FIELD OF THE INVENTION

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

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

BACKGROUND OF THE INVENTION

Esomeprazole is S-isomer of omeprazole and is chemically (5)-5-methoxy-2-[(4-memoxy-3,5-dimethylpyridin-2-yl)methylsulfinyl]-3H-benzimidazole. It is a proton pump inhibitor and is used for treatment of gastric and duodenal ulcer, severe erosive esophagitis, Zolinger-Ellison syndrome and H-pylori eradication. It is marketed in the form of magnesium trihydrate under the tradename Nexium® 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 4,738,974 disclose various salts of omeprazole including magnesium salt of esomeprazole and US 6,369,085 specifically discloses esomeprazole magnesium trihydrate and dihydrate form. The patent discloses that the trihydrate form is more stable and easy to handle as compared to other forms of esomeprazole magnesium including dihydrate form. The patent discloses the method of preparing the trihydrate form from the dihydrate form.

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 7:3atapH of6.75-6.85is96%.

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 pharmaceutically acceptable 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 pharmaceutically acceptable 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 2010/122583 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.

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.

The prior art references discloses that the benzimidazole compounds are unstable at acidic pH and in the presence of organic solvents.

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

The esomeprazole magnesium dihydrate has the tendency to convert to esomeprazole magnesium trihydrate during formulation using water and/or during the stability or storage.

The inventors of the present invention have surprisingly found that the use of organic solvent for the preparation of active layer provides stable pharmaceutical composition comprising esomeprazole magnesium dihydrate. Further, the stable oral pharmaceutical composition according to present invention, comprising inert core, an inner coating layer comprising alkaline substance, an active layer comprising esomeprazole magnesium dihydrate, a sub-coating layer and an enteric layer, shows better/comparable stability and in-vitro dissolution w.r.t marketed formulation, which comprises esomeprazole magnesium trihydrate.

OBJECTIVE OF THE INVENTION

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

Another objective of the present invention is to provide a process for the preparation of stable pharmaceutical composition comprising esomeprazole magnesium and one or more pharmaceutically acceptable excipients.

SUMMARY OF THE INVENTION

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

The present invention relates to a stable pharmaceutical composition comprising:

a) an inert core,

b) an inner coating layer comprising alkaline substance,

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

d) a sub-coating layer, and

e) an enteric coating layer.

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

a) coating an inert core with a inner coating layer,

b) applying an active layer comprising esomeprazole magnesium dihydrate and a film forming polymer using organic solvent, over the inner coating layer,

c) applying a sub-coating layer over the active layer,

d) applying an enteric coating layer.

DETAILED DESCRIPTION OF THE INVENTION

The present invention relates to a stable pharmaceutical composition comprising:

a) an inert core,

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

c) a sub-coating layer, and

d) an enteric coating layer.

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

a) an inert core,

b) an inner coating layer,

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

d) optionally a sub-coating layer, and

e) an enteric coating layer.

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

a) an inert core,

b) an inner coating layer,

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

d) optionally a sub-coating layer,

e) an enteric coating layer, and

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

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

a) an inert core,

b) an inner coating layer comprising an alkaline substance,

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

d) a sub-coating layer, and

e) an enteric coating layer.

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

a) an inert core,

b) a inner coating layer comprising an alkaline substance,

c) an active layer comprising esomeprazole magnesium dihydrate, an alkaline substance and one or more pharmaceutically acceptable excipients,

d) a sub-coating layer, and

e) an enteric coating layer.

The present invention further relates to a stable pharmaceutical composition comprising:
a) an inert core,

b) a inner coating layer comprising an alkaline substance,

c) an active layer comprising esomeprazole magnesium dihydrate, an alkaline substance and one or more pharmaceutically acceptable excipients,

d) a sub-coating layer comprising an alkaline substance, and

e) an enteric coating layer.

In a preferred embodiment, the present invention further relates to a stable pharmaceutical composition comprising:

a) an inert core,

b) a inner coating layer comprising a film forming substance selected from hydroxypropyl methylcellulose and hydroxypropyl cellulose or mixture thereof, an alkaline substance selected from magnesium oxide and magnesium carbonate and one or more pharmaceutically acceptable excipients,

c) an active layer comprising esomeprazole magnesium dihydrate, a film forming substance selected from hydroxypropyl methylcellulose and hydroxypropyl cellulose or mixture thereof, an alkaline substance selected from magnesium oxide and magnesium carbonate and one or more pharmaceutically acceptable excipients,

d) a sub-coating layer comprising a film forming substance selected from hydroxypropyl methylcellulose and hydroxypropyl cellulose or mixture thereof, an alkaline substance selected from magnesium oxide and magnesium carbonate and one or more pharmaceutically acceptable excipients, and

e) an enteric coating layer comprising an enteric polymer selected from methacrylic acid copolymers and cellulosic derivatives and one or more pharmaceutically acceptable excipients.

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

a) coating an inert core with a inner coating layer,

b) applying an active layer comprising esomeprazole magnesium dihydrate over the inner coating layer,

c) applying a sub-coating layer over the active layer,

d) applying an enteric coating layer.

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

a) coating an inert core with a inner coating layer,

b) applying an active layer comprising esomeprazole magnesium dihydrate using organic solvent, over the inner coating layer,

c) applying a sub-coating layer over the active layer,

d) applying an enteric coating layer.

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

a) coating an inert core with a inner coating layer comprising an alkaline substance,

b) applying an active layer comprising esomeprazole magnesium dihydrate using organic solvent, over the inner coating layer,

c) applying a sub-coating layer over the active layer,

d) applying an enteric coating layer.

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

a) coating an inert core with a inner coating layer comprising an alkaline substance,

b) applying an active layer comprising esomeprazole magnesium dihydrate and an alkaline substance using organic solvent, over the inner coating layer,

c) applying a sub-coating layer over the active layer,

d) applying an enteric coating layer.

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

a) coating an inert core with a inner coating layer comprising an alkaline substance,

b) applying an active layer comprising esomeprazole magnesium dihydrate and an alkaline substance using organic solvent, over the inner coating layer,

c) applying a sub-coating layer comprising an alkaline substance over the active layer,

d) applying an enteric coating layer.

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

a) coating an inert core with a solution/dispersion of one or more film forming polymers in a solvent,

b) applying an active layer comprising esomeprazole magnesium dihydrate and film forming polymer using organic solvent,

c) applying a sub-coating layer comprising solution/dispersion of one or more film forming polymers in a solvent,

d) applying an enteric coating layer.

In another embodiment according to the present invention, the stable pharmaceutical composition can further be coated with an inert overcoating layer.

Esomeprazole magnesium dihydrate according to the present invention can be in any polymorphic form such as crystalline Form A, Form B or amorphous form.

The esomeprazole magnesium dihydrate present in the stable pharmaceutical composition according to the present invention does not convert to any other esomeprazole magnesium forms, more particularly trihydrate form. The pharmaceutical composition remains stable throughout the stability or storage period and provides better/comparable bioavailability to the marketed formulation containing esomeprazole magnesium trihydrate.

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, 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.

Inner coating layer is applied on to the inert core and provides the alkaline environment to esomeprazole 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 esomeprazole 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 film forming polymer and one or more pharmaceutical acceptable excipients including, 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 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 esomeprazole used may be in the range from about 5 to about 100 mg.

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 pharmaceutical^ 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 esomeprazole are given below:

a) hydroxypropyl cellulose, hydroxypropyl methylcellulose and light magnesium oxide were dissolved/dispersed in methanol,

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

c) esomeprazole magnesium, hydroxypropyl cellulose and light magnesium carbonate were dissolved/dispersed in isopropyl alcohol,

d) the inner coated sugar spheres were coated with solution/dispersion of step (c),

e) hydroxypropyl cellulose, hydroxypropyl methylcellulose, and magnesium carbonate were dissolved/dispersed in methanol,

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

g) methacrylic acid copolymer, triethyl citrate, Tween 80, glyceryl monostearate and talc were dissolved/dispersed in purified water,

h) solution/dispersion of step (g) was coated over the sub coated sugar spheres, and i) enteric coated pellets were lubricated with talc and filled into capsule or compressed into tablets.

Example 2

Example 3

Example 4

The pharmaceutical compositions according to Examples 2, 3 and 4 were prepared using the process followed in Example 1.

Example 5

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

a) hydroxypropyl cellulose, light magnesium oxide and hydroxypropyl methylcellulose were dissolved/dispersed in methanol,

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

c) esomeprazole magnesium, hydroxypropyl cellulose, light magnesium carbonate and talc were dissolved/dispersed in isopropyl alcohol,

d) the inner coated sugar spheres were coated with solution/dispersion of step (c),

e) hydroxypropyl cellulose, hydroxypropyl methylcellulose, light magnesium oxide, polysorbate 80 and glyceryl monostearate were dissolved/dispersed in methanol,

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

g) Eudragit L 100 55, acetyl tributyl citrate, polyethylene glycol 6000, poloxamer 188 and talc were dissolved/dispersed in methanol,

h) solution/dispersion of step (g) was coated over the sub coated sugar spheres, and

i) hydroxypropyl cellulose and polyethylene glycol 8000 were dissolved/dispersed in
purified water,

j) the solution/dispersion of step (i) was coated over the enteric coated sugar spheres,

k) microcrystalline cellulose and hydroxypropyl cellulose were blended and granulated using binder solution of povidone,

l) over coated enteric coated pellets of step (j) were blended with the granules obtained in step (k) and crospovidone,

m) the blend of step (1) was lubricated with sodium stearyl fumarate and compressed into tablets,

n) the obtained tablets were film coated with instacoat.

Example 6

The pharmaceutical composition according to Example 6 was prepared using the process followed in Example 5.

Table 1 given below shows the comparative dissolution profile of esomeprazole formulations according to the present invention (Examples 1-3) and Nexium® DR capsules carried out in 1000ml of Phosphate buffer pH 6.8 using Apparatus USP II (Paddle), at 100 rpm speed.

Table 1

Table 2 given below shows the comparative dissolution profile of esomeprazole formulations according to the present invention (Examples 5 and 6) and Nexium® DR tablets carried out in 1000ml of Phosphate buffer pH 6.8 using Apparatus USP II (Paddle), at 100 rpm speed.

Table 2

Table 3 given below shows the total impurities of esomeprazole formulations according to the present invention (Examples 1-3).

Table 3

Claims:

1. A stable pharmaceutical composition comprising:

a) an inert core,

b) an inner coating layer comprising alkaline substance,

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

d) a sub-coating layer, and

e) an enteric coating layer.

2. The composition according to claim 1, wherein the inert core is selected from sugar spheres, microcrystalline cellulose, lactose, 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 alkaline substance is selected from sodium, potassium, calcium, magnesium and aluminium salts with weak inorganic or organic acids selected from phosphoric acid, carbonic acid, citric acid; aluminium hydroxide/sodium bicarbonate co-precipitate; aluminium, calcium and magnesium hydroxides; magnesium oxide; tromethamine, basic amino acids and combinations thereof.

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

6. 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.

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

8. The composition according to claim 1, wherein the enteric coating layer comprises an enteric polymer 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 ethylcellulose; polyvinyl acetate phthalate, shellac and combination thereof.

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

a) coating an inert core with an inner coating layer comprising an alkaline substance,

b) applying an active layer comprising esomeprazole magnesium dihydrate using organic solvent, over the inner coating layer,

c) applying a sub-coating layer over the active layer,

d) applying an enteric coating layer.

10. A stable pharmaceutical composition comprising:

a) an inert core,

b) a inner coating layer comprising a film forming substance selected from hydroxypropyl methylcellulose and hydroxypropyl cellulose or mixture thereof, an alkaline substance selected from magnesium oxide and magnesium carbonate and one or more pharmaceutically acceptable excipients,

c) an active layer comprising esomeprazole magnesium dihydrate, a film forming substance selected from hydroxypropyl methylcellulose and hydroxypropyl cellulose or mixture thereof, an alkaline substance selected from magnesium oxide and magnesium carbonate and one or more pharmaceutically acceptable excipients,

d) a sub-coating layer comprising a film forming substance selected from hydroxypropyl methylcellulose and hydroxypropyl cellulose or mixture thereof, an alkaline substance selected from magnesium oxide and magnesium carbonate and one or more pharmaceutically acceptable excipients, and

e) an enteric coating layer comprising an enteric polymer selected from methacrylic acid copolymers and cellulosic derivatives and one or more pharmaceutically acceptable excipients.