FIELD OF THE INVENTION

The present invention relates to stable pharmaceutical composition comprising omeprazole or pharmaceutically acceptable salts thereof. More particularly, the present invention relates to stable pharmaceutical composition comprising omeprazole magnesium.

The present invention further relates to a process for the preparation of stable pharmaceutical composition comprising omeprazole magnesium.

BACKGROUND OF THE INVENTION

Omeprazole is chemically 5-methoxy-2-[(4-methoxy-3,5-dimethylpyridin-2-yl)methyl sulfinyl]- 3//-benzimidazole. It is a proton pump inhibitor and is used for treatment of gastric and duodenal ulcer, gastroesophageal reflux disease, erosive esophagitis, long-term treatment of pathological hypersecretory conditions (like Zollinger-Ellison syndrome, multiple endocrine adenomas and systemic mastocytosis) and H. pylori infection. It is marketed in the form of free base as well as magnesium salt under the tradename Prilosec® as delayed release capsules, tablets and suspension.

Benzimidazole compounds have been reported to be acid labile. As such, they are generally designed as enteric coated dosage forms in order to avoid degradation of the active pharmaceutical ingredient (API) at the low pH found in the stomach. However, because enteric coatings are generally comprised of acidic compounds, direct covering of the benzimidazole compounds with these types of coatings has been reported to cause degradation and decomposition of the active pharmaceutical ingredient, causing the active pharmaceutical ingredient preparation to undergo discoloration and to lose its active ingredient content over time. To avoid the contact between the core and the enteric coating, a subcoating layer is established between the acidic drugs and enteric coating.

US 4,255,431 discloses omeprazole and US 4,738,974 discloses various salts of omeprazole including magnesium salt of omeprazole.

Several references describe compositions that are suitable for oral administration of acid-labile benzimidazole derivatives which are as follows:

US 4,786,505 and US 4,853,230 relates to a preparation comprising: (a) an alkaline reacting core comprising an acid-labile pharmaceutically active substance and an alkaline reacting compound different from said active substance, an alkaline salt of an acid labile pharmaceutically active substance, or an alkaline salt of an acid labile pharmaceutically active substance and an alkaline reacting compound different from said active substance (b) an inert subcoating and (c) an enteric coating layer.

US 5,232,706 relates to a composition comprising: (a) a core containing omeprazole and an alkaline salt of omeprazole mixed with a first basic compound; (b) at least one intermediate layer formed by an excipient and a second basic compound and (c) an outer layer formed by an enteric coating and further discloses that said basic compounds are sodium, potassium, magnesium, calcium, aluminum or dihydroxyaluminium salts of amino acids.

US 5,626,875 discloses a composition comprising (a) a nucleus formed by an inert core coated with a layer containing mixture of benzimidazole compound, a non-alkaline water soluble polymer and non-alkaline reacting excipients; (b) an inert non-alkaline coating comprising non-alkaline water soluble polymer and non-alkaline pharmaceutical excipients and (c) an enteric coating.

US 5,753,265 and US 5,817,338 discloses a composition in the form of a multiple unit tablet comprising: a tablet excipient; a multiple of a core unit comprising as an active ingredient an acid-labile H+ K+ -ATPase inhibitor compound in a neutral form or a salt form, a single enantiomer or an alkaline salt of a single enantiomer, wherein the core unit being covered with at least one enteric coating layer having mechanical properties so as not to significantly affect the acid resistance of the enteric coating layered unit by compression during tableting. The patents discloses that the stability of the acid-labile H* K+ -ATPase inhibitor is also affected by moisture, heat, organic solvents and to some degree by light.

US 6,090,827 discloses an enteric coated oral formulation comprising: (a) a core material comprising omeprazole, (b) a separating layer; and (c) an enteric coating layer, wherein the separating layer comprise a hydroxypropyl methylcellulose (HPMC) of low viscosity with a cloud point of at least 45.6°C, and wherein the light transmission at cloud point of a system comprising the HPMC dissolved in a concentration of 1.2% (w/w) in a mixed solution of phosphate buffer 0.235M and simulated gastric fluids pH 1.2 in the proportions 4:5 at a pH of 6.75-8.5 is 96%.

US 6,207,198 discloses compositions comprising (a) a core containing an acid-labile omeprazole, said core being constituted of pharmaceutically inert nuclei and said active ingredient compressed together, and said omeprazole active principle not being in the form of an alkaline salt; (b) an intermediate layer and (c) an enteric layer, said composition exempt from alkaline-reacting compounds.

US 6,248,355 discloses a stable composition exempt of alkaline-reacting compounds comprising: (a) omeprazole core comprising pharmaceutical inert nuclei and said active ingredient granulated together and then compressed together and said omeprazole active principle being in a form different from an alkaline salt; (b) an intermediate layer; and (c) an enteric layer.

US 6,346,269 discloses an oral formulation for acid-sensitive drugs comprising a inert core made from one or more excipients, an active ingredient layer, a sub coating layer and an enteric layer.

US 6,391,342 discloses an oral pharmaceutical formulation comprising a benzimidazole derivative, said formulation comprising granules having a substantially inert core coated with an inner coating layer comprising the benzimidazole, a disintegrant and a surfactant in a matrix of a melt coating substance essentially consisting of one or more esters of glycerol and fatty acids, an outer coating layer being an enteric coating, and an intermediate coating layer separating the enteric coating layer from the inner coating layer for protection of the benzimidazole against degradation by the ingredients of the enteric coating.

US 6,428,810 discloses an enteric coated oral pharmaceutical formulation comprising: (a) a core material comprising omeprazole, (b) a separating layer; and (c) an enteric coating layer, wherein the separating layer comprises a hydroxypropyl cellulose (HPC) with a cloud point of at least 38°C, and wherein the light transmission at cloud point of a system comprising the HPC dissolved in a concentration of 1.0% (w/w) in a mixed solution of disodium hydrogen phosphate buffer 0.086 M and hydrochloric acid 0.1 M in the proportions 7:3 at a pH of 6.75-6.85 is 96%.

US 6,576,258 discloses a method for stabilizing a therapeutically active substance comprising a benzimidazole derivative, comprising anhydrous granulation with an organic solvent of the active substance and dried auxiliary substances for the preparation of pellet cores or granules, which are then either coated with a gastro-resistant coating or compressed into tablets under addition of a dried auxiliary substance, which tablets are in further procedure coated with a gastro-resistant coating.

US 2003/0118650 discloses a tabletted dosage form covered with an enteric coating, consisting of (a) a plurality of units containing an inert core; an active layer deposited on said inert core formed by a benzimidazole compound, a non-alkaline water-soluble inert polymer and an intermediate layer consisting of an inert non-alkaline coating formed by a non-alkaline, water-soluble inert polymer over the active layer; (b) one or more pharmaceutically acceptable inert excipients, of which one or more are compression excipients; and (c) an enteric coating layer that coats said plurality of units.

US 2005/0191353 discloses a stable oral multiple unit pharmaceutical composition in the form of enteric coated pellets comprising non-pareil seeds coated with an alkaline material layer comprising a water insoluble alkaline material; a drug layer, disposed over the alkaline material layer, comprising benzimidazole in an amount of upto about 40% w/w of the composition and being substantially free of propylene glycol; a sealant polymer layer, disposed over the drug layer, which is substantially free of propylene glycol; and an enteric polymer layer, disposed over the sealant polymer layer, containing surfactants; wherein the pharmaceutical composition is substantially free of surfactants, disintegrating agents, or fillers in contact with the benzimidazole.

WO 03/077829 discloses a process for preparation of a pharmaceutical composition comprises steps of manufacturing a) a core containing a pharmacologically effective acid labile compounds, and/or its alkaline salts, optionally with alkaline reacting substance, b) an inert subcoating layer which is a first coating layer, coated on the core, comprising film forming materials c) second coat, termed as a seal coat, comprising of a mixture of polymers over the sub-coat, d) an enteric coating layer surrounding said seal coat layer.

WO 2005/034924 discloses preparations comprising an inert core, constituted by starch and sugar, surrounded by active coating containing enantiomers, salts of the enantiomers of omeprazole such as esomeprazole in micronised form, which is mixed with pharmaceutically acceptable non-alkaline and inert excipients, followed by intermediate coating and an enteric coating.

WO 2010/018593 A2 discloses a stable, gastric acid resistant multiple unit tableted dosage form comprises multiple layered units, cushioning agent and pharmaceutically acceptable excipients, wherein each unit comprises of: a) core comprising benzimidazole compound and at least one pharmaceutically acceptable excipient; b) optionally a barrier layer over the core; and c) an enteric coating layer.

WO 2010/034425 Al discloses a tablet, containing an inner phase, comprising a) a first type of pellets (I), which contain a first active ingredient and which comprise a coating and/or which release the modified active ingredient, or b) a first type of coated first active ingredient (I), in a mixture with c) spherical particles (II), and an outer phase having one or more additives present in non-granulated form before the tabletting, selected from disintegrants, lubricants, flow regulating agents, fillers, and binders, wherein the weight of the outer phase accounts for no more than 25 percent of the total weight of the tablet.

WO 2010/122583 discloses a composition for administration of acid labile compounds comprising one or more active units, wherein each active unit comprises a core of at least one acid labile compound, an intermediate layer of at least one lipophilic substance and an enteric layer.

WO 2011/054930 A2 discloses a pharmaceutical oral solid dosage form comprising a) a core comprising a benzimidazole; b) a separating layer comprising a water soluble polymer and glyceryl monostearate; and c) an enteric coating.

WO 2011/144975 Al discloses a compressed tablet composition comprising (a) coated multiple units comprising at least one pharmaceutically active ingredient and at least one functional coating, (b) at least one compressibility enhancing agent comprising neutral spheres, (c) at least one cohesiveness imparting agent comprising binder(s), and (d) optionally, other compression excipients.

WO 2012/010944 A2 discloses a multiple unit tablet composition comprising: (i) enteric coated multiple unit cores comprising a pharmaceutically active ingredient, wherein plasticizer content of enteric coating is less than about 10% by weight of the enteric coating polymer; (ii) at least two diluents and optionally one or more other pharmaceutically acceptable excipient, wherein one diluent is highly compactable microcrystalline cellulose.

WO 2012/072570 A2 discloses a process for the preparing a pharmaceutical composition comprising a PPI (proton pump inhibitor) in the form of spherical granules(pellets), comprising the steps of: (a) preparing PPI containing cores by granulating the PPI, at least one basic compound, at least one pharmaceutically acceptable excipients, and at least one alcohol, preferably ethanol and/or isopropanol, especially isopropanol, using a high speed mixer, (b) drying of the cores, (c) coating the dried cores with an inert intermediate layer, (d) film coating of the coated cores with a enteric coating layer, and (e) drying the enteric coated cores to obtain PPI pellets having a residual moisture of less than or equal to 1.5 wt%, preferably less than or equal to 1 wt%, said revolution speed of the rapid mixer is greater than or equal to 50 rev/min, preferable greater than or equal to 65 rev/min, more preferably in the range of 70 to 140 rev/min, the granulation time is preferably less than 20 minutes, more preferably less than or equal to 10 minutes, more preferably less than or equal to 8 minutes, most preferably 5 to 8 minutes, and the granulation (a) preferably takes place in the absence of water.

WO 2012/092486 A2 discloses a pharmaceutical formulation comprising, in combination: a) one or more particles containing omeprazole or a salt thereof and having a drug release modifying coating comprising one or more of the polymers hydroxypropyl methyl cellulose phthalate, cellulose acetate phthalate, carboxymethylethyl cellulose, methyl methacrylate-methacrylic acid copolymer, methacrylic acid-ethyl acrylate copolymer, methacrylic acid-methyl acrylate-methyl methacrylate copolymer, hydroxypropyl cellulose acetate succinate, polyvinyl acetate phthalate, or shellac, the coating being soluble at pH values about 5 to about 7.5; and b) one or more particles containing omeprazole or a salt thereof and having a polymer coating that is soluble at pH values about 5 to about 6.

EP 1 837 016 A2 discloses a pharmaceutical multiple-unit composition comprising (a) units which comprise at least one benzimidazole compound as active ingredient and at least one coating, (b) protective granules which comprise (i) binder or filler selected from lactose, lactose hydrate, starch, cellulose, sugar alcohol, calcium hydrogen phosphate, and mixtures thereof, and (ii) additive selected from polyethylene glycol, poloxamer, sugar ester, glycerol fatty acid mono ester, and mixtures thereof, and (c) optionally at least one tableting excipient.

EP 2 081 546 A2 discloses a multiple unit tablet comprising: a) one or more tablet excipients, and b) a multiple of enteric coating layered core units containing a benzimidazole compound, wherein each core unit is covered with an enteric coating layer comprising a plasticizer in an amount of less than 15% by weight of the enteric coating layer polymer and wherein the enteric coating layer is further covered by an over-coating layer.

EP 2 345 408 discloses a pharmaceutical formulation comprising: (a) a pharmacologically inert core; (b) a drug layer over the core comprising a benzimidazole drug, at least one metal compound and/or at least one alkaline compound, and one or more excipients; (c) a barrier coating layer or intermediate layer over the drug layer, comprising at least one excipient; (d) an enteric layer over the barrier coating layer or intermediate layer comprising an enteric coating polymer; and (e) optionally, an overcoating layer over the enteric coating layer.

IN 489/CHE/2009 A discloses a new process for making a pharmaceutical dosage formulation of omeprazole which is stable upon prolonged storage having faster release rates with the desired therapeutic effect. This patent publication further discloses that it has been found that the addition of cross linked polyvinyl pyrrolidone and calcium carbonate to the core and optionally to the enteric coating greatly improves the storage stability and release rates of the omeprazole formulation according to the invention compared with formulations of the state of the art.

IN 39/CHE/2010 A discloses a stable multiple-unit pharmaceutical composition comprising: a) individually enteric-coated cores comprising: i) a benzimidazole compound selected from omeprazole or esomeprazole or their pharmaceutically acceptable salts, ii) at least one separating layer containing a sugar alcohol, iii) at least one enteric coating layer, b) a mixture of two or more tablet diluents of similar particle size, wherein said enteric coating layer comprises a mixture of at least one water-soluble plasticizer and at least one water-insoluble plasticizer, having a weight ratio from about 1:0.2 to about 1:1, relative to each other.

The prior art references discloses various oral formulations of omeprazole magnesium and has attempted various technologies for providing the stable oral formulation for omeprazole magnesium. Still, there exists a need to develop a stable pharmaceutical composition of omeprazole magnesium which shows better/comparable stability and bioavailability w.r.t marketed formulation.

The inventors of the present invention have surprisingly found that the use of hydroxyethyl cellulose in the sub-coating layer provides stable pharmaceutical composition comprising omeprazole magnesium which shows better/comparable stability and in-vitro dissolution w.r.t marketed formulation, which comprises omeprazole magnesium.

OBJECTIVE OF THE INVENTION

The main objective of the present invention is to provide a stable pharmaceutical composition comprising omeprazole magnesium and one or more pharmaceutically acceptable excipients.

SUMMARY OF THE INVENTION

The present invention relates to a stable pharmaceutical composition comprising omeprazole magnesium and one or more pharmaceutically acceptable excipients.

The present invention relates to a stable pharmaceutical composition comprising:

a) core comprising omeprazole magnesium and one or more pharmaceutically acceptable excipients,

b) a sub-coating layer comprising hydroxyethyl cellulose, and

c) an enteric coating layer.

The present invention relates to a stable pharmaceutical composition comprising:

a) an inert core,

b) an active layer comprising omeprazole magnesium and one or more pharmaceutically acceptable excipients,

c) a sub-coating layer comprising hydroxyethyl cellulose, and

d) an enteric coating layer.

The present invention further relates to a process for preparing a stable pharmaceutical composition comprising omeprazole magnesium comprising the steps of:

a) coating an inert core with an active layer comprising omeprazole magnesium,

b) applying a sub-coating layer comprising hydroxyethyl cellulose over the active layer,

c) applying an enteric coating layer over the sub-coating layer.

d) processing the enteric coated units into a suitable dosage form.

DETAILED DESCRIPTION OF THE INVENTION

The present invention relates to a stable pharmaceutical composition comprising:

a) core comprising omeprazole and one or more pharmaceutically acceptable excipients,

b) a sub-coating layer comprising hydroxyethyl cellulose, and

c) an enteric coating layer.

The present invention relates to a stable pharmaceutical composition comprising:

d) core comprising omeprazole magnesium and one or more pharmaceutically acceptable excipients,

e) a sub-coating layer comprising hydroxyethyl cellulose, and

f) an enteric coating layer.

The present invention further relates to a stable pharmaceutical composition comprising:

a) an inert core,

b) optionally an inner coating layer,

c) an active layer comprising omeprazole magnesium and one or more pharmaceutically acceptable excipients,

d) a sub-coating layer comprising hydroxyethyl cellulose, and

e) an enteric coating layer.

The present invention further relates to a stable pharmaceutical composition comprising:

a) an inert core,

b) an active layer comprising omeprazole magnesium and one or more pharmaceutically acceptable excipients,

c) a sub-coating layer comprising hydroxyethyl cellulose,

d) an enteric coating layer, and

e) optionally an over coating layer over the enteric coating layer.

In another embodiment of the present invention, the sub-coating layer is directly coated over the active layer and enteric coating layer is directly coated over the sub-coating layer. In another embodiment of the present invention, the sub-coating layer is free of a lipophilic substance and/or glyceryl monostearate.

In another embodiment the present invention relates to a process for preparing a stable pharmaceutical composition comprising omeprazole magnesium comprising the steps of:

a) coating an inert core with an active layer comprising omeprazole magnesium,

b) applying a sub-coating layer comprising hydroxyethyl cellulose over the active layer,

c) applying an enteric coating layer over the sub-coating layer,

d) processing the enteric coated units into a suitable dosage form.

In another embodiment the present invention relates to a process for preparing a stable pharmaceutical composition comprising omeprazole magnesium comprising the steps of:

a) coating an inert core with an active layer comprising omeprazole magnesium,

b) applying a sub-coating layer comprising hydroxyethyl cellulose over the active layer,

c) applying an enteric coating layer over the sub-coating layer,

d) blending the enteric coated units with one or more pharmaceutically acceptable excipients and filling into a capsule.

In another embodiment the present invention relates to a process for preparing a stable pharmaceutical composition comprising omeprazole magnesium comprising the steps of:

a) coating an inert core with an active layer comprising omeprazole magnesium,

b) applying a sub-coating layer comprising hydroxyethyl cellulose over the active layer,

c) applying an enteric coating layer over the sub-coating layer,

d) blending the enteric coated units with one or more pharmaceutically acceptable excipients and compressing into a tablet.

In another embodiment the present invention relates to a process for preparing a stable pharmaceutical composition comprising omeprazole magnesium comprising the steps of:

a) coating an inert core with an active layer comprising omeprazole magnesium,

b) applying a sub-coating layer comprising hydroxyethyl cellulose over the active layer,

c) applying an enteric coating layer over the sub-coating layer,

d) blending the enteric coated units with one or more pharmaceutically acceptable excipients and compressing into a tablet,

e) optionally coating the tablet with film coating material.
"Omeprazole" according to the present invention includes, but not limited to, racemic mixture, individual enantiomers including esomeprazole, esters, ethers, solvates, hydrates, polymorphs, salts and the like.

Inert core according to the present invention can be any inert substance/excipient which includes, but not limited to, sugar spheres (non-pareil seeds), microcrystalline cellulose, lactose, silicon dioxide, pellets, tablets, mini tablets and the like.

"Pharmaceutically acceptable excipient/s" are the components added to pharmaceutical formulation to facilitate manufacture, enhance stability, control release, enhance product characteristics, enhance bioavailability, enhance patient acceptability, etc. Pharmaceutically acceptable excipients includes, but not limited to, alkaline substances, film forming polymers, plasticizers, surfactants, anti-sticking agents, diluents/fillers, binders, disintegrants, sugars, lubricants, glidants, compression aids, colors, sweeteners, preservatives, suspending agents, dispersing agents, film formers, flavors, printing inks, etc.

The inert core may optionally be coated with an inner coating layer which provides alkaline environment to omeprazole in the composition and prevents degradation due to acidic excipients present in the composition. The inner coating layer comprises film forming polymer and one or more pharmaceutically acceptable excipients selected from alkaline substances, plasticizers, surfactant, anti-sticking agents and the like.

The active layer is applied to the inner coating layer and it contains omeprazole or its pharmaceutically acceptable salts and one or more pharmaceutically acceptable excipients including, but not limited to, surfactant agents, alkaline substance, film forming polymers, plasticizer, disintegrants, anti-sticking agents and the like.

A sub-coating layer is applied to the active layer in order to separate the layer containing the benzimidazole(s) from the enteric coating layer. In fact, gastro-resistant polymers generally have free carboxyl groups with acidic characteristics, meaning that if they were to come into direct contact with the benzimidazole compounds they would cause the degradation thereof. For this reason, a sub-coating should be applied between the active layer and the enteric coating layer. The sub-coating layer comprises hydroxyethyl cellulose and one or more pharmaceutical acceptable excipients including film forming polymers, alkaline substances, plasticizers, surfactants, anti-sticking agents and the like.

In the pharmaceutical dosage form, the enteric coating layer is applied to the sub-coating layer. The enteric coating layer comprises enteric polymer and one or more pharmaceutically acceptable excipients including plasticizers, surfactants, anti-sticking agents and the like. The amounts of polymer and plasticizer have to be strictly selected in order to guarantee the intended gastro-resistance.

The enteric coating layer makes the dosage form insoluble in acid media, but quickly disintegrable for neutral and alkaline pH values, as in the case of the fluids present in the proximal fraction of the small intestine, where the dissolution and the absorption of the benzimidazole(s) will occur.

The enteric coated units may optionally be covered with one or more overcoating layers. The over coating layer should be water soluble or rapidly disintegrating in water. The overcoating layer comprises one or more pharmaceutically acceptable excipients including film forming polymers, plasticizers, colorants, anti-sticking agents and the like.

Alkaline substance according to the present invention is any substance which provides the basic pH which includes, but not limited to, sodium, potassium, calcium, magnesium and aluminium salts with weak inorganic or organic acids such as phosphoric acid, carbonic acid, citric acid or other suitable; aluminium hydroxide/sodium bicarbonate co-precipitate;

substances normally used in antacid preparations such as aluminium, calcium and magnesium hydroxides; magnesium oxide or composite substances; organic pH-buffering substances such as tromethamine, basic amino acids and their salts or other similar pharmaceutically acceptable pH- buffering substances. The alkaline substance may be used in the range of 1-30% by weight of the composition.

Film forming polymers according to the present invention include, but not limited to, cellulosic polymers such as hydroxyethyl cellulose, hydroxypropyl cellulose, hydroxypropyl methylcellulose, methylcellulose, ethylcellulose, carboxymethyl cellulose sodium; acrylic polymers; polyethylene glycol, polyvinyl pyrrolidone, polyvinyl alcohol, polyvinyl acetate, sugar and other water soluble polymers used alone or in mixtures. The film forming polymer may be used in the range of 5-75% by weight of the composition.

Enteric polymers according to the present invention include, but not limited to, solutions or dispersions of polymethacrylates including methacrylic acid copolymers, cellulosic derivatives such as cellulose acetate phthalate, hydroxypropyl methylcellulose phthalate, hydroxypropyl methylcellulose acetate succinate, cellulose acetate trimellitate, cellulose acetate butyrate, carboxymethyl ethylcellulose; polyvinyl acetate phthalate, shellac or other suitable enteric coating polymer(s). The enteric polymer may be used in the range of 5-50% by weight of the composition.

Plasticizers according to the present invention include, but not limited to, glyceryl monostearate, diethyl phthalate, dibutyl phthalate, dibutyl sebacate, cetyl alcohol, polyethylene glycol, triethyl citrate, triacetin, acetyl tributyl citrate and the like. The plasticizer used according to the present invention is less than 20% by weight of the coating layer. The plasticizer may be used in the range of 1-30% by weight of the composition.

Binders hold the ingredients in the composition together. Exemplary binders include, but not limited to, cellulose and its derivatives including, ethyl cellulose, hydroxypropyl cellulose, hydroxypropyl methylcellulose, methylcellulose and hydroxyethyl cellulose, carboxymethyl cellulose; starch and its derivatives; hydrocolloids; sugars; polyvinyl pyrrolidone, copovidone, methacrylic acid copolymers and combinations comprising one or more of the foregoing binders. The binder may be used in the range of 1-40%, preferably 1-20% by weight of the dosage form.

Diluents increase the bulk of the composition. Diluents according to the present invention include, but not limited to, sugars such as lactose, sucrose, dextrose; sugar alcohols such as mannitol, sorbitol, xylitol, lactitol; Starlac® (co-processed mixture of Starch and lactose), Microcelac® (co-processed mixture of microcrystalline cellulose and lactose), starch, corn starch, modified starches, pregelatinized starch, dibasic calcium phosphate, tribasic calcium phosphate, powdered cellulose, microcrystalline cellulose, silicified microcrystalline cellulose and the like or combinations thereof. The diluent may be used in the range of 5-95%, preferably 10-70% by weight of the dosage form.

Surfactants according to the present invention include, but not limited to, polyoxyethylene alkylaryl ethers such as polyoxyethylene lauryl ether, polyoxyethylene cetyl ether, polyoxyethylene stearyl ether; polyethylene glycol fatty acid esters such as PEG monolaurate, PEG dilaurate, PEG distearate, PEG dioleate; polyoxyethylene sorbitan fatty acid ester such as polysorbate 40, polysorbate 60, polysorbate 80; sorbitan fatty acid mono esters such as sorbitan monolaurate, sorbitan monooleate, sorbitan sesquioleate, sorbitan trioleate, polyoxyethylene castor oil derivates such as polyoxyl castor oil, polyoxyl hydrogenated castor oil, sodium lauryl sulphate, poloxamers and the like or combinations thereof. The surfactant may be used in the range of 1-20% by weight of the composition.

Disintegrants according to the present invention include, but not limited to, crospovidone, sodium starch glycolate, croscarmellose sodium, hydroxypropyl cellulose, magnesium aluminum silicate, pregelatinized starch, cornstarch, sodium carboxymethyl cellulose and the like or a combination thereof. The disintegrant may be used in the range of 1-20% by weight of the composition.

Anti-sticking agents according to the present invention include, but not limited to, talc, magnesium stearate, titanium dioxide, sodium stearyl fumarate, stearic acid, glyceryl behenate and the like or a mixture thereof. The antisticking agent may be used in the range of 0.1-20% by weight of the composition.

The coating layers according to the present invention may be applied by using different techniques known in the art.

Suitable solvents according to the present invention include, but not limited to, aqueous solvents such as water and organic solvent such as alcohol including isopropyl alcohol, methanol, ethanol; acetone, methylene chloride and the like or mixtures thereof.

In another embodiment, the amount of omeprazole used may be in the range from about 5 to about 100 mg.

In another embodiment, the stable pharmaceutical composition comprising omeprazole magnesium according to the present invention can be used for the treatment of gastric and duodenal ulcer, gastroesophageal reflux disease, erosive esophagitis, long-term treatment of pathological hypersecretory conditions (like Zollinger-Ellison syndrome, multiple endocrine adenomas and systemic mastocytosis) and H. pylori infection.

In another embodiment, the stable pharmaceutical composition comprising omeprazole magnesium according to the present invention was found to be stable after storage at 40°C/75% RH for atleast two months.

In another embodiment the stable pharmaceutical composition according to the present invention may be presented in any dosage form including, but not limited to, capsule, tablet, granules, pellets, mini-tablets, beads or the like.

The dosage form according to the present invention may be uncoated or optionally coated with film coating/moisture barrier coating composition.

Film coating composition includes one or more polymeric carriers along with one or more pharmaceutically acceptable excipients such as plasticisers, opacifier, anti-sticking agent, colorants, sugars, pore forming agent, surfactants and the like.

The following examples further exemplify the invention and are not intended to limit the scope of the invention. It is obvious to those skilled in the art to find out the composition for other dosage forms and substitute the equivalent excipients as described in this specification or with the one known to the industry.

The processing steps involved in manufacturing stable formulation of omeprazole magnesium are given below:

a) omeprazole magnesium, hydroxypropyl cellulose and talc were dissolved/dispersed in purified water,

b) sugar spheres were coated with the solution/dispersion of step (a),

c) hydroxyethyl cellulose, magnesium stearate and talc were dissolved/dispersed in purified water,

d) the solution/dispersion of step (c) was coated over the drug layered sugar spheres,

e) methacrylic acid copolymer, triethyl citrate, glyceryl monostearate and polysorbate 80 were dissolved/dispersed in purified water,

f) solution/dispersion of step (e) was coated over the sub coated sugar spheres,

g) microcrystalline cellulose was granulated using binder solution of povidone in purified water, dried, milled and sifted,

h) extragranular blend was prepared by blending crospovidone with the microcrystalline granules of step (g), i) enteric coated pellets of step (f) were blended with extragranular blend of step (h), j) the blend of step (i) was lubricated with sodium stearyl fumarate and compressed into tablets and finally film coated using film coating material.

Example 2

Example 3

The compositions given in Examples 2 to 4 were prepared using the similar procedure described in Example 1.

Table 1 given below shows the comparative dissolution profile of omeprazole magnesium formulations according to the present invention (Examples 1-4) and Prilosec® tablets carried out in 300ml of 0.1N HC1 for 2 hours and 1000ml pH 6.8 buffer using USP Apparatus II (Paddle), at 100 rpm speed.

Table 1

Table 2 given below shows the impurity profile of omeprazole magnesium formulations prepared according to the present invention (Example 2) after storing at 40°C/75% RH for 2 months.

We Claim:

1. A stable pharmaceutical composition comprising:

a) an inert core,

b) an active layer comprising omeprazole magnesium and one or more pharmaceutically acceptable excipients,

c) a sub-coating layer comprising hydroxyethyl cellulose , and

d) an enteric coating layer.

2. The composition according to claim 1, wherein the inert core is selected from sugar spheres, microcrystalline cellulose, lactose, silicon dioxide, pellets, tablets and mini tablets.

3. The composition according to claim 1, wherein one or more pharmaceutically acceptable excipients are selected from the group comprising diluents, binders, disintegrants, lubricants, alkaline substances, film forming polymers, plasticizers, surfactant, anti-sticking agents and combination thereof.

4. The composition according to claim 3, wherein the film forming polymer is selected from hydroxypropyl cellulose, hydroxypropyl methylcellulose, methylcellulose, ethyl cellulose, carboxymethyl cellulose sodium; acrylic polymers; polyethylene glycol, polyvinyl pyrrolidone, polyvinyl alcohol, polyvinyl acetate, sugar and combinations thereof.

5. The composition according to claim 3, wherein the plasticizer is selected from glyceryl monostearate, diethyl phthalate, dibutyl phthalate, dibutyl sebacate, cetyl alcohol, polyethylene glycol, triethyl citrate, triacetin, acetyl tributyl citrate and combinations thereof.

6. The composition according to claim 1, wherein the sub-coating layer comprises one or more pharmaceutically acceptable excipients selected from alkaline substances, plasticizers, surfactant, anti-sticking agents and combinations thereof.

7. The composition according to claim 1, wherein the enteric coating layer comprises one or more pharmaceutically acceptable excipients selected from enteric polymer, plasticizers, surfactants, anti-sticking agents and combinations thereof.

8. The composition according to claim 7, wherein the enteric polymer is selected from methacrylic acid copolymers, cellulosic derivatives selected from cellulose acetate phthalate, hydroxypropyl methylcellulose phthalate, hydroxypropyl methylcellulose acetate succinate, cellulose acetate trimellitate, cellulose acetate butyrate, carboxymethyl ethyl cellulose; polyvinyl acetate phthalate, shellac and combination thereof.

9. A process for preparing a stable pharmaceutical composition comprising omeprazole magnesium comprising the steps of:

a) coating an inert core with an active layer comprising omeprazole magnesium,

b) applying a sub-coating layer comprising hydroxyethyl cellulose over the active layer,

c) applying an enteric coating layer over the sub-coating layer.

d) processing the enteric coated units into a suitable dosage form.

10. A stable pharmaceutical composition comprising omeprazole magnesium prepared by a process comprising the steps of:

a) coating an inert core with an active layer comprising omeprazole magnesium,

b) applying a sub-coating layer comprising hydroxyethyl cellulose over the active layer,

c) applying an enteric coating layer over the sub-coating layer,

d) blending the enteric coated units with one or more pharmaceutically acceptable excipients and compressing into a tablet,

e) optionally coating the tablet with film coating material.