
SUMMARY OF THE INVENTION
[0004] The present invention provides a novel stable pharmaceutical
composition of omeprazole for oral administration which consists
essentially of:
[0005] (a) a core of omeprazole or a pharmaceutically equivalent
salt, a filler and an alkaline material selected from the group
consisting of lysine and arginine; and
[0006] (b) a single layer of coating on said core which comprises a
layer of an enteric coating agent applied from an organic based
solvent coating system.
[0007] The core of the pharmaceutical composition can be in the
form of a compressed tablet which is further comprised essentially
of a surface active agent, and a binder. Alternatively, the
pharmaceutical composition can have a pelleted core which is
further comprised essentially of an inert core component, a surface
active agent and a binder.
[0008] Accordingly, it is a primary object of this invention to
provide a pharmaceutical dosage formulation of omeprazole which is
stable upon prolonged storage, is stable when administered to a
patient and is capable of providing the desired therapeutic
effect.
[0009] It is also an object of this invention to provide a
pharmaceutical dosage form of omeprazole which is bioequivalent to
dosage forms of omeprazole which have an intermediate layer of an
inert coating material.
[0010] It is also an object of this invention to provide a stable
dosage form of omeprazole which may be produced without the need to
provide an intermediate coating layer that separates the omeprazole
containing core from the enteric coating layer.
[0011] These and other objects of the invention will become
apparent from a review of the appended specification.
DETAILED DESCRIPTION OF THE INVENTION
[0012] The omeprazole formulation of the invention is preferably
based on a core of omeprazole or pharmaceutically equivalent salt,
a filler and an alkaline material selected from the group
consisting of arginine or lysine; and a single layer of coating on
said core which comprises a layer of an enteric coating agent
applied from an organic solvent based system. The Omeprazole core
can either be pelleted or tabletted as described herein.
[0013] In the case of both the pelleted form and the tabletted form
of the core a filler is used. A filler is used as a granulation
substrate. Sugars such as lactose, dextrose, sucrose, maltose, or
microcrystalline cellulose and the like may be used as fillers in
either the pellet or the granulation composition. In the case of
the pelleted form the filler may comprise from 20 to 90 wt % and
preferably 65-85 wt % based on the total weight of the drug layer
composition. In the case of the tabletted form the filler may
comprise from 20 to 60 wt % and preferably 20 to 40 wt % based on
the total weight of the granulation. In the case of the tabletted
form of the invention a tablet disintegrant may be added which
comprises corn starch, potato starch, croscarmelose sodium,
crospovidone and sodium starch glycolate in an effective amount. An
effective amount which may be from 3 to 10 wt % based on the total
weight of the granulation.
[0014] In the case of both the tabletted form and the pelleted form
of the core an alkaline agent that is either lysine or arginine is
used as a stabilizer. In the case of the tabletted form a level of
from 20 to 60 wt % and preferably 30 to 55 wt % based on the weight
of the granulation may be employed. In the case of the pelleted
form a level of from 0.5 to 10 wt % and preferably 1 to 3 wt %
based on the weight of the pellet may be employed.
[0015] In the case of both the pelleted form and the tabletted form
of the invention an enteric coating agent is placed over the core.
In both cases the enteric coating may comprise an acid resisting
material which resists acid up to a pH of above about 5.0 or higher
which is selected from the group consisting of cellulose acetate
phthalate, hydroxypropylmethyl cellulose phthalate, polyvinyl
acetate phthalate, carboxymethylethylcellu- lose, Eudragit L
(poly(methacrylic acid, methylmethacrylate), 1:1 ratio; MW (No. Av.
135,000--USP Type A) or Eudragit S (poly(methacrylic acid,
methylmethacrylate, 1:2 ratio MW (No. Av. 135,000--USP Type B) and
mixtures thereof.
[0016] The enteric coating agent may also include an inert
processing aid in an amount in the case of the tabletted form from
15 to 55 wt % and preferably 20 to 45 wt % based on the total
weight of the acid resisting component and the inert processing
aid. In the case of the pelleted form the inert processing aid is
preferably in an amount from 5 to 50 wt % and most preferably 10-20
wt %. The inert processing aids include finely divided forms of
talc, silicon dioxide, magnesium stearate etc. Typical solvents
which may be used to apply the acid resisting component-inert
processing aid mixture include isopropyl alcohol, acetone,
methylene chloride and the like. Generally the acid resistant
component-inert processing aid mixture will be applied from a 5 to
20 wt % of acid resisting component-inert processing aid mixture
based on the total weight of the solvent and the acid resistant
component-inert processing aid.
[0017] In the case of both the tabletted form and the pelleted form
of the invention omeprazole or a pharmaceutically equivalent salt
is used in the core. in the tabletted formulation the omeprazole
may comprise from 5 to 70 wt % and preferably 10 to 30 wt % of the
granulation. In the pelleted form the Omeprazole may comprise from
10 to 50 wt % and preferably 10 to 20 wt % of the drug layer
composition.
[0018] A surface active agent is used in both the tabletted and the
pelleted form of the invention. The surface active agent may be any
pharmaceutically acceptable, non-toxic surfactant. Suitable surface
active agents include sodium lauryl sulfate, polysorbate 20,
polysorbate 40, polysorbate 60, polysorbate 80 and the like. The
surface active agent may be present at a level of from 0.1 to 5 wt
%. In the case of the tabletted form the surface active agent is
preferably 0.20 to 2.0 wt % based on the total weight of the
granulation. In the pelleted form the surface active agent is
preferably 0.20 to 2.0 wt % of the total weight of the drug layer
composition.
[0019] The binder is used in both the tabletted and the pelleted
form of the invention. The binder may be any pharmaceutically
acceptable, non-toxic pharmaceutically acceptable binder. The
binder is preferably a water soluble polymer of the group
consisting of polyvinyl alcohol, polyvinylpyrrolidone,
methylcellulose, hydroxypropyl cellulose, hydroxymethyl cellulose
and the like. A water soluble binder is preferred which is applied
from an aqueous medium such as water at a level of from 0.1 to 10
wt % and preferably from 0.25 to 7.5 wt % of binder based on the
total weight of the granulation.
[0020] In the case of the tabletted form of the invention a
granulation is formed by contacting the alkaline agent, the
omeprazole, the surface active agent and the binder with a medium
which may comprise any low viscosity solvent such as water,
isopropyl alcohol, acetone, ethanol or the like. When fluids such
as water are employed, this will usually require a weight of fluid
which is about three times the weight of the dry components of the
coating composition.
[0021] After the granulation is formed and dried, the granulation
is tabletted and the tablets are directly coated with the enteric
coating agent. A color imparting agent may be added to the enteric
coating agent mixture or a rapidly dissolving seal coat containing
color may be coated over the enteric coating agent layer provided
that the seal coat is compatible with and does not affect the
dissolution of the enteric coating layer. The rapidly dissolving
seal coat may comprise Opadry pink which comprises approximately 91
wt % hydroxypropyl methylcellulose (E-6), color and 9 wt %
polyethylene glycol which is applied as a 8-15% w/w solution in
purified water. In addition the color may be provided as
Chromateric which is available from Crompton & Knowles. This
product contains water, talc, TiO.sub.2, triethyl citrate,
propylene glycol, synthetic red iron oxide, potassium sorbate,
xanthan gum, sodium citrate and synthetic yellow iron oxide. If
desired, conventional sugar based seal coats may be used which
contain FDA certified dyes.
[0022] In the case of a pelleted form the invention is preferably
based on pellets having a core forming inert component which may
comprise a starch or sugar sphere such as non-pareil sugar seeds
having an average size of 14 to 35 mesh, preferably about 18 to 20
mesh. The core forming inert component is coated with a formulation
which comprises Omeprazole, a surface active agent, a filler, an
alkaline material that is either lysine or arginine and a binder,
which are collectively referred to as the drug layer composition.
The core forming inert component is employed at 1:1 to 5:1 and
preferably from 2:1 to 3:1 weight ratio to the drug layer
composition.
[0023] The cores are formed by spraying the non-pareil seeds with
an aqueous or non-aqueous suspension which contains the alkaline
agent, the omeprazole, the surface active agent and the binder. The
suspension medium may comprise any low viscosity solvent such as
water, isopropyl alcohol, acetone, ethanol or the like. When fluids
such as water are employed , this will usually require a weight of
fluid which is about seven times the weight of the dry components
of the coating composition.
[0024] After the cores are dried, the cores are coated with the
enteric coating agent. A color imparting agent may be added to the
enteric coating agent mixture or a rapidly dissolving seal coat
over the enteric coating agent layer provided that the seal coat is
compatible with and does no affect the dissolution of the enteric
coating layer.
DESCRIPTION OF THE PREFERRED EMBODIMENTS
[0025] Examples 1 to 5 describe a tabletted form of the invention
and Example 6 describes a pelleted form of the invention.
EXAMPLE 1
[0026] Granulation.
[0027] A granulation containing omeprazole is formed in a fluid bed
coater using a top spray granulation forming suspension containing
omeprazole, micronized to 95% less than 15 microns, 5% w/w of the
total amount of L-arginine, polyvinyl pyrrolidone, sodium lauryl
sulfate and purified water which is sprayed onto a mixture of
microcrystalline cellulose, 95% w/w of the total amount of
L-arginine and sodium starch glycolate. The formulation for making
the granulation has the following composition:
1 povidone, USP (Plasdone K90) 100.0 g sodium starch glycolate
100.0 g sodium lauryl sulfate, NF/USP 6.0 g microcrystalline
cellulose (AvicelPH101) 965.6 g L-arginine, USP/FCC 1020.0 g
omeprazole, USP (micronized) 340.0 g purified water, USP 1100.0
g
[0028] Tabletting.
[0029] The granulation is tabletted into tablets containing 20 mg
of omeprazole by first mixing the omeprazole granules with glyceryl
monostearate:
2 omeprazole granules 118.0 g glyceryl monostearate (Myvaplex) 6.0
g Tabletting tools: 0.2812" target weight: 124 mg/tab target
hardness: 7 Kp LOD of granules: less than 3%
[0030] Enteric Coating.
[0031] An enteric coating is applied to prepare enteric coated
tablets as follows:
3 omeprazole tablets 124.0 g (prepared above) hydroxypropyl
methylcellulose 14.7 g phthalate talc 4.2 g acetyl tributyl citrate
2.9 g acetone 148.0 g isopropyl alcohol 148.0 g
[0032] The solid coating materials were dissolved in the acetone
and isopropyl alcohol and this solution was coated onto the
omeprazole tablets using a perforated pan
[0033] Seal Coat:
[0034] A seal coat was applied to the enteric coated tablets as
follows:
4 Enteric coated tablet 146.0 g Opadry II pink 4.5 g Water 450.0
g
[0035] The seal coat was applied onto the enteric coated omeprazole
tablets using a perforated pan coater.
EXAMPLE 2
[0036] Granulation.
[0037] A granulation containing omeprazole is formed in fluid bed
coater using a top spray granulation forming suspension containing
omeprazole, micronized to 95% less than 15 microns, 2.68% w/w of
the total amount of L-arginine, polyvinyl pyrrolidone, polysorbate
80 and purified water which is sprayed onto a mixture of
microcrystalline cellulose and 95.0% w/w of the total amount of
L-arginine. The formulation for making the granulation has the
following composition:
5 mg/ tablet povidone, USP (Plasdone K90) 5.88 polysorbate 80
(Tween 80) 0.58 L-arginine, USP/FCC 60.0 omeprazole, USP
(micronized) 20.0 microcrystalline cellulose (Avicel PH102) 25.54
purified water, USP n/a
[0038] Tabletting.
[0039] The granulation is tabletted into tablets containing 20 mg
of omeprazole by first mixing the omeprazole granules with glyceryl
monostearate:
6 omeprazole granules 112.0 mg glyceryl monostearate (Myvaplex) 6.8
mg crospovidone XL 16.2 mg Tabletting tools: 0.2812" target weight:
135 mg/tab target hardness: 7 Kp LOD of granules: less than 3%
[0040] Enteric Coating.
[0041] An enteric coating was applied to prepare enteric coated
tablets as follows:
7 omeprazole tablets 135.0 mg (prepared above) Eudragit L30D-55
14.0 mg color (Chromateric) 7.0 mg 1M NaOH (to adjust pH to 5.0)qs
na Purified water qs na
[0042] The solid coating materials were dispersed in the water and
this mixture was coated onto the omeprazole tablets using a
perforated pan.
EXAMPLE 3
[0043] Granulation.
[0044] A granulation containing omeprazole is formed in fluid bed
coater using a top spray granulation forming suspension containing
omeprazole, micronized to 95% less than 15 microns, 5.0% w/w of the
total amount of L-arginine, polyvinyl pyrrolidone, sodium lauryl
sulfate and purified water which is sprayed onto a mixture of
microcrystalline cellulose and 95.0% w/w of the total amount of
L-arginine. The formulation for making the granulation has the
following composition:
8 mg/tablet povidone, USP (Plasdone K90) 5.0 sodium lauryl sulfate
0.3 L-arginine, USP/FCC 60.0 omeprazole, USP (micronized) 10.0 g
microcrystalline cellulose (AvicelPH102) 24.7 purified water, USP
n/a
[0045] Tabletting.
[0046] The granulation is tabletted into tablets containing 10 mg
of omeprazole by first mixing the omeprazole granules with glyceryl
monostearate:
9 omeprazole granules 100.0 mg glyceryl monostearate (Myvaplex) 5.0
mg sodium starch glycolate 5.0 mg Tabletting tools: 0.2812" target
weight: 110 mg/tab target hardness: 7 Kp LOD of granules: less than
3%
[0047] Enteric Coating.
[0048] The tablets were coated with the same enteric coating that
was applied to the tablets in Example 2.
EXAMPLE 4
[0049] Granulation.
[0050] A granulation containing omeprazole is formed in fluid bed
coater using a top spray granulation forming suspension containing
omeprazole, micronized to 95% less than 15 microns, 5.0% w/w of the
total amount of L-arginine, polyvinyl pyrrolidone, sodium lauryl
sulfate and purified water which is sprayed onto a mixture of
microcrystalline cellulose and 95.0% w/w of the total amount of
L-arginine. The formulation for making the granulation has the
following composition:
10 mg/tablet povidone, USP (Plasdone K90) 5.88 polysorbate 80 0.60
L-arginine, USP/FCC 60.0 omeprazole, USP (micronized) 20.0
crospovidone XL 5.88 microcrystalline cellulose 25.54 purified
water, USP n/a
[0051] Tabletting.
[0052] The granulation is tabletted into tablets containing 20 mg
of omeprazole by first mixing the omeprazole granules with glyceryl
monostearate:
11 omeprazole granules 117.9 mg glyceryl monostearate (Myvaplex)
6.1 mg Tabletting tools: 0.2812" target weight: 124 mg/tab target
hardness: 7 Kp LOD of granules: less than 3%
[0053] Enteric Coating.
[0054] The tablets were coated with the same enteric coating that
was applied to the tablets in Example 1.
EXAMPLE 5
[0055] The granulation of Example 1 was prepared and tabletted into
tablets containing 20.0 mg of omeprazole. These tablets were coated
as follows:
[0056] Enteric coating.
[0057] An enteric coating was applied to prepare enteric coated
tablets as follows:
12 omeprazole tablets 126.00 mg (prepared above) Eudragit L30D-55
17.00 mg 1M NaOH (to adjust pH to 5.0) qs na acetyl tributyl
citrate 1.70 mg talc 3.80 mg polysorbate 80 1.50 mg Purified water
qs na
[0058] The solid coating materials were dispersed in the water and
this mixture was coated onto the omeprazole tablets using a
perforated pan. A seal coat was applied using the procedure of
Example 1.
EXAMPLE 6
[0059] In the case of a pharmaceutical formulation with a pelleted
omeprazole core, the core is comprised of omeprazole, a surface
active agent, a filler, an alkaline material and a binder.
[0060] Omeprazole activated pellets (sodium free) are prepared as
follows: 13.650 kg of Purified water is dispensed into a suitably
sized stainless steel container. L-Arginine Base (0.210 kg),
Lactose Anhydrous, NF (1.75 kg) and Povidone (Plasdone .RTM.K-90)
(0.056 kg) is added to the purified water while homogenizing at
full speed (about 5,000 rpm). Homogenizing is continued until the
materials are completely dissolved. Polysorbate 80, NF (0.044 kg)
is added to the solution while homogenizing at a lower speed
(700-3300 rpm) to avoid excess foaming.
[0061] The material is homogenized until dissolved completely. Half
of the solution (7.855 kg) is transferred into a 5-10 gallon
stainless steel container. The original container is hereafter
referred to as "container A" and the new container is henceforth
referred to as "container B." Micronized omeprazole 95% less than
15 microns (0.980 kg) is added to container A while homogenizing at
a lower speed (700-3300 rpm) to avoid excess foaming. The
Omeprazole is allowed to disperse into the solution completely and
then homogenized for another 10 minutes. The homogenizer is
replaced with a mechanical stirrer and the suspension is
continuously stirred throughout the coating process. When
approximately three fourth of the omeprazole suspension in
container A is consumed, 0.980 kg of micronized omeprazole is added
to container B while homogenizing at a lower speed (700-3300) to
avoid excess foaming. The Omeprazole is allowed to disperse in the
solution completely and homogenization is continued for another 10
minutes. The homogenizer is replaced with a mechanical stirrer and
the suspension is continuously stirred throughout the coating
process. 9.98 kg of sugar spheres are added to a fluidized bed
coater and preheated until the product reaches 40-45.degree. C. The
drug suspension from containers A and B are sprayed onto the
spheres. The atomization pressure is between 1.5 to 3.5 bar and
the; pump rate is 2-100 ml/min. The spray rate does not exceed 20
ml/min in the first two hours to avoid agglomeration of the sugar
spheres. The coating suspension is transferred to a smaller
container to facilitate stirring when the surface of the coating
suspension reaches the stirring blade. After the coating suspension
has been consumed the pump is stopped and the fluidization is
continued in the fluidized bed coater with the heat off until the
product temperature drops below 32.degree. C.
[0062] The pellets are then transferred to a fluidized bed coater
into a 50.degree. C. oven (45-55.degree. C.). The pellets are dried
until the moisture content of the pellets is not more then 2.5%.
The pellets are separated into different size fractions by using a
SWECO Separator equipped with 14 and 24 mesh screens. The pellets
are collected in doubled polyethylene lined plastic containers and
stored with desiccant.
[0063] Enteric Coating Process
[0064] 10.844 kg of isopropyl alcohol, USP is dispensed into a
suitably sized stainless steel container. 10.844 kg of acetone is
added to the isopropyl alcohol. 1.683 kg of hydroxypropyl
methylcellulose phthalate (Hypromellose 55, Substitution type
200731) and cetyl alcohol, NF (0.084 kg) are added to the solution
while homogenizing at full speed until all the materials are
dissolved completely. The homegnizer is then removed and replaced
with a mechanical stirrer.
[0065] Talc (1.683 kg) is added while stirring. The talc is mixed
until fully dispersed in the solution and the mixing is continued
throughout the entire coating process. A fluidized bed coater is
preheated to 32.degree. C. The omeprazole active pellets (11.550
kg) are loaded into the fluidized bed coater and preheated until
the temperature reaches 30.degree. C.
[0066] The coating suspension is sprayed on the pellets using a
product temperature of 25-35.degree. C., an atomization pressure of
1.5 to 3.0 bar and a pump rate of 200-300 ml/min. The coating
suspension is transferred to a smaller container to facilitate
stirring when the surface of the coating suspension reaches the
stirring blade.
[0067] After the coating suspension has been consumed the coated
pellets are dried in a fluidized bed coater for 20 minutes using
the same coating conditions except lowering the atomization
pressure to 2 bars or below. The coated pellets are discharged into
double polyethylene bags. The pellets are separated into different
size fractions by using a SWECO separator equipped with 14 and 24
mesh screens. The pellets which are larger than 14 mesh and smaller
than 24 mesh are rejected. The pellets that passed through the 14
mesh and retained on the 24 mesh are retained in polyethylene
bags.
[0068] Blending
[0069] Omeprazole enteric coated pellets (Sodium Free), blended are
prepared as follows:
[0070] 14.400 kg of omeprazole enteric coated pellets (Sodium free)
are charged into a blender. Talc, USP (0.225 kg) is sprinkled on
top of the pellet bed and then blended at 28 rpm for 5 minutes. 0.2
to 0.5 grams of each sample is withdrawn into separate vials from
the blender. The blended pellets are unloaded into plastic
containers lined with double polyethylene. The excess talc is
screened off using a SWECO separator equipped with a 24 mesh
screen. The pellets are collected in containers lined with double
polyethylene bags and stored with desiccant.
[0071] Encapsulation
[0072] An encapsulation room is prepared in which the relative
humidity is in the range of 35-65% and the temperature is in the
range of 15-25.degree. C. Omeprazole enteric coated pellets (Sodium
Free) blended are encapsulated using the following equipment and
guidelines. A capsule machine model MACOFAR MT-20 is prepared for
the procedure placing the machine setting at 4, using capsule
machine size part 1, capsule magazine 1. The target filled capsule
weight is 457.15 mg. If the total weight is not within 3% of the
target weight, further adjustment must be performed. Capsule fill
verification is performed at twenty minutes intervals on ten
individual capsules. Acceptable capsules are collected in
containers lined with double polyethylene bags and placed under
desiccant.
[0073] While certain preferred and alternative embodiments of the
invention have been set forth for purposes of disclosing the
invention, modifications to the disclosed embodiments may occur to
those who are skilled in the art. Accordingly, the appended claims
are intended to cover all embodiments of the invention and
modifications thereof which do not depart from the spirit and scope
of the invention.
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