Introduction The present invention relates to an improved stable pharmaceutical composition. The pharmaceutical composition containing enantiomers, salts of the enantiomers of omeprazole such as esomeprazole. The present invention particularly relates to an improved pharmaceutical composition in the form of hard gelatin capsules containing enantiomers, salts of the enantiomers of omeprazole such as esomeprazole which is useful in the treatment of gastric and duodenal ulcers and a process for its preparation.

The pharmaceutical composition of the present invention guarantees the integrity of the composition until it reaches the proximal part of the small intestine, where the composition will be disaggregated to facilitate the absorption of the enantiomers, salts of the enantiomers of omeprazole such as esomeprazole contained therein. This invention also involves a process of preparing the above mentioned pharmaceutical composition (hard capsules) The present invention provides a stable pharmaceutical composition containing enantiomers, salts of the enantiomers of omeprazole such as esomeprazole, in the form of hard gelatin capsules useful for treating gastro intestinal ulcers. The pharmaceutical composition of the present invention is in the form of hard gelatin capsules suitable for oral administration. The composition of the present invention would dissolve in the intestine to facilitate absorption in the neutral/alkali environment.

Prior art of the invention Benzimidazolic compounds such as omeprazole (5-methoxy-2 ( ( (4-methoxy-3, 5-di met hyl-2-pyridinyt)-methyl-sulfinyl) lH-benzimidazole), lansoprazole (2- ( (3-methyl- 4- (2, 2,2-trifluoro etoxy) -2-piridyl) methyl (sulfinyl 1H-benzimidazole) (U. S. Pat No.

4,628, 098), pantoprazole (U. S. Pat. No. 4,758, 579) ), and rabeprazole, are anti- ulcerous substances known for decreasing gastric acid secretion (Olbe L. , et al., Gastroenterol., 83: 193-198 (1982); Saton H. et al. , Jpn. J. Pharmacol. 40 (suppl.), 226 (1986); Saton H, et al. , J. Pharmacol. Exp. Ther, 248 (2), 806-815 (1989), These

compounds are used in the therapeutics of diseases related to gastric acidity in mammals and especially in humans, including gastric and duodenal ulcers, reflux oesophagitis, gastritis and duodenitis..

It is also known that these substituted benzimidazoles possess a very low level of solubility in water. They solubilize easily in alkaline solutions. They degrade quickly in acidic and neutral media (Pilbrand and Cederberg, Scand. J. Gastroenterol, 20 (Suppl. 108), p. 113-120 (1985) ) and they are stabilized in the presence of alkaline reacting compounds.

The maximum stability of omeprazole solution is reached at pH 11 [Drug. Dev. Ind.

Pharm. , 21 (8), 965 (1995) ]. Degradation occurs very quickly below a pH of 7.0. On the other hand, it is necessary that the formulations dissolve quickly in the intestine, where the benzimidazolic compounds should be absorbed, i. e. when the pH becomes higher than 6.8.

There are various prior art information showing benzimidazoles such as omeprazole and its enantioner such as esomeprazole with the above activity.

U. S. Pat. No. 4,786, 505 proposes the mixture. of a mass of cellulose derivatives and disaggregants, with an appropriate amount of omeprazole and alkaline agents or alkaline salts of the drug, in order to obtain, by extrusion, a core which is spheronized and coated with gastroresistant agents dissolved in alcoholic solutions also containing considerable percentages of acetone. However, the pellets obtained may be extremely irregular in shape and dimensions, and this can have repercussions on a relative dispersion of the average weight of the capsules and of the respective dosage.

The US Patent no 6,248, 355, describes a composition of omeprazole without the use of alkaline-reacting compounds and in which the active ingredient is granulated together and compressed together along with inert ingredients followed by a coating of intermediate coat containing one or several inert water soluble layer or layers which rapidly disintegrate in aqueous medium and contains non-acid inert pharma excipients.

This layer comprises at least one polymer conventionally used in application where a film is provided by coating with such materials as sugars, polyethyleneglycol, polyvinylalcohol, hydroxy propyl methyl cellulose, an intermediate coat, and an enteric coating containing entero-soluble gastro resistants made of latex suspension of polymers such as cellulose acetate phthalate, methacrylic acid, methacrylic esters, methacrylic acid copolymers.

This process involves multi-step processing such as preparation of core, intermediate layer and enteric coatings and may involve a number of controlling points like dry mixing of the drug with inert excipients, granulation of the mass, lubrication, compression, followed by a coating of intermediate layer and finally coating by an enteric layer, thereby making the process a multi-step process with each step subjected to the active ingredient analysis thereby not only making the process cumbersome but also increasing the cost of the product.

The US Patent no 5,714, 504 provides methods for the preparation of pure crystalline enantiomeric salts of omeprazole which is having a dosage strength of equivalent 20 mg base and eqivalent 40 mg base in the form of oral delayed release tablets or granules.

The US patent no 5,877, 192 describes a method for the treatment of gastric acid related diseases and production of medication using enantiomer of omeprazole by a method of inhibiting gastric acid secretion comprising the oral administration of a pharmaceutical compositions which is having a dosage strength of equivalent 20 mg base and equivalent 40 mg base in the form of oral delayed release tablets or granules.

The US Patent no 6,132, 770 provide a tableted multiple unit effervescent dosage form comprising esomeprazole or an alkaline salt of esomeprazole, in which the active substance is in the form of enteric coating layered units compressed together with effervescent tablet excipients into such an effervescent tablet.

The US Patent no 6,132, 771 describes a preparation comprise a gastric acid suppressing agent, such as a proton pump inhibitor selected from esomeprazole, in combination with one or more prokinetic agents such as mosapride, cisapride in a new fixed unit dosage form, especially a tablet.

The US Patent no 6,136, 344 discloses a preparations which comprise an acid susceptible proton pump inhibitor, esomeprazole magnesium salt in combination with one or more antibacterial compounds in a new fixed unit dosage form, especially a tableted dosage form.

The US Patent no 6,183, 776 provides oral, fixed unit dosage forms, i. e. multiple unit tableted dosage forms, layered formulations comprising an enteric coating layered tablet core, multilayered tablets or a sachet filled with pharmaceutically active compound selected from S-omeprazole magnesium salts.

The US Patent no 6,328, 993 discloses an oral administration form such as tablet, an effervescent, tablet, powder in a sachet, a coated tablet or a capsule made of a proton pump inhibitor selected from the group consisting of pantoprazole, omeprazole, esomeprazole, lansoprazole and rabeprozole.

The US Patent no 6,365, 184 provides oral adminstration such as fixed unit dosage forms, i. e. multiple unit tableted dosage forms, enteric coating layered tablets, multilayered tablets or capsules filled with pharmaceutically active compound such as esomeprazole magnesium salt, lansoprazole, pantoprazole.

The US Patent no 6,428, 810 discloses a oral pharmaceutical formulation with a core comprising active pharmaceutical ingredients selected from omeprazole or enantiomers of omeprazole, a separating layer and an enteric layer. The dosage forms are pellets filled in hard gelatin capsules or tablets.

The US Patent 6,489, 346 provides a solid pharmaceutical composition in a dosage

form that is not enteric-coated having active ingredients selected from omeprazole, lansoprazole, rabeprazole, esomeprazole, pantoprazole, pariprazole and leminoprazole or an enantiomer such as esomeprazole and at least one buffering agent for treating gastrointestinal disorder. Due to the absence of enteric coating, the stability of the drug may not be optimum.

In our co-pending Indian application no 388 MAS 03 and the corresponding PCT application no PCT/IN03/00179 we have disclosed a process for the production of hard gelatin capsules in a conventional manner comprise an inert core, constituted by starch and sugar, surrounded by active core containing at least one substituted benzimidazole in the micronized form which is mixed with pharmaceutically acceptable non-alkaline and inert excipients followed by intermediate coating and an enteric coating, in order to gurantee the integrity of the product until it reaches the proximal part of the small intestine where the formulation will be disaggregated to facilitate the absorption of the substituted benzimidazole compound.

The said inventjion has been developed based on our finding as a result of sustained R & D work, that the incorporation of benzimidazole derivatives, particularly useful for the treatment of duodenal ulcers, without the necessity of using an alkali agent or alkali salt of the substituted benzimidazole for the stability of the formulation.

Such a composition will have an advantage over the existing form of the formulation as the available dosage forms for benzimidazole derivatives are having the total amount of active ingredient in the form of solid particles engulfed in a solid matrix of excipients preferably hydrophilic substances, further coated with protective and gastric resistant enteric polymer coatings. It may take some time to dissolve these coats before the benzimidazole derivative is dissolved into the surronding intestinal fluid and gets absorbed.

Our continued research in the above directions resulted in our surprised and unexpected finding that when esomeprazole, is used as the benzimidazole

derivatives, the resulting composition has also found to have extended periods of stability during which period the composition does not get discolored and/or degraded.

None of the above said prior art discloses and/or envisages such a composition and therefore the composition of the present invention is unique and novel.

Accordingly the present invention provides, composition containing enantiomers, salts of the enantiomers of omeprazole such as esomeprazole, and a method of making the said composition that are not taught or suggested by the prior art Considering the importance gained for the composition containing benzimidazole derivatives, particularly omeprazole, more particularly esomeprazole and other enentiomers of omeprazole or its salts, for the treatment of duodenal ulcers, there is a need for the development of pharmaceutical composition containing said derivatives having stability for an extended period during which period the composition does not get discoloured and/or degraded.

Objectives of the present invention.

The main objective of the present invention is, therefore, to provide an improved stable pharmaceutical composition in the form of hard gelatine capsules containing enantiomers, salts of the enantiomers of omeprazole such as esomeprazole useful in the treatment of gastric and duodenal ulcers.

Another objective of the present invention is to provide an improved stable pharmaceutical composition in the form of hard gelatine capsules containing enantiomers, salts of the enantiomers of omeprazole such as esomeprazole containing useful in the treatment of gastric and duodenal ulcers without the necessity of using an alkali agent or alkali salt of the substituted benzimidazole for the stability of the formulation.

Yet another objective of the present invention is to provide an improved stable pharmaceutical composition in the form of hard gelatine capsules containing enantiomers, salts of the enantiomers of omeprazole such as esomeprazole useful in the treatment of gastric and duodenal ulcers by using most commonly available inert and non-acid/non-alkaline and safe pharmaceutical excipients to create an appropriate microenvironment for the active drug, since they are unstable in acidic/ neutral environment and to release the active ingredient only in an alkaline environment.

Still another objective of the present invention is to provide an improved stable pharmaceutical composition in the form of hard gelatine capsules containing enantiomers, salts of the enantiomers of omeprazole such as esomeprazole useful in the treatment of gastric and duodenal ulcers which does not release the drug in the stomach (acidic environment) but releases the drug (esomeprazole) in the intestine (alkaline environment).

Still another objective of the present invention is to provide an improved and stable pharmaceutical composition in the form of hard gelatine capsules containing enantiomers, salts of the enantiomers of omeprazole such as esomeprazole capsules useful in the treatment of gastric and duodenal ulcers to facilitate to disaggregate quickly in the neutral to alkaline environment in the intestine with complete dissolution of the active drug in the intestine.

Yet another objective of the invention is to provide a process for the preparation of an improved and stable pharmaceutical composition in the form of hard gelatine capsules containing enantiomers, salts of the enantiomers of omeprazole such as esomeprazole useful in the treatment of gastric and duodenal ulcers as described above useful for oral adminstration in capsule form.

The present invention has been developed based on our finding that when some of the most commonly available pharmaceutically inert, non-alkaline/non-acid

pharmaceutical excipients such as dioctyl sodiumsulphosuccinate, talc, titaniumdioxide, starch, sodium lauryl sulphate, micro crystalline cellulose powder, magnesium stearate and the like are mixed judiciously along with enantiomers, salts of the enantiomers of omeprazole such as esomeprazole and processed resulting in a composition which is stable during its passage through the stomach and remains in a microenvironment that is not acidic or lower than pH 7.0, at the same time when the composition exits from the stomach and reaches the proximal part of the intestine, the drug dissolves rapidly.

The present invention provides a composition composed of an inert core coated with a layer which contains the active ingredient (s) devoid of any alkali reacting compounds, coated in turn with an intermediate coat, also devoid of any alkali reacting compounds and a final external gastro resistant or enteric coating. The composition of the present invention is also characterized in that it does not dissolve in an acid medium, but dissolves quickly at an alkaline pH and present good stability in terms of dosage and in gastroresistance and dissolution in the small intestine.

The present invention provides an improved stable pharmaceutical composition as a hard gelatin capsule dosage containing enantiomers, salts of the enantiomers of omeprazole such as esomeprazole constituted by a succession of layers arranged around an inert, spherical core prepared from sugar and starch.

The composition of the present invention in the dosage hard gelatin capsule form which comprises 1) An inert core 2) An active coating containing enantiomers, salts of the enantiomers of omeprazole such as esomeprazole in microionised form.

3) An intermediate coating and 4) An enteric coating

The inert core are constituted by pharmaceutically acceptable inert excipients and which are coated with a layer containing enantiomers, salts of the enantiomers of omeprazole such as esomeprazole in microionised form, mixed with pharmaceutically acceptable inert excipients, so that this layer quickly disaggregates. This drug layer is covered by intermediate coating comprising of a neutral film-forming agent and finally this layer is coated with an enteric coating. The pellets have spherical symmetry and have a moisture level that guarantees good stability under normal storage conditions. The pellets are placed in hard gelatine capsules and it is in this form that they are administered to patients.

Accordingly, the present invention provides an improved stable pharmaceutical composition containing enantiomers, salts of the enantiomers of omeprazole such as esomeprazole enantiomers in microionised form useful for the treatment of gastric and duodenal ulcers in the form of hard gelatine capsules which comprises 1) An inert core comprising of sugar and starch.

2) The inert core having an active coating comprising enantiomers, salts of the enantiomers of omeprazole such as esomeprazole in micronised form with an inert pharmaceutically acceptable film forming agent and inert non-acidic/non- alkaline pharmaceutical excipients.

3) The resulting product having a coating of an intermediate coating comprising the same film forming agent as used for the coating of the inert core and the same inert non-acidic/non-alkaline pharmaceutical excipients and.

4) The resulting product having an enteric coating of a mixture of an enteric polymer, plasticizer and anti-adherent in an aqeous/solvent base.

According to another feature of the present invention there is provided a process for the preparation of an improved and stable pharmaceutical composition comprising enantiomers, salts of the enantiomers of omeprazole such as esomeprazole in micronised form in the form of hard gelatin capsules useful for treating gastric and deuodonal ulcers which comprises

a) Forming an inert core comprising of sugar and starch in the form of spherical or nearly spherical pellets. b) Providing to the inert core an active coating comprising enantiomers, salts of the enantiomers of omeprazole such as esomeprazole in micronised form, an inert pharmaceutically acceptable film forming agent and inert non-acidic/non- alkaline pharmaceutical excipients. c) Providing the resulting spherical or nearly spherical pellets with an intermediate coating comprising of the same film forming agent as used in step (ii) above and the same inert non-acidic/non-alkaline pharmaceutical excipients. d) Providing to the resulting spherical or nearly spherical pellets with an yet another coating of an enteric coating layer comprising of a mixture of an enteric polymer, plasticizer and anti-adherent in an aqeous/solvent base and e) Filling the enteric coated pellets into hard gel capsules by conventional methods.

The sugar used for the inert core may consist of sugars such as sucrose, mannitol, lactose and the like. The core may be formed in a spherical or nearly spherical shape pellets. The amount of sugars and starch may range from 150.0 mg to 800.0 mg and 100. Omg to 600.0 mg per gram of composition preferably may range from 200.0 mg to 600.0 mg and 150.0 mg to 500.0 mg.

The active pharmaceutical agents employed may be selected from enantiomers, salts of the enantiomers of omeprazole such as esomeprazole in micronised form. The amount of the active drug may range from 30.0 mg to 200.0 mg preferably may range from 50.0 mg to 150.0 mg per gram of the composition.

The film forming agent used in the active coating for binding the active pharmaceutical ingredient to the inert core is selected from cellulose derivatives such as hydroxypropyl cellulose, hydroxypropyl methylcellulose, sodium carboxy methyl cellulose, carboxy methyl cellulose and polyvinyl pyrrolidone derivatives and alginate derivatives or a mixture thereof. The amount of film forming agent may range from

20.0 mg to 200.0 mg preferably may range from 25.0 mg to 150.0 mg per gram of composition.

The excipients when used in the active coating may be selected from materials such as microcrystalline cellulose powder, sodium lauryl sulphate, dioctyl sodium sulpho succinate, alginic acid, talc, magnesium stearate, titanium dioxide, starch and a mixture thereof and the coating solvent employed for active coating is purified water.

The amount of the excipient may range from 0.2 mg to 100.0 mg preferably may range from l. Omg to 80.0 mg per gram of composition.

The intermediate coating consists of a film forming agent The film forming agent is selected from cellulose derivatives such as hydroxypropyl cellulose, hydroxypropyl methylcellulose, sodium carboxy methyl cellulose, carboxy methylcellulose, polyvinyl pyrrolidone derivatives and alginate derivatives or a mixture thereof. The amount of the film forming agent may range from 20.0 mg to 200.0 mg preferably may range from 25.0 mg to 150.0 mg per gram of composition.

The intermediate cores may also contain excipients. The excipient used may be selected from materials such as microcrystalline cellulose powder, sodium lauryl sulphate, dioctyl sodium sulfosuccinate, alginic acid, talc, magnesium stearate, titanium dioxide, starch, etc or a mixture thereof. The amount of excipient employed may range from 1.0 mg to 100.0 mg preferably may range from 2.0 mg to 80.0 mg per gram.

The polymer used for the enteric coating of the composition may be those such as cellulose derivatives or methacrylic acid derivatives or the mixture thereof. The enteric polymeric composition also contains plasticizer and anti-adherents. Further it may also optionally contain colorants and opacifiers.

The amount of polymer employed for the enteric coating may range from 20.0 mg to 300.0 mg preferably may range from 50.0 mg to 250.0 mg per gram of composition.

The cellulose derivatives used in the enteric coating may be selected from materials such as cellulose acetate phthalate, hydroxypropyl methylcellulose phthalate and methacrylic acid derivatives such as Eudragit L 100-55, Eudragit L 30D-55.

The plasticizer used may be selected from materials such as fatty alcohol derivatives such as cetyl alcohol, stearyl alcohol or phthalate derivatives such as diethyl phthalate, dipropyl phthalate, dibutyl phthalate, dioctyl phthalate or polyethelene glycol derivatives.

The amount of plasticizer employed for enteric coating may range from 1.0 mg to 60.0 mg, preferably may range from 2.0 mg to 50.0 mg per gram of composition.

The anti-adherents used in the enteric coating may be selected from materials such as talc, stearate, stearic acid, hydrogenated castor oil or the mixture thereof. The colorants and opacifiers may be selected from iron oxides, titanium dioxide, or mixture thereof.

The amount of anti-adherents if employed may range from 2.0 mg to 120.0 mg, preferably may range from 4.0 mg to 100.0 mg per gram of composition.

The amount of opacifiers may range from 0.1 mg to 40.0 mg preferably may range from 0.5 to 30.0 mg per gram of composition.

The solvent used for enteric coating may be selected from aqueous or organic solvents or mixture thereof. The aqueous solvents used may be purified water and the organic solvents such as isopropyl alcohol, acetone, ethanol or mixture thereof may be used.

They are present in traces after processing is completed.

The composition is made in the form of pellets, which are then filled, into hard gelatin capsules of suitable size depending upon the assay and required therapeutic dose of the drug. Automatic or semi automatic equipments can be used for filling the composition for preparing the hard gelatin capsules.

Inert core may be used as fillers or excipients to adjust the fill weight of the capsules. The hard gelatin capsules comes in various sizes such as 00,0, 1,2, 3, etc., to accommodate various amounts of the composition.

The details of the invention are given in the examples provided below which are given to illustrate the invention only and therefore should not be construed to limit the scope of the present invention.

In the example-1 given below, for 20 mg of esomeprazole size'2'is selected as capsule size for holding the composition, namely 20 mg of esomeprazole is distributed over a number of coated pellets, before filling into the capsule, we need to analyse the coated pellets to find out how many of these coated pellets shall be filled into size'2'capsule to achieve 20mg of esomeprazole.

Similar explanation holds good for other capsule sizes described in other examples also.

Example 1 Ingredients Quantity (mg/gm) Active coating Inert cores 490.00 Esomeprazole 90.00 Hydroxypropyl methylcellulose E5 50.00 Microcrystalline cellulose 20.00 Starch 22.00 Dioctyl sodium sulpho succinate 30.00 Talc 5.00 Titanium dioxide 2.00 Purified water q. s Intermediate coating Hydroxypropyl methylcellulose E5 25.00 Microcrystalline cellulose 10.00 Starch 11. 00 Dioctyl sodium sulpho succinate 3.00 Talc 30. 00 Titanium dioxide 2.00 Purified water q. s Enteric coating Hydroxypropyl methylcellulose phthalate 120.00

Cetyl alcohol 24.00 Diethyl phthalate 12.00 Talc 54.00 Titanium dioxide 5.00 Isopropyl alcohol q. s Acetone q. s Manufacturing Procedure : A. Active coating Hydroxypropyl methylcellulose E5 and dioctyl sodiumsulphosuccinate were dissolved in water and the micronised mixture of esomeprazole, microcrystalline cellulose, starch, talc and titanium dioxide were added to it with continuous stirring. A perforated coating pan was loaded with the inert cores and the drug suspension prepared as described above was sprayed on to the inert cores. The resulting pellets were dried in the perforated coating pan to a moisture content below 2% w/w.

B. Intermediate coating Hydroxypropyl methylcellulose E5 and dioctyl sodiumsulphosuccinate were dissolved in water and microcrystalline cellulose with starch was added to it. Talc and titanium dioxide were sifted through 200# and added to the polymer solution with continuous stirring. A perforated coating pan was loaded with the active coating pellets prepared and described as above and the intermediate coating dispersion was applied on to the pellets. The resulting pellets were dried in a coating pan to a moisture content below 2% w/w.

C. Enteric coating Diethyl phthalate and cetyl alcohol were dissolved in a solvent blend of Isopropyl alcohol and acetone followed by Hydroxypropyl methylcellulose phthalate. Talc and titanium dioxide were sifted through 200# and added to the polymer solution. The intermediate coated pellets prepared as described as above were loaded in fluid bed coater and the enteric coating dispersion was applied on to these pellets. The pellets were then dried to a moisture content below 2% w/w.

The enteric coated pellets are filled into hard gelatin capsules size"2"after dilution with inert core, to obtain the dose of 20mg of esomeprazole., depending on the assay.

Example 2 Ingredients Quantity (mg/gm) a) Active coating Inert cores 481.00 Esomeprazole 86.00 Hydroxypropyl methylcellulose E5 60.00 Microcrystalline cellulose powder 50.00 Sodium lauryl sulphate 10.00 Titanium dioxide 4.00 Talc 5.00 Purified water q. s b) Intermediate coating Hydroxypropyl methylcellulose E5 50.00 Microcrystalline cellulose powder 42.00 Sodium lauryl sulphate 5.00 Titanium dioxide 2.00 Talc 3.00 Purified water q. s c) Enteric coating Hydroxypropyl methylcellulose phthalate 120.00 Cetyl alcohol 24.00 Diethyl phthalate 12.00 Talc 36.00 Titanium dioxide 10.00 Isopropyl alcohol q. s Acetone q. s Manufacturing Procedure: A. Active coating Hydroxypropyl Methylcellulose E5 and sodium lauryl sulphate were dissolved in water and the micronised mixture of esomeprazole, microcrystalline cellulose powder and titanium dioxide and talc were added to it with continuous stirring. A perforated coating pan was loaded with the inert cores and the drug suspension was sprayed on to the inert cores. The pellets were dried in the perforated coating pan to a moisture content below 2% w/w.

B. Intermediate coating Hydroxypropyl methylcellulose E5 and sodium lauryl sulphate were dissolved in water. Microcrystalline cellulose powder, titanium dioxide and talc were sifted through 200# and added to the polymer solution with continuous stirring. A perforated coating pan was loaded with the active coated pellets and the intermediate coating dispersion was applied on to the pellets. The resulting pellets were dried in the perforated coating pan to a moisture content below 2% w/w.

C. Enteric coating Diethyl phthalate and cetyl alcohol were dissolved in a solvent blend of isopropyl alcohol and acetone followed by hydroxypropyl methylcellulose phthalate. Talc and titanium dioxide were sifted through 200&num and added to the polymer solution. The intermediate coated pellets prepared as described above were loaded in a perforated coating pan and the enteric coating dispersion was applied on to these pellets. The resulting pellets were dried to a moisture content below 2% w/w.

The enteric coated pellets are filled into hard gelatin capsules size"0"after dilution with inert core, to obtain the dose of 40 mg of esomeprazole., depending on the assay.

Example 3 Ingredients Quantity (mg/gm) a. Active coating Inert cores 400.00 Esomeprazole 85.00 Hydroxypropyl methylcellulose E5 55.00 Starch 40.00 Magnesium stearate 25. 00 Dioctyl sodium sulpho succinate 8.00 Titanium dioxide 3.00 Purified water q. s b. Intermediate coating Hydroxypropyl methylcellulose E5 25.00 Starch 18.00 Magnesium stearate 11.00

Dioctyl sodium sulpho succinate 3.00 Titanium dioxide 4.00 Purified water q. s c. Enteric coating Eudragit L-30D-55 720mg of dispersion eq. to 240. 00mg of solids Polyethylene glycol 6000 12.00 Talc 45.00 Titanium dioxide 15.00 Triethyl citrate 12.00 Purified Water q. s Manufacturing Procedure : A. Active coating Hydroxypropyl methylcellulose E5 and dioctyl sodiumsulphosuccinate were dissolved in water and the micronised mixture of esomeprazole, starch, magnesium stearate and titanium dioxide were added to it with continuous stirring. A fluidbed coater was loaded with the inert cores and the drug suspension was sprayed on to the inert cores.

The resulting pellets were dried in the fluidbed coater to a moisture content below 2% w/w.

B. Intermediate coating Hydroxypropyl methylcellulose E5 and dioctyl sodiumsulphosuccinate were dissolved in water. Titanium dioxide, starch and magnesium stearate were sifted through 200# and added to the polymer solution with continuous stirring. A fluid bed coater was loaded with the active coated pellets and the intermediate coating dispersion was applied on to these pellets. The resultant pellets were dried in the fluidbed coater to a moisture content below 2% w/w.

C. Enteric coating Polyethlene glycol 6000 was dissolved in water and added to Eudragit L-30D-55 dispersion with continuous stirring and added triethyl citrate. Talc and titanium dioxide were sifted through 200# and added to the polymer solution with continuous stirring. The intermediate coated pellets were loaded in fluid bed coater and the enteric

coating dispersion was applied on to the pellets. The resulting pellets were dried to a moisture content below 2% w/w.

The enteric coated pellets are filled into hard gelatin capsules size"2"after dilution with inert core, to obtain the dose of 20mg of esomeprazole., depending on the assay Example 4 Ingredients Quantity (mg/gm) a) Active coating Inert cores 490.00 Esomeprazole 90.00 Hydroxypropyl methylcellulose E5 50.00 Microcrystalline cellulose 10.00 Starch 32.00 Dioctyl sodium sulpho succinate 30. 00 Talc 5.00 Titanium dioxide 2.00 Purified water q. s b) Intermediate coating Hydroxypropyl methylcellulose ES 25.00 Microcrystalline cellulose 5.00 Starch 16.00 Dioctyl sodium sulpho succinate 4.50 Talc 30. 00 Titanium dioxide 2.00 Purified water q. s c) Enteric coating Hydroxypropyl methylcellulose phthalate 120.00 Cetyl alcohol 24.00 Diethyl phthalate 12.00 Talc 54.00 Titanium dioxide 5.00 Isopropyl alcohol q. s Acetone q. s

Manufacturing Procedure: A. Active Coating Hydroxypropyl methylcellulose E5 and dioctyl sodium sulpho succinate were dissolved in water and the micronised mixture of esomeprazole, microcrystalline cellulose, starch, talc and titanium dioxide were added to it with continuous stirring. A perforated coating pan was loaded with the inert cores and the drug suspension on to the inert core was sprayed on to the inert cores. The resulting pellets were dried in the perforated coating pan to a moisture content reached below 2% w/w.

B. Intermediate coating Hydroxypropyl methylcellulose E5 and dioctyl sodiumsulphosuccinate were dissolved in water and microcrystalline cellulose with starch was added to it. Talc and titanium dioxide were sifted through 200# and added to the polymer solution with continuous stirring. A perforated coating pan was loaded with the active coated pellets and the intermediate coating dispersion was applied on to the pellets. The resulting pellets were dried in the perforated coating pan to a moisture content below 2% w/w.

C. Enteric coating Diethyl phthalate and cetyl alcohol were dissolved in a solvent blend of isopropyl alcohol and acetone followed by Hydroxypropyl methylcellulose phthalate. Talc and titanium dioxide were sifted through 200# and added to the polymer solution. The intermediate coated pellets were loaded in a perforated coating pan and the enteric coating dispersion was applied on to these pellets. The resulting pellets were dried to a moisture content below 2% w/w.

The enteric coated pellets are filled into hard gelatin capsules size"3"after dilution with inert core, to obtain the dose of 10 mg of esomeprazole., depending on the assay.

Example 5 Ingredients Quantity (mg/gm) a) Active Coating Inert cores 481.00

Esomeprazole 86.00 Hydroxypropyl methylcellulose E5 60.00 Microcrystalline cellulose powder 60.00 Sodium lauryl sulphate 10.00 Titanium dioxide 4.00 Talc 5.00 Purified water q. s b) Intermediate coating Hydroxypropyl methylcellulose E5 50.00 Microcrystalline cellulose powder 32.00 Sodium lauryl sulphate 5.00 Titanium dioxide 2.00 Talc 3.00 Purified water q. s c) Enteric coating Hydroxypropyl methylcellulose phthalate 120.00 Cetyl alcohol 24.00 Diethyl phthalate 12.00 Talc 36.00 Titanium dioxide 10.00 Isopropyl alcohol q. s Acetone q. s Manufacturing Procedure : a) Active Coating Hydroxypropyl methylcellulose E5 and sodium lauryl sulphate were dissolved in water and the micronised mixture of esomeprazole, microcrystalline cellulose powder and titanium dioxide and talc were added to it with continuous stirring. A perforated coating pan was loaded with the inert cores and the drug suspension was sprayed on to the inert cores. The resulting pellets were dried in the perforated coating pan to a moisture content below 2% w/w.

B. Intermediate coating Hydroxypropyl methylcellulose E5 and sodium lauryl sulphate were dissolved in water. Microcrystalline cellulose powder, titanium dioxide and talc were sifted

through 200# and added to the polymer solution with continuous stirring. A perforated coating pan was loaded with the active coated pellets and the intermediate coating dispersion was applied on the pellets. The resulting pellets were dried in the perforated coating pan to a moisture content below 2% w/w.

C. Enteric coating Diethyl phthalate and cetyl alcohol were dissolved in a solvent blend of isopropyl alcohol and acetone followed by Hydroxypropyl methylcellulose phthalate. Talc and titanium dioxide sifted through 200# and added to the polymer solution. The intermediate coated pellets were loaded in fluid bed coater and the enteric coating dispersion was applied on to these pellets. The resulting pellets were dried till the moisture content reached below 2% w/w.

The enteric coated pellets are filled into hard gelatin capsules size"1"after dilution with inert core, to obtain the dose of 30 mg of esomeprazole., depending on the assay.

Example 6 Ingredients Quantity (mg/gm) a) Active Coating Inert cores 400.00 Esomeprazole 85.00 Hydroxypropyl methylcellulose E5 55.00 Starch 50. 00 Magnesium stearate 15.00 Dioctyl sodium sulpho succinate 8.00 Titanium dioxide 3.00 Purified water q. s b) Intermediate coating Hydroxypropyl methylcellulose E5 25.00 Starch 12.00 Magnesium stearate 17.00 Dioctyl sodium sulpho succinate 4. 00 Titanium dioxide 4.00 Purified water q. s c) Enteric coating Eudragit L-30D-55 720mg of dispersion eq. to 240. 00mg of solids

Polyethylene glycol 6000 12.00 Talc 45.00 Titanium dioxide 15.00 Triethyl citrate 12.00 Purified Water q. s Manufacturing Procedure : A. Active Coating Hydroxypropyl methylcellulose E5 and dioctyl sodiumsulphosuccinate were dissolved in water and the micronised mixture of esomeprazole, starch, magnesium stearate and titanium dioxide were added to it with continuous stirring. A fluid bed coater was loaded with the inert cores and the drug suspension was sprayed on to the inert cores.

The resulting pellets were dried in the coating pan to a moisture content below 2% w/w.

B. Intermediate coating Hydroxypropyl methylcellulose E5 and dioctyl sodiumsulphosuccinate were dissolved in water. Titanium dioxide, starch and magnesium stearate were sifted through 200# and added to the polymer solution with continuous stirring. A fluid bed coater was loaded with the active coated pellets and the intermediate coating dispersion was applied on to the pellets. The resulting pellets were dried in the coating pan to a moisture content below 2% w/w.

C. Enteric coating Polyethlene glycol 6000 was dissolved in water and added to Eudragit L-30D-55 dispersion with continuous stirring and. triethyl citrate was added to it. Talc and titanium dioxide were shifted through 200# and added to the polymer solution with continuous stirring. The intermediate coated pellets were loaded in fluid bed coater and the enteric coating dispersion was applied on these pellets. The resulting pellets were dried in a coating pan to a moisture content below 2% w/w.

The enteric coated pellets are filled into hard gelatin capsules size"1"after dilution with inert core, to obtain the dose of 30 mg of esomeprazole. , depending on the assay.

Example 7 Ingredients Quantity (mg/gm) a) Active Coating Inert cores 490. 00 Esomeprazole 90.00 Hydroxypropyl methylcellulose E5 50.00 Microcrystalline cellulose 15.00 Starch 27.00 Dioctyl sodium sulpho succinate 30.00 Talc 5.00 Titanium dioxide 2.00 Purified water q. s b) Intermediate coating Hydroxypropyl methylcellulose E5 25.00 Microcrystalline cellulose 12.00 Starch 9. 00 Dioctyl sodium sulpho succinate 5.00 Talc 30 00 Titanium dioxide 2.00 Purified water q. s c) Enteric coating Hydroxypropyl methylcellulose phthalate 120.00 Cetyl alcohol 24.00 Diethyl phthalate 12.00 Talc 54.00 Titanium dioxide 5.00 Isopropyl alcohol q. s Acetone q. s Manufacturing Procedure: A. Active coating Hydroxypropyl methylcellulose E5 and dioctyl sodium sulpho succinate were dissolved in water and the micronised mixture of esomeprazole, microcrystalline cellulose, starch, talc and titanium dioxide were added to it with continuous stirring. A perforated coating pan was loaded with the inert cores and the drug suspension was sprayed on to the inert cores. The resulting pellets were dried in the perforated coating pan to a moisture content below 2% w/w.

B. Intermediate coating Hydroxypropyl methylcellulose E5 and dioctyl sodiumsulphosuccinate were dissolved in water and microcrystalline cellulose with starch was added to it. Talc and titanium dioxide were sifted through 200# and added to the polymer solution with continuous stirring. A perforated coating pan was loaded with the active coated pellets and the intermediate coating dispersion was applied on to the pellets. The resulting pellets were dried in the perforated coating pan to a moisture content below 2% w/w.

C. Enteric coating Diethyl phthalate and cetyl alcohol were dissolved in a solvent blend of isopropyl alcohol and acetone followed by Hydroxypropyl methylcellulose phthalate. Talc and titanium dioxide were sifted through 200# and added to the polymer solution. The intermediate coated pellets were loaded in fluid bed coater and the enteric coating dispersion was applied on to these pellets. The resulting pellets were dried to a moisture content below 2% w/w.

The enteric coated pellets are filled into hard gelatin capsules size"1"after dilution with inert core, to obtain the dose of 40 mg of esomeprazole., depending on the assay.

Example 8 Ingredients Quantity (mg/gm) a) Active Coating Inert cores 481.00 Esomeprazole 86.00 Hydroxypropyl methylcellulose E5 60.00 Microcrystalline cellulose powder 48.00 Sodium lauryl sulphate 12.00 Titanium dioxide 4.00 Talc 5.00 Purified water q. s b) Intermediate coating Hydroxypropyl methylcellulose E5 50.00 Microcrystalline cellulose powder 44.00

Sodium lauryl sulphate 3.00 Titanium dioxide 2.00 Talc 3.00 Purified water q. s c) Enteric coating Hydroxypropyl methylcellulose phthalate 120.00 Cetyl alcohol 24.00 Diethyl phthalate 12.00 Talc 36.00 Titanium dioxide 10.00 Isopropyl alcohol q. s Acetone q. s Manufacturing Procedure : A. Active Coating Hydroxypropyl methylcellulose E5 and sodium lauryl sulphate were dissolved in water and the micronised mixture of esomeprazole, microcrystalline cellulose powder , titanium dioxide and talc was added to it with continuous stirring. A perforated coating pan was loaded with the inert cores and the drug suspension was applied on to the inert cores. The resulting pellets are dried in the perforated coating pan to a moisture content below 2% w/w.

B. Intermediate coating Hydroxypropyl methylcellulose E5 and sodium lauryl sulphate were dissolved in water. Microcrystalline cellulose powder and titanium dioxide were sifted through 200# and added to the polymer solution with continuous stirring. A fluid bed coater was loaded with the active coated pellets and the intermediate coating dispersion was applied on to the pellets. The resulting pellets are dried in the fluid bed coater to a moisture content below 2% w/w.

C) Enteric coating Diethyl phthalate and cetyl alcohol were dissolved in a solvent blend of isopropyl alcohol and acetone followed by Hydroxypropyl methylcellulose phthalate. Talc and titanium dioxide were sifted through 200# and added to the polymer solution. The intermediate coatinged pellets were loaded in fluid bed coater and the enteric coating

dispersion was applied on to these pellets. The resulting pellets were dried to a moisture content below 2% w/w.

The enteric coated pellets are filled into hard gelatin capsules size"2"after dilution with inert core, to obtain the dose of 20 mg of esomeprazole., depending on the assay.

Example 9 Ingredients Quantity (mg/gm) A) Active Coating Inert cores 400.00 Esomeprazole 85.00 Hydroxypropyl methylcellulose E5 55.00 Starch 43. 00 Magnesium stearate 22.00 Dioctyl sodium sulpho succinate 8.00 Titanium dioxide 3.00 Purified water q. s B) Intermediate coating Hydroxypropyl methylcellulose E5 25.00 Starch 22.00 Magnesium stearate 7.00 Dioctyl sodium sulpho succinate 3.00 Titanium dioxide 4.00 Purified water q. s C) Enteric coating Eudragit L-30D-55 720mg of dispersion eq. to 240. 00mg of solids Polyethylene glycol 6000 12.00 Talc 45.00 Titanium dioxide 15.00 Triethyl citrate 12.00 Purified Water q. s Manufacturing Procedure: A. Active Coating Hydroxypropyl methylcellulose E5 and dioctyl sodiumsulphosuccinate were dissolved in water and the micronised mixture of esomeprazole, starch, magnesium stearate and titanium dioxide were added to it with continuous stirring. A perforated coating pan

was loaded with the inert cores and the drug suspension was sprayed on to the inert cores. The pellets were dried in the coating pan to a moisture content below 2% w/w.

B. Intermediate coating Hydroxypropyl methylcellulose E5 and dioctyl sodium sulpho succinate were dissolved in water. Titanium dioxide, starch and magnesium stearate were sifted through 200# and added to the polymer solution with continuous stirring. A perforated coating pan was loaded with the active coated pellets and the intermediate coating dispersion was applied on to the pellets. The resulting pellets were dried in the coating pan to a moisture content below 2% w/w.

C. Enteric coating Polyethlene glycol 6000 was dissolved in water and added to Eudragit L-30D-55 dispersion with continuous stirring and added triethyl citrate. Talc and titanium dioxide were sifted through 200# and added to the polymer solution with continuous stirring. The intermediate coated pellets were loaded in a perforated coating pan and the enteric coating dispersion was applied on to these pellets. The resulting pellets were dried to a moisture content below 2% w/w.

The enteric coated pellets are filled into hard gelatin capsules size"1"after dilution with inert cores, to obtain the dose of 40 mg of esomeprazole., depending on the assay.

Advantages of the present invention: 1. The composition is stable.

2. The composition does not employ any alkali agent.

3. The composition is simple, commercially viable, economical and highly reproduceable.

4. All the materials used in the composition, particularly those used for preparing the active coating and intermediate coating are widely available, pharmaceutically inert, economical and have a high degree of safety.

5. The active ingredient is not released in the stomach but released only in the intestine (namely in an alkaline environment). In other words, the composition is protected in the acidic environment of the gastric system and is released in the alkaline environment of the intestinal system.

6. The pellets can be processed in any type of available equipments, for example, from the perforated coating pan to automatic fluidised bed pelletisation and coating equipments making the preparation of the composition simple and versatile.

7. The pellets can be processed free from organic solvents thereby making it safe to handle for operational staff as it is non hazardous.

8. The process does not create pollution ie it is environmentally safe.