FORM 2
THE PATENTS ACT 1970
(39 OF 1970)
COMPLETE SPECIFICATION
(SECTION 10)
"EFFERVESCENT PHARMACEUTICAL COMPOSITIONS OF OMEPRAZOLE"
UNICHEM LABORATORIES LIMITED, A COMPANY REGISTERED UNDER .
THE INDIAN COMPANY ACT, 1956, HAVING ITS REGISTERED OFFICE
LOCATED AT UNICHEM BHAVAN, PRABHAT ESTATE, OFF S. V. ROAD,
JOGESHWARI (WEST), MUMBAI - 400 102,
MAHARASTRA, INDIA.
The following specification particularly describes the invention and the manner in which it is to be performed.

FIELD OF THE INVENTION
The present invention relates to an effervescent pharmaceutical composition of omeprazole. More particularly, the present invention relates to the stable, pseudo dose proportional, solid oral pharmaceutical composition of acid labile proton pump inhibiting agent, omeprazole in the form of effervescent tablets and a novel method for its manufacture thereof, useful for the treatment of gastric ulcers, duodenal ulcers, gastroesophageal reflux disease.
BACKGROUND OF THE INVENTION
Omeprazole is a proton pump inhibitor. Chemically it is called as substituted benzimidazole of 5-methoxy-2-[[(4-methoxy-3, 5-dimethyl-2-pyridinyl)methyl]sulfinyl]-lH- benzimidazole. It has molecular formula of C17H19N3O3S with a molecular weight of 345.42. It is a racemic mixture of two enantiomers that inhibits gastric acid secretion. The mechanism by which omeprazole exerts its effect is by suppression of gastric acid secretion by specific inhibition of the H+/K+ ATP'ase enzyme system at secretary surface of the gastric parietal cell thereby finally blocking steps of acid production. Omeprazole has been developed in various strengths like 10, 20 & 40 mg for the short term treatment of active duodenal ulcer and active benign gastric ulcer. Omeprazole capsules containing delayed release pellets are currently marketed by ASTRA ZENECA under the brand name of PRILOSEC in three different strengths i.e., 30 mg, 20 mg, and 40 mg in the USA. Omeprazole: Sodium bicarbonate capsules and packets are currently marketed by SANTARUS under the brand name of ZEGERID in two different strengths i.e., 20mg and 40mg in the USA.
US 6699885 B2 (Phillips, 2004) discloses a method of treating a gastric acid related disorder by a solid pharmaceutical composition for oral administration containing therapeutically effective at least one substituted benzimidazole H+/ K+ ATP'ase proton pump inhibitor, buffering agents, a binder, a suspending agent, a flavoring agent, a sweetening agent, a colorant, a lubricant, a flow aid, an adjuvant, diluents, a parietal cell activator, anti-oxidants, chelating agents, anti-fungal agents, anti-bacterial agents, isotonic agents, moistening agents, preservatives and anti-foaming agents.
US 6489346 Bl (Phillips, 2002) discloses a solid pharmaceutical composition in a dosage form that is not enteric-coated, comprising an active proton pump inhibitor. This

composition utilizes micronized active substance, which may increase number of unit operations and hence the manufacturing cost of the drug product.
US 6645988 B2 (Phillips, 2003) discloses a solid pharmaceutical composition containing non enteric-coated or delayed release proton pump inhibitor along with the primary essential buffer, optional secondary essential buffer with the other pharmaceutically-acceptable excipients and method of manufacture.
US 7399772 B2 (Phillips, 2008) discloses a liquid or solid pharmaceutical composition consisting of a proton pump inhibitor and at least one buffering agent other pharmaceutically acceptable excipients like parietal cell activator, an anti-forming agent, a flavoring agent and combinations for treating acid-related gastrointestinal disorder.
US 6132770 (Lundberg, 2000) discloses an oral pharmaceutical composition in the form of a multiple unit effervescent tablet comprising an acid susceptible proton pump inhibitor wherein the core material is in the form of pellets covered with enteric coating layer having a same mechanical properties, such that the proton pump inhibitor is not significantly affected by compression of the pellets with the other tablets components during tableting. The core material is covered by a separating layer located between the core material the enteric coating layer. This method involves usage of enteric coating and thus increases the unit operations and manufacturing cost.
US 5824339 (Shimizu et al. 1998) discloses an effervescent composition comprising a core-shell powder consisting of a fine granular core spray- coated with a liquid mixture containing a water-soluble polymer such as hydroxypropyl cellulose or hydroxypropylmethyl cellulose such and at least one physiologically active substance, especially an acid-sensitive drugs, and enteric coating film, an effervescing component and for controlled release of the physiologically active substance and in useful for preparing uniform solution or suspension having a refreshing sensation o ingestion. This method also involves usage of enteric coating which utilizes costlier equipment and hence may increase the manufacturing cost.
US2005/0112193 Al (Phillips et al. 2005) discloses a solid pharmaceutical composition utilizes enteric coating of micronized proton pump inhibitor with at least one buffering agent. Micronization and enteric coating of active substance increases the number of unit operations as well as the manufacturing cost of the drug product.

Even though many technologies with different compositions of omeprazole oral dosage forms (capsules containing enteric-coated granules or enteric coated tablets) are available in the market, their administration is difficult or impossible to patients who are either unwilling or unable to swallow tablets or capsules, such as critically ill patients, children, the elderly, and patients suffering from dysphagia. Hence, there is a need for the development stable, easily swallowable, non-enteric coated omeprazole oral dosage form.
The present invention relates to pseudo dose proportional, solid oral pharmaceutical composition comprising omeprazole or its pharmaceutically acceptable salt, solvate, enantiomers or mixtures thereof and novel method of its manufacture thereof.
OBJECT OF THE INVENTION
An object of the present invention is to provide a stable pharmaceutical composition comprising acid labile proton pump inhibiting agent, omeprazole or its pharmaceutically acceptable salt, solvate, enantiomers or mixtures thereof.
Another object of the present invention is to provide a pseudo dose proportional pharmaceutical composition comprising omeprazole or its pharmaceutically acceptable salt, solvate, enantiomers or mixtures thereof.
Yet another object of the present invention is to provide a stable, easily swallowable, non-enteric coated omeprazole oral dosage form.
Yet another object of the present invention is to provide a method of manufacturing, which prevents the degradation of omeprazole in presence of acids without carrying out the enteric coating for the drug particles i.e., by granulating the composition into two different parts, one part containing omeprazole, disintegrant, alkalizing agent and binder whereas another part containing other pharmaceutically acceptable excipients including effervescent agents.
SUMMARY OF THE PRESENT INVENTION
The present invention relates to stable oral pharmaceutical composition comprising acid labile proton pump inhibiting agent, omeprazole or its pharmaceutically acceptable salt, solvate, enantiomers or mixtures thereof along with pharmaceutically acceptable

excipients like effervescent agents, alkalizing agents, diluents, disintegrants, binders, lubricants, sweeteners, flavoring agents, coloring agents, suspending agents, cooling agents, taste masking agents, humectants and anti foaming agents.
Further, the present invention also provides processes for the preparation of pharmaceutical composition. This method for preparation of stable immediate release solid oral pharmaceutical composition involves wet granulation, dry granulation and direct compression, preferably by wet granulation or dry granulation and more preferably by wet granulation method.
Furthermore, the method for the preparation of an effervescent stable pharmaceutical composition comprises of:
Srep-I: Dry mixing of omeprazole in a therapeutically effective amount with other pharmaceutically acceptable excipients like disintegrant, alkalizer and binder, then granulation, drying, and milling, or Dispersing acid labile proton pump inhibiting agent, omeprazole in a therapeutically effective amount with other pharmaceutically acceptable excipients like disintegrant, alkalizer and binder, then granulation, drying, and milling. Step-II: Preparation of placebo granules comprising pharmaceutically acceptable excipients like sweetening agents, flavoring agents, diluents, binder, taste masking agents, anti-foaming agent, suspending agents, coloring agents, humectants, including effervescent agents &
Step-III: Mixing of said step-I granules containing active substance, said step-II
placebo granules and extra-granular excipients like flavouring agent, cooling agent and lubrication by using lubricants and then compressing into tablets.
DETAILED DESCRIPTION OF THE PRESENT INVENTION
The present invention provides a stable, pseudo dose proportional, immediate release solid oral pharmaceutical composition comprising acid labile proton pump inhibiting agent, omeprazole or its pharmaceutically acceptable salt, solvate or enantiomers or mixtures thereof and novel method of manufacturing thereof. In particular, the present invention provides stable, solid oral pharmaceutical composition comprising therapeutically effective amount of omeprazole or its pharmaceutically acceptable salt, solvate or enantiomers or mixtures thereof.

The term 'active ingredient' used herein refers to omeprazole or its pharmaceutically
acceptable salt, solvate, enantiomers or mixtures thereof.
The term 'pharmaceutical composition' used herein, means solid oral formulations, which
comprises tablets or sachet of granules.
The term 'therapeutically effective amount' as used herein means the amount of a
compound that, when administered to a mammal for treating a state, disorder or condition
is sufficient to effect such treatment. The therapeutically effective amount will vary
depending on the compound, the disease and its severity and the age, weight, physical
condition and responsiveness of the mammal to be treated.
The term ' pharmaceutically acceptable excipients' as used herein, refers to ingredients of
composition excluding the active drug substances.
In accordance with the present invention, manufacturing methods comprises of wet
granulation, dry granulation and direct compression techniques, preferred manufacturing
methods are wet granulation or direct compression techniques and more preferred
manufacturing method is wet granulation method.
In accordance with the present invention, method of manufacturing by wet granulation
includes, (i) Dry mixing of omeprazole in a therapeutically effective amount with other
pharmaceutically acceptable excipients like disintegrants, alkalizers and binders, then
granulation, drying, and milling, (ii) Preparation of placebo granules containing
pharmaceutically acceptable excipients like sweetening agents, flavoring agents, diluents,
binder, taste masking agents, anti-foaming agent, suspending agents, coloring agents,
humectants, including effervescent agent and (iii) mixing of step-i and step-ii granules
with extra-granular excipients like cooling agents, flavouring agent, and lubrication and
then compression into tablets.
In accordance with the present invention, method of manufacturing by dry granulation includes mixing of omeprazole with one or more of pharmaceutically acceptable excipients, then slugging, sieving and addition of pharmaceutically acceptable extra-granular excipients, lubrication and compression.
In accordance with the present invention, method of manufacturing by direct compression includes mixing of omeprazole with pharmaceutically acceptable excipients, lubrication and compression.

The pharmaceutical composition of the present invention contains the active ingredient in the range of about 5 mg to about 80 mg, preferably from about 7.5 mg to about 60 mg of active ingredient and more preferably from about 10 mg to 40 mg of active ingredient.
In accordance with the present invention, pharmaceutical composition of omeprazole is in the form of solid dosage form i.e., either a tablet or sachet of granules, more preferably solid dosage form is present in the form of effervescent tablets, suitable for oral administration.
In accordance with the present invention, pharmaceutical compositions comprise omeprazole or its pharmaceutically acceptable salt, solvate, enantiomers or mixtures and at least one or more of pharmaceutically acceptable excipients. In particular, the pharmaceutical compositions comprise omeprazole and one or more of effervescent agents, alkalizing agents, diluents, disintegrants, binders, lubricants, sweeteners, flavoring agents, coloring agents, suspending agents, cooling agent, taste masking agent, humectants and antifoaming agents.
The effervescent tablets, when added to water, generate a gas, which causes effervescence and produces a clear sparkling solution. The gas, which gives the effervescence, is always carbon dioxide, which derives from the reaction of an acid and a base like carbonates or bicarbonates. The effervescent tablet consists of at least at two components viz., an acid component and a basic component.
The acidic component is present in the effervescent agent in an amount ranging from about 5% to about 50%, preferably from about 7.5% to about 45% and more preferably between about 10% to about 40%. The basic component is present in the effervescent agent in an amount between about 10% to about 70% preferably the basic component ranges in an amount from about 15% to about 65% and more preferably between about 15% and about 60%.
Acid components used in the present invention are at least one or more of organic acids and related salts for example acetic, formic, propionic, malic, tartaric, citric, glycolic, fumaric, adipic, succinic, lactic, gluconic, sodium citrate, sodium mono citrate, calcium citrate, butyric acids and boric acid.
Preferred acid components used in the present invention are at least one or more of organic acids and related salts for example malic, tartaric, citric, glycolic, fumaric, adipic,

succinic, lactic, gluconic, sodium citrate, sodium mono citrate, calcium citrate, butyric
acids and boric acid.
More preferred acid component used in the present invention are at least one or more of
tartaric, citric, glycolic, fumaric, adipic, succinic, lactic, gluconic, sodium citrate, sodium
mono citrate and calcium citrate.
Basic component used in the present invention are at least one or more of carbonates like
sodium carbonate, potassium carbonate, lithium carbonate, calcium carbonate, &
magnesium carbonate; bicarbonates like sodium bicarbonates, potassium bicarbonates,
and sequicarbonates like sodium sesquicarbonates.
Preferred basic component present in the invention are at least one or more of carbonates
like sodium carbonate, potassium carbonate, calcium carbonate, & magnesium
carbonate; bicarbonates like sodium bicarbonates, potassium bicarbonates and
sequicarbonates like sodium sesquicarbonate.
More preferred basic component present in the invention are at least one or more of
sodium carbonate, potassium carbonate, sodium bicarbonate, potassium bicarbonate and
sesquicarbonate.
Alkalizing agents used in the present invention are at least one or more of aluminum salts
such as magnesium aluminum silicate ; magnesium salts such as magnesium carbonate,
magnesium trisilicate, magnesium aluminum silicate, magnesium stearate; calcium salts
such as calcium carbonate; bicarbonates such as calcium bicarbonate and sodium
bicarbonate; phosphates such as monobasic calcium phosphate, dibasic calcium
phosphate, dibasic sodium phosphate, tribasic sodium phosphate (TSP), dibasic potassium
phosphate, tribasic potassium phosphate; metal hydroxides such as aluminum hydroxide,
sodium hydroxide and magnesium hydroxide; metal oxides such as magnesium oxide; N-
methyl glucamine; arginine and salts thereof; amines such as monoethanolamine,
diethanolamine, triethanolamine, meglumine and tris (hydroxymethyl) aminomethane
(TR1S).
Preferable alkalizing agents in the present invention are at least one or more of aluminum
salts such as magnesium salts such as magnesium carbonate, magnesium trisilicate;
calcium salts such as calcium carbonate; bicarbonates such as calcium bicarbonate and
sodium bicarbonate; phosphates such as monobasic calcium phosphate, dibasic calcium
phosphate, dibasic sodium phosphate, tribasic sodium phosphate (TSP), dibasic potassium
phosphate, tribasic potassium phosphate; metal hydroxides such as aluminum hydroxide,
sodium hydroxide and magnesium hydroxide; metal oxides such as magnesium oxide; N-

methyl glucamin ; arginine and salts thereof; amines such as monoethanolamine,
diethanolamine, triethanolamine, meglumine and tris (hydroxymethyl) aminomethane
(TRIS).
More preferred alkalizing agents in the present invention are at least on or more of
magnesium carbonate, calcium bicarbonate, sodium bicarbonate, dibasic sodium
phosphate, tribasic sodium phosphate (TSP), aluminum hydroxide, sodium hydroxide,
meglumine, magnesium oxide, N-methyl glucamine and triethanolamine.
Diluents used in the present invention are at least one or more of microcrystalline
cellulose, lactose monohydrate, starch, calcium phosphate (dibasic/tribasic), calcium
sulphate, calcium sulphate dihydrate, fructose, sucrose, sorbitol, mannitoi, xylitol,
dextrose, compressible sugar, dextrates, dextrin, powdered cellulose, cellulose acetate,
polymethacrylates, sodium alginate and tragacanth.
Preferred diluents used in the present invention include one or more of microcrystalline
cellulose, lactose monohydrate, starch, calcium phosphate (dibasic/tribasic), fructose,
sucrose, sorbitol, mannitoi, xylitol, dextrose, compressible sugar, dextrates, dextrin,
powdered cellulose, sodium alginate and tragacanth.
More preferred diluents used in the present invention include one or more of
microcrystalline cellulose, lactose monohydrate, starch, mannitoi, Xylitol, compressible
sugar and powdered cellulose.
Disintegrants used in the present invention are at least one or more of the croscarmellose
sodium, crospovidone, sodium starch glycollate, pregelatinized starch, microcrystalline
cellulose, emcosoy (Soya polysaccharide) and potassium polacrilin.
Preferred disintegrants used in the present invention are at least one or more of the
croscarmellose sodium, crospovidone, sodium starch glycollate, pregelatinized starch,
microcrystalline cellulose and potassium polacrilin.
More preferred disintegrants used in the present invention are at least one or more of the
croscarmellose sodium, crospovidone, sodium starch glycollate, pregelatinized starch and
potassium polacrilin.
Binders used in the present invention may be at least one or more of polyvinyl
pyrrolidone, co-povidone, polyethylene oxide, cellulose derivatives like ethyl cellulose,
methyl cellulose, carboxymethyl cellulose sodium, hydroxypropyl cellulose,
hydroxypropylmethyl cellulose, hyroxyethyl cellulose etc., acacia gum, guar gum,
xanthan gum, karaya gum, gellan gum, hupu gum, carob gum, caramania gum, gelatin,
glucose, sugar, dextrin, sorbitol, maltose, pregelatinised starch, agar, alginic acid, sodium

alginate, carbomers, carrageenan, ceratonia, chitosan, poloxamer, magnesium aluminum silicate, glyceryl monostearate, glyceryl behenate, gelyceryl monooleate, glyceryl palmitostearate, microcrystalline wax, stearyl alcolhol, cetyl alcohol, cetostearyl alcohol, hydrogenated caster oil, tristearin, waxes, ethylene glycol palmitostearate and Kollicoat protect.
Preferred binders used in the present invention may be at least one or more of polyvinyl pyrrolidone, co-povidone, polyethylene oxide, cellulose derivatives like ethyl cellulose, methyl cellulose, carboxymethyl cellulose sodium, hydroxypropyl cellulose, hydroxypropylmethyl cellulose, hyroxyethyl cellulose etc., acacia gum, guar gum, xanthan gum, karaya gum, gellan gum, hupu gum, carob gum, caramania gum, gelatin, dextrin, sorbitol, pregelatinised starch, agar, alginic acid, sodium alginate, carbomers, carrageenan, ceratonia, chitosan, magnesium aluminum silicate, glyceryl monostearate, glyceryl behenate, gelyceryl monooleate and glyceryl palmitostearate and Kollicoat protect.
More preferred binders used in the present invention may be at least one or more of polyvinyl pyrrolidone, co-povidone, polyethylene oxide, cellulose derivatives like ethyl cellulose, methyl cellulose, carboxymethyl cellulose sodium, hydroxypropyl cellulose, hydroxypropylmethyl cellulose and hyroxyethyl cellulose and Kollicoat protect. Lubricants used in the present invention are one or more of magnesium stearate, calcium stearate, stearic acid, sodium stearyl fumerate, talc, hydrogenated vegetable oils, magnesium lauryl sulfate, wax, polyethylene glycol, glyceryl behenate, glyceryl palmitostearate, palmitic acid, poloxamer, sodium benzoate and sodium lauryl sulfate. Preferred lubricants used in the present invention are one or more of magnesium stearate, calcium stearate, stearic acid, sodium stearyl fumerate, talc, hydrogenated vegetable oils, polyethylene glycol, glyceryl behenate, glyceryl palmitostearate, palmitic acid, poloxamer, sodium benzoate and sodium lauryl sulfate.
More preferred lubricants used in the present invention are one or more of magnesium stearate, calcium stearate, stearic acid, sodium stearyl fumarate, sodium benzoate, polyethylene glycol, hydrogenated vegetable oils and talc.
Sweetening agents used in the present invention are one or more of aspartame, acesulfame potassium, cyclamate, dextrose, isomalt, Magnasweet®, mannitol, neohesperidine, saccharin, sorbitol, sucralose, thaumatin and xylitol. Preferred sweetening agents used in the present invention is one or more of aspartame, cyclamate, dextrose, saccharin, sorbitol, sucralose, xylitol, mannitol and thaumatin.

More preferred sweetening agents used in the present invention are one or more of aspartame, cyclamate, saccharin, sorbitol, xylitol, mannitol and sucralose. Flavoring agents used in the present invention are one or more of apple, banana, black current, butter, butterscotch, camphor, cherry, citrus, cinnamon, cocoa, coffee, cola, eucalyptus, eugenol, ginger, grape, glycyrrhiza syrup, lime, lemon, maple, mint, menthol, orange, peppermint, saccharin, spearmint, strawberry, sucralose, sucrose, vanilla, watermelon, xylitol,
Preferred flavoring agent in the present invention are one or more of apple, banana, cherry, citrus, cinnamon, lemon, maple, mint, menthol, orange, peppermint, strawberry, sucralose, sucrose, vanilla and watermelon.
More preferred flavoring agent used in the present invention are one or more of citrus, cinnamon, lemon, mint, menthol, orange, peppermint, strawberry, sucralose, sucrose, vanilla, watermelon.
Coloring agents used in the present invention are one or more of titanium dioxide, dyes such as FD.&C yellow, FD.&C red, FD.&C blue, FD.&C green, iron oxide red, iron oxide yellow, iron oxide black, D&C red, D&C yellow, brilliant green and natural coloring agents such as grape skin extract, beet red powder, beta-carotene, annatto, carmine, turmeric, and paprika.
Preferred coloring agents used in the present invention are one or more of FD.&C yellow, FD.&C red, FD.&C blue, FD.&C green, iron oxide red, iron oxide yellow, iron oxide black, D&C red, D&C yellow, beta-carotene, carmine, turmeric.
More preferred coloring agents used in the present invention are one or more of FD.&C yellow, FD.&C red, iron oxide red, iron oxide yellow D&C red, D&C yellow, beta-carotene and turmeric.
Suspending agents used in the present invention are one or more of polyvinylpyrolidone, polyethylene glycol, polyvinylalcohol, polyvinylacetate, polymethacrylates, sodium alginate, cellulose such as sodium carboxymethyl- cellulose, hydroxyethylcellulose, sugar, gums such as gum arabic, gum tragacanth, locust bean gum, gum karaya, guar gum, carrageenan, algin, biopolymers, hydroxyethylcellulose, hydroxyethyl ghatti gum, hydroxyethyl arabic gum, hydroxyethyl tragacanth gum, hydroxyethyl karaya gum, hydroxyethyl guar gum, hydroxyethyl carrageenan, hydroxyethyl alginate, hydroxyethyl xanthan gum, carboxymethyl arabic gum, carboxymethyl tragacanth gum, carboxymethyl locust bean gum, carboxymethyl guar gum, carboxymethyl carrageenan, carboxymethyl alginates, carboxymethyl xanthan gum, carboxymethylhydroxymethyl cellulose

carboxymethylhydroxyethyl ghatti gum, carboxymethylhydroxyethyl arabic gum,
carboxymethylhydroxyethyl tragacanth gum, carboxymethylhydroxyethyl guar gum,
carboxymethylhydroxyethyl carrageenan, carboxymethylhydroxyethyl xanthan gum,
carboxymethylhydroxyethyl cellulose, hydroxypropyl ghatti gum, hydroxypropyl arabic
gum, hydroxypropyl tragacanth gum, hydroxypropyl guar gum, hydroxypropyl
carrageenan, hydroxypropyl xanthan gum, alkyl hydroxypropyl cellulose, carboxymethyl
starch, hydroxyethylstarch, carboxymethylhydroxyethyl starch
Preferred suspending agents used in the present invention are one or more of
polyvinylpyrolidone, sodium carboxymethylcellulose, hydroxyethylcellulose, sugar,
polyvinylalcohol, polyvinylacetate, polymethacrylates, sodium alginate, xanthan gum,
hydroxypropyl alginates, carboxymethyl starch, hydroxypropyl tragacanth gum and
hydroxypropyl karaya gum
More preferred suspending agent used in the present invention are one or more of
tragacanth gum, xanthan gum, sodium alginate, sodium carboxymethylcellulose,
hydroxyethylcellulose and sugar.
Cooling agents used in the present invention are one or more of menthol, isopulegul,
menthyl succinate, peppermint oil, menthone, menthyl pyrrolidone carboxylate, cornmint
oil eucalyptol, menthol propylene glycol carbonate, linalool, geraniol and
hydroxycitronellal.
Preferred cooling agent used in the present invention are one or more of menthol,
peppermint oil, menthone, eucalyptol, menthol propylene glycol carbonate, linalool,
geraniol and hydroxycitronellal.
More preferred cooling agent used in the present invention are one or more of menthol,
peppermint oil, menthone, eucalyptol, linalool, geraniol and hydroxycitronellal.
Taste masking agents used in the present invention are one or more of cellulose polymers,
a vinyl carboxylate-alkylene glycol copolymer, an acrylic polymer, a methacrylic
polymer, or an acrylic-methacrylic copolymer, acrylic acid derivatives [e.g., alkyl esters,
substituted alkyl esters (e.g., aminoalkyl esters), primary amides, secondary amides, and
tertiary amides], aspartame, cyclamate, saccharin, thaumatin, sucralose and polacrilin
potassium,
Preferred taste masking agents used in the present invention are one or more of acrylic
polymer, acryclic acid derivatives, a methacrylic polymer, primary amides, aspartame,
cyclamate, saccharin, thaumatin, sucralose and polacrilin potassium.

More preferred taste masking agent used in the present are one or more of acrylic
polymer, acrylic acid derivatives, a methacrylic polymer, aspartame, cyclamate,
saccharin, thaumatin, sucralose and polacrilin potassium.
Humectants used in the present invention are one or more of ethylene glycols, glycerols,
sorbitol, mannitol, xylitol, maltitol, polyethylene glycol, dipropylene glycol, collagen,
hyaluronic acid, chitosan derivatives, sodium lactate.
Preferred humectants used in the present invention are one or more of ethylene glycols,
glycerols, sorbitol, mannitol, xylitol, maltitol, polyethylene glycol, dipropylene glycol,
collagen, hyaluronic acid.
More preferred humectants used in the present invention are one or more of one or more
of sorbitol, mannitol, xylitol, maltitol and polyethylene glycol.
Antifoaming agents used in the present invention are one or more of polyether surfactant,
polyhydric alcohol fatty acid ester, silicone dioxide, silicone derivatives and
organopolysiloxane polymers, simethicone and dimethicone.
Preferred antifoaming agent used in the invention are one or more of polyoxyalkylated
glycerol, sucrose, and, polyethylene glycol 200-600, silicone derivatives and
organopolysiloxane polymers, simethicone and dimethicone.
More preferred antifoaming agent used in the invention are one or more of polyethylene
glycol 200-600, silicone derivatives, organopolysiloxane polymers, simethicone and
dimethicone.
According to the present invention, the pharmaceutical composition contains from about
0.25 to 6 % of the active ingredient omeprazole, preferably from about 0.5 to 5% of the active ingredient and more preferably from about 1 to 4% of the active ingredient; diluents ranges from 1 to 45%, preferably from 1 to 35% of and more preferably from 1 to 25%; disintegrants ranges from 1 to 20%, preferably from 1 to 15% and more preferably from 1 to 10 %; binders ranges from 0.25 to 25%, preferably from 0.5 to 20% and more preferably from 0.75 to 15%; acid component of effervescent agents ranges from 5 to 50%, preferably from 7.5 to 45% of and more preferably from 10 to 40%.; basic component of effervescent agents ranges from 10 to 70%, preferably from 15 to 65% of and more preferably from 15 to 60%.; alkalizing agents ranges from 0.25 to 50%, preferably from 0.5 to 45% and more preferably from 0.75 to 40 %; sweetening agents ranges from 1 to 40 %, preferably from 2 to 35% and more preferably from 3 to 30%; anti-foaming agents ranges from 0.1 to 8 %, preferably from 0.2 to 6% and more preferably from 0.3 to 4%; flavoring agents ranges from 0.25 to 25%, preferably from 0.5

to 20% and more preferably from 1 to 15%; cooling agents ranges from 0.1 to 20%, preferably from 0.2 to 15% and more preferably from 0.3 to 10%; coloring agents ranges from 0.1 to 10%, preferably from 0.2 to 7.5% and more preferably from 0.3 to 5%; suspending agents ranges from 0.05 to 25%, preferably from 0.1 to 20% and more preferably from 0.15 to 15%; taste masking agents ranges from 0.5 to 45%, preferably from 1 to 40% and more preferably from 1.5 to 35%; humectants ranges from 0.1 to 40%, preferably from 0.2 to 35% and more preferably from 0.3 to 30%; and lubricants ranges from 0.1 to 5%, preferably from 0.1 to 4 % and more preferably from 0.1 to 3%. The pharmaceutical composition of present invention comprises omeprazole, used in the treatment of gastric ulcers, duodenal ulcers and gastroesophageal reflux diseases. The amount of the omeprazole in the pharmaceutical composition of present invention is preferably therapeutically effective amount of omeprazole.
The composition of the present invention may be administered to the mammals. Preferably the mammal is a human.
Although the invention has been described with reference to specific embodiments, these descriptions are not meant to be constructed in a limiting sense. Various modifications of the disclosed embodiments, as well as alternate embodiments of the invention, will become apparent to person skilled in the art upon reference to the description of the invention. It is therefore contemplated that such modifications can be made without departing from the spirit or scope of the present invention as defined.
EXAMPLES
The following examples are presented for illustration only, and are not intended to limit the scope of the invention or appended claims.
Example-1
Table 1: Formula of Example-1

s.
No. Ingredients Quantity per tablet (in

40 mg strength
1. Omeprazole 40.0
2. Magnesium Oxide 520.0
3. Xylitol 366.5

4. Sucrose 1666.0
5. Sucralose 90.0
6. Macrocrystalline cellulose 70.0
7. Xanthan gum 17.5
8. Povidone 105.0
9. Sodium bicarbonate 200.0
10. Citric acid 300.0
11. Peppermint flavor 90
12. Magnesium stearate 35.0
Total weight 3500.0
Manufacturing process:
1. Sifted xylitol, sucrose, microcrystalline cellulose, sodium bicarbonate, citric acid, povidone through ASTM # 40 mesh and mixed.
2. Sifted sucralose, xanthan gum, peppermint flavor through ASTM # 40 mesh and mixed.
3. Sifted omeprazole and magnesium oxide through ASTM # 40 mesh and mixed.
4. Mix materials of step 1, step 2 and step 3.
5. Sifted magnesium stearate through ASTM # 60 mesh, added to blend of Step 4 and mixed.
6. Lubricated blend of step 5 were filled into sachets of specified amount as well as compressed into tablets with suitable tooling.
Example-2
Table: Formula of Example-2

S. No. Ingredients Quantity per tablet (in mg)

40mg strength
1. Omeprazole 40.0
2. Magnesium oxide 175.0
3. Sucrose 401.25
4. Xylitol 185.0
5. Crospovidone 60.0

6. Xanthan gum 8.75
7. Sucralose 200.0
8. Orange flavor 120.0
9. Sodium bicarbonate 400.0
10. Citric acid 200.0
11. FD&C yellow no 6 10.0
12. Povidone 60.0
13. Isopropyl alcohol q.s
14. Simethicone 10.0
15. Crospovidone 60.0
16. Menthol 50.0
17. Magnesium stearate 20.0
Total weight 2000.0
Manufacturing process:
1. Sifted sucrose, xylitol, crospovidone, sodium bicarbonate, citric acid through ASTM
# 40 mesh and mixed.
2. Sifted sucralose, orange flavor, xanthan gum through ASTM # 60 mesh and sifted FD&C yellow no. 6 through ASTM #200 and mixed.
3. Simethicone was dispersed in specified amount of isopropyl alcohol to obtain a dispersed solution. In this solution povidone was dissolved to get a binder solution.
4. Material of step 1 and step 2 were mixed and granulated with the solution of step 3.
5. Granules were dried and sifted through ASTM # 20 mesh.
6. Sifted omeprazole and magnesium oxide, crospovidone through ASTM # 40 mesh, menthol thorough ASTM # 200 mesh and mixed.
7. Materials of step 5 and step 6 were mixed.
8. Sifted magnesium stearate through ASTM # 60 mesh, added to blend of Step 7 and were mixed.
9. The lubricated blend of step 8 were filled into sachets of specified amount as well as compressed with specified punch tooling.
Example-3
Table: Formula of Example-3

s.
No. Ingredients Quantity per tablet (in mg)

40mg strength
1. Omeprazole 40.0
2. Magnesium oxide 165.0
3. Crospovidone 20.0
4. Meglumine 50.0
5. Hydroxy propyl methyl cellulose 15.0
6. Purified water q.s
7. Xylitol 171.25
8. Xanthan gum 8.75
9. Sucralose 200.0
10. Orange flavor 120.0
11. Sodium bicarbonate 700.0
12. Citric acid 350.0
13. FD&C yellow no 6 10.0
14. Simethicone 20.0
15. Povidone 60.0
16. Isopropyl alcohol q.s
17. Pepperm int flavor 50.0
18. Magnesium stearate 20.0
Total weight 2000.0
Manufacturing process:
1. Sifted sucrose, xylitol, crospovidone, sodium bicarbonate, citric acid through
ASTM # 40 mesh and mixed.
2. Sifted sucralose, orange flavor, xanthan gum through ASTM # 60 mesh and sifted FD&C yellow no. 6 through ASTM #200 and mixed.
3. Simethicone was dispersed in specified amount of isopropyl alcohol to obtain a dispersed solution. In this solution povidone was dissolved to get a binder solution.
4. Step 1 and step 2 blends were mixed and then granulated with the step 2 solution.
5. Granules were dried and sifted through ASTM # 20 mesh.
6. Sifted omeprazole and magnesium oxide, crospovidone through ASTM # 40 mesh and mixed.

7. Meglumine was dissolved in the specified amount of purified water to get a solution and then hydroxy propyl methylcellulose was dissolved to obtain a binder solution.
8. Step 6 blend was granulated by using solution of step 7.
9. Obtained granules were dried and sifted through ASTM #30mesh.
10. Sifted peppermint flavor through ASTM #40
11. Materials of step 5, step 9 and step 10 were mixed for a specified time.
12. Sifted magnesium stearate through ASTM # 60 mesh, added to blend of Step 11 and then mixed.
13. The lubricated blend of step 12 were filled into sachets of specified amount as well as compressed with specified punch tooling.
Example-4
Table Formula of Example 4

Sr. no. Ingredients Quantity per tablet (in mg)

40mg strength
1 Omeprazole 40.0
2 Polacrilin potassium (Kyron T-134) 100.0
3 Meglumine 50.0
4 Purified water q.s.
5 Sodium carbonate 500.0
7 Kollicoat protect 50.0
8 Croscarmellose sodium 60.0
9 Xylitol 133.75
10 Sucralose 140.0
11 Orange flavour 120.0
12 Sodium bicarbonate 1100.0
13 Anhydrous citric acid 455.0
14 FD & C yellow No. 6 12.5

15 Simethicone 30 % 20.0
16 Povidone 60.0
17 Isopropyl alcohol q.s.
18 Xanthan gum 8.75
19 Syloid 60.0
20 Peppermint flavour 60.0
21 Sodium benzoate 30.0
Total 3000.0
Manufacturing process:
1. Weighed all the ingredients on calibrated balance.
2. Meglumine was dissolved in purified water and polacriline potassium (Kyron T-134) was added to it and finally omeprazole was added with continuous stirring and stirred to get uniform dispersion.
3. Sifted sodium carbonate, Kollicoat protect and croscarmellose sodium through # 40 ASTM mesh and were mixed in Rapid Mixer Granulator (RMG).
4. Step 3 blend was granulated with the dispersion in step 2. Additional purified water was added as per requirement.
5. The granules were semi-dried and these semidried granules were sifted through #16 ASTM mesh.
6. The semi-dried granules of step 5 were dried and sifted through # 30 ASTM mesh.
7. Sifted xylitol, sucralose, orange flavour, sodium bicarbonate, anhydrous citric acid through # 40 ASTM mesh and sifted FD & C yellow No. 6 through # 200 ASTM mesh and mixed in RMG.
8. Simethicon emulsion was dispersed in isopropyl alcohol and povidone K-30 was added to it. Stirring was done to uniform granulating solution.
9. Step 7 blend was granulated with the dispersion of step 8. Additional isopropyl alcohol was added as per requirement.
10. The granules were semi-dried and these semidried granules were sifted through #16 ASTM mesh.

11. The semi-dried granules of step 10 were dried and sifted through # 20 ASTM mesh.
12. Sifted xanthan gum, syloid and peppermint flavour through # 40 ASTM mesh.
13. Materials in step 6, step 11 and 12 were mixed in a blender.
14. Sodium benzoate was sifted through # 60 ASTM mesh and mixed with the blend in step 13 in a blender.
15. The lubricated blend in step 14 was compressed and filled into sachets of specified amount as well as with specified punch tooling.

We Claim:
1. An effervescent stable pharmaceutical composition comprising acid labile
proton pump inhibiting agent omeprazole or its pharmaceutically acceptable salts,
solvates, enantiomers or mixtures thereof along with pharmaceutically acceptable
excipients like effervescent agents, alkalizing agents, diluents, disintegrants,
binders, lubricants, sweeteners, flavoring agents, coloring agents, suspending
agents, cooling agents, taste masking agents, humectants and anti foaming agents.
2. An effervescent stable pharmaceutical composition of claim 1, wherein effervescent agents comprises acid components like one or more of tartaric, citric, glycolic, fumaric, adipic, succinic, lactic, gluconic, sodium citrate, sodium mono citrate and calcium citrate; basic components like one or more of sodium carbonate, potassium carbonate, sodium bicarbonate, potassium bicarbonate and sodium sequicarbonate
3. An effervescent stable pharmaceutical composition of claim 1, wherein alkalizing agents comprises one or more of magnesium carbonate, calcium bicarbonate, sodium bicarbonate, dibasic sodium phosphate, tribasic sodium phosphate (TSP), aluminum hydroxide, sodium hydroxide, meglumine, magnesium oxide; N-methyl glucamine and triethanolamine.
4. An effervescent stable pharmaceutical composition of claim 1, wherein diluents
comprises of one or more of microcrystaliine cellulose, lactose monohydrate,
starch, mannitol, compressible sugar, xylitol and powdered cellulose.
5. An effervescent stable pharmaceutical composition of claim 1, wherein
disintegrants comprises one or more of the croscarmellose sodium, crospovidone,
sodium starch glycolate, pregelatinized starch and polacrilin potassium.
6. An effervescent stable pharmaceutical composition of claim 1, wherein binders comprises one or more of polyvinyl pyrrolidone, co-povidone, polyethylene oxide, cellulose derivatives like ethyl cellulose, methyl cellulose, carboxymethyl cellulose sodium, hydroxypropyl cellulose, hydroxypropylmethyl cellulose, hyroxyethyl cellulose and Kollicoat protect.
7. An effervescent stable pharmaceutical composition of claim 1, wherein lubricants comprises one or more of magnesium stearate, calcium stearate, stearic acid, sodium stearyl fumarate, sodium benzoate, polyethylene glycol, hydrogenated vegetable oils and talc.

8. An effervescent stable pharmaceutical composition of claim I, wherein sweetening agents comprises one or more of aspartame, cyclamate, saccharin, sorbitol, xylitol, mannitol and sucralose.
9. An effervescent stable pharmaceutical composition of claim 1, wherein flavoring agents comprises one or more of citrus, cinnamon, lemon, mint, menthol, orange, peppermint, strawberry, sucralose, sucrose, vanilla and watermelon.

10. An effervescent stable pharmaceutical composition of claim 1, wherein coloring agents comprises one or more of FD.&C yellow, FD.&C red, iron oxide red, iron oxide yellow D&C red, D&C yellow, beta-carotene and turmeric.
11. An effervescent stable pharmaceutical composition of claim 1, wherein suspending agents comprises one or more of tragacanth gum, xanthan gum, sodium alginate, sodium carboxymethylcellulose, hydroxyethyicellulose and sugar.
12. An effervescent stable pharmaceutical composition of claim 1, wherein cooling agents comprises one or more of menthol, peppermint oil, menthone, eucalyptol, linalool, geraniol and hydroxycitronellal.

13. An effervescent stable pharmaceutical composition of claim 1, wherein taste masking agents comprises one or more of acrylic polymer, acrylic acid derivatives, a methacrylic polymer, aspartame, cyclamate, saccharin, thaumatin, sucralose and polacrilin potassium.
14. An effervescent stable pharmaceutical composition of claim 1, wherein humectants comprises one or more of sorbitol, mannitol, xylitol, maltitol and polyethylene glycol.
15. An effervescent stable pharmaceutical composition of claim 1, wherein anti-foaming agents comprises one or more of polyethylene glycol 200-600, silicone derivatives, organopolysiloxane polymers, simethicone and dimethicone.
16. An effervescent stable pharmaceutical composition of claim 1, wherein omeprazole is in the range of 0.25 % to 6%, preferably in the range of 0.5% to 5%, more preferably in the range of 1% to 4%.
17. An effervescent stable pharmaceutical composition of claim 1, wherein diluents ranges from 1 to 45%, preferably from 1 to 35% and more preferably from 1 to 25%; disintegrants ranges from 1 to 20%, preferably from 1 to 15% and more preferably from 1 to 10 %; binders ranges from 0.25 to 25%, preferably

from 0.5 to 20% and more preferably from 0.75 to 15%; acid component of effervescent agents ranges from 5 to 50%, preferably from 7.5 to 45% of and more preferably from 10 to 40%.; basic component of effervescent agents ranges from 10 to 70%, preferably from 15 to 65% of and more preferably from 15 to 60%.; alkalizing agents ranges from 0.25 to 50%, preferably from 0.5 to 45% and more preferably from 0.75 to 40 %.
18. An effervescent stable pharmaceutical composition of claim 1, wherein sweetening agents ranges from 1 to 40 %, preferably from 2 to 35% and more preferably from 3 to 30%; anti-foaming agents ranges from 0.1 to 8 %, preferably from 0.2 to 6% and more preferably from 0.3 to 4%; flavoring agents ranges from 0.25 to 25%, preferably from 0.5 to 20% and more preferably from 1 to 15%; cooling agents ranges from 0.1 to 20%, preferably from 0.2 to 15% and more preferably from 0.3 to 10%; coloring agents ranges from 0.1 to 10%, preferably from 0.2 to 7.5% and more preferably from 0.3 to 5%; suspending agents ranges from 0.05 to 25%, preferably from 0.1 to 20% and more preferably from 0.15 to 15%; taste masking agents ranges from 0.5 to 45%, preferably from 1 to 40% and more preferably from 1.5 to 35%; humectants ranges from 0.1 to 40%, preferably from 0.2 to 35% and more preferably from 0.3 to 30%; and lubricants ranges from 0.1 to 5%, preferably from 0.1 to 4 % and more preferably from 0.1 to 3%.
19. An effervescent stable pharmaceutical composition of claim I, wherein the solid dosage form suitable for oral administration selected from tablet or sachet of granules, more preferably selected from tablet dosage form.
20. A method for the preparation of an effervescent stable pharmaceutical composition of claim 1, wherein manufacturing process comprises of:
Step-I: Dry mixing of omeprazole in a therapeutically effective amount with other pharmaceutically acceptable excipients like disintegrant, alkalizer and binder, then granulation, drying, and milling, or Dispersing acid labile proton pump inhibiting agent, omeprazole in a therapeutically effective amount with other pharmaceutically acceptable excipients like disintegrant, alkalizer and binder, then granulation, drying, and milling.
Step-II: Preparation of placebo granules comprising pharmaceutically acceptable excipients like sweetening agents, flavoring agents, diluents, binder, taste masking

agents, anti-foaming agent, suspending agents, coloring agents, humectants,
including effervescent agents &
Step-III: Mixing of said step-I granules containing active substance, said
step-II placebo granules and extra-granular excipients like flavouring agent,
cooling agent and lubrication by using lubricants and then compressing into
tablets.
21. A method for the preparation of an effervescent stable pharmaceutical
composition of claim 20 wherein, manufacturing process involves wet
granulation, dry granulation and direct compression, preferably wet granulation or
dry granulation and more preferably wet granulation method.
22. An effervescent stable pharmaceutical composition of claim 1, wherein the pharmaceutical composition is of immediate release type of composition.
23. An effervescent stable pharmaceutical composition of claim 1, wherein the dosage form used in the treatment of gastric ulcers, duodenal ulcers, and gastroesophageal reflux diseases.
24. The effervescent stable pharmaceutical composition substantially as herein described and illustrated with reference to the accompanying examples.