FORM 2
THE PATENTS ACT 1970
(Act 39 of 1970)
&
THE PATENTS RULE, 2003
COMPLETE SPECIFICATION (SECTION 10 and Rule 13)
TITLE OF THE INVENTION
"ESOMEPRAZOLE ENTERIC COATED TABLET"
Zuventus Healthcare Limited, an Indian company, registered under the Indian Company's Act 1957 and having
its registered office at
Emcure House, T-184, M.I.D.C., Bhosari, Pune-411026, India.
THE FOLLOWING SPECIFICATION PARTICULARLY DESCRIBES THE INVENTION AND THE MANNER IN WHICH IT IS TO BE PERFORMED

FIELD OF THE INVENTION
The present invention relates to a stable oral dosage form of esomeprazole or salt thereof and processes for their preparation. The invention provides stable pharmaceutical composition comprising a core tablet consisting of a therapeutically effective amount of someprazore magnesium trihydrate an inert barrier coating surrounding the core tablet and an outer enteric coating surrounding the inert barrier coating, wherein the core tablet and inert barrier coating comprises light magnesium oxide as an alkalizing agent.
BACKGROUND OF THE INVENTION
Proton-pump inhibitors (PPIs) are a class of medications that cause a profound and prolonged reduction of stomach acid production. Since their introduction in the late 1980s, these efficacious acid suppressants have rapidly assumed a major role for the treatment of acid-peptic disorders. They do so by irreversibly inhibiting the stomach's H+/K+ ATPase proton pump. They are the most potent inhibitors of acid secretion available. Proton-pump inhibitors have largely superseded the H2-receptor antagonists, a group of medications with similar effects but a different mode of action. These are among the most widely sold medications in the world. The class of proton-pump inhibitor medications is on the World Health Organization's List of Essential Medicines.
Esomeprazole is one such widely used proton-pump inhibitor. Esomeprazole is the S-isomer of omeprazole, which is a mixture of the S- and R- isomers. Chemically, it is bis(5-methoxy-2-[(S)-[(4-methoxy-3,5-dimethyl-2-pyridinyl)methyl]sulfinyl]-lH-benzimidazole-1-yl) magnesium trihydrate, as shown in Formula 1. Stability of esomeprazole magnesium is a function of pH; it rapidly degrades in acidic media, but it has acceptable stability under alkaline conditions.


Esomeprazole is a protonated compound and is converted in the acidic compartment of the parietal cell of the stomach forming the active inhibitor, the achiral sulphenamide. Because this enzyme system is regarded as the acid (proton) pump within the gastric mucosa, esomeprazole has been characterized as a gastric acid-pump inhibitor, in that it blocks the final step of acid production. This effect is dose-related and leads to inhibition of both basal and stimulated acid secretion irrespective of the stimulus. Esomeprazole exhibits significantly higher bioavailability, leading to the greater inhibition of gastric acid secretion compared to Omeprazole.
Esomeprazole is indicated for the short-term treatment in the healing of Erosive Esophagitis, maintenance of healing of Erosive Esophagitis, treatment of Symptomatic Gastroesophageal Reflux Disease (GERD), risk reduction of Nonsteroidal Anti-Inflammatory Drugs (NSAID)-associated gastric ulcer, Helicobacter pylori eradication to reduce the risk of duodenal ulcer recurrence, pathological hypersecretory conditions including Zollinger-Ellison Syndrome.
Early studies indicated that esomeprazole achieves greater and more sustained acid control than Omeprazole, with a similar tolerability and safety profile. Furthermore, esomeprazole shows a more rapid onset of acid-suppression effect than Omeprazole, and less inter-individual variation in acid control.
PCT publication W09854171 discloses magnesium salt of S-omeprazole trihydrate.

PCT publication WO2005065726 discloses a solid pharmaceutical dosage form comprises a core particle containing at least one pharmaceutical active ingredient and/or excipient that is sensitive to acid, a subcoating containing a chemically reactive component disposed over the core, and an enteric coating over the subcoating.
US Patent 4786505 describes a method of preparing a stable formulation of the acid-sensitive drug omeprazole, wherein a water-soluble intermediate coat is layered onto the drug-containing core surface. An enteric coating is then layered over the water-soluble intermediate layer.
US Patent 5035899 discloses a formulation of acid labile benzimidazole derivatives, having a sub coating of slightly water-soluble film-forming material and fine particles of a slightly water-soluble substance, suspended in the coating material.
There are various prior art documents which disclose enteric coated dosage forms of proton pump inhibitors which were prepared by specific technology. These routine used technologies such as MUPS technology are costly and time consuming whereas proposed formulation utilizes simple conventional wet granulation (High Shear Granulation) technology to prepare core tablets containing active. These tablets are to be coated with inert barrier coating and enteric coating, which is cost effective, user friendly and time saving.
The Esomeprazole Magnesium Trihydrate is very prone to acid degradation hence there existed a continuing need to develop new compositions with improved stability of the active ingredient, wherein the active ingredient is esomeprazole magnesium trihydrate which will be stable in composition throughout the shelf life of the product.
OBJECT OF THE INVENTION

The object of this invention was to develop stable oral composition of esomeprazole enteric coated tablet.
SUMMARY OF THE INVENTION
In one of the aspect of the invention, there is provided a stable pharmaceutical composition comprising a core tablet consisting of a therapeutically effective amount of esomeprazole magnesium trihydrate, an inert barrier coating surrounding the core tablet and an outer enteric coating surrounding the inert barrier coating, wherein the core tablet and inert barrier coating comprises light magnesium oxide as an alkalizing agent
In another aspect of the invention, the inner tablet is prepared by wet granulation process.
DETAILED DESCRIPTION OF THE INVENTION
The present inventors while working on pharmaceutical composition comprising esomeprazole magnesium trihydrate have noted that esomeprazole magnesium trihydrate is very prone to acid degradation. Hence the purpose of this invention was to develop stable oral composition of esomeprazole enteric coated tablet.
This invention is related to new composition & process developed for the stabilization of esomeprazole magnesium trihydrate by preparing core tablet formulation by using simple conventional wet granulation process by using isopropyl alcohol as a granulation vehicle. Further the core tablet was coated with inert barrier coating and gastro resistant coating. In order to avoid degradation of esomeprazole magnesium trihydrate, light magnesium oxide was added as an alkalizer in the core tablet formulation as well as in the inert barrier coating. The light magnesium oxide gives

alkaline microenvironment to the core tablet formulation as well as in the inert barrier coating, which helps to prevent its degradation.
In one of the embodiments of the invention, the composition comprises esomeprazole magnesium trihydrate in the core, in the form of tablet prepared by wet granulation. The tablet further coated with inert barrier coating and enteric coat.
The pharmaceutical dosage form of the present invention further comprises other pharmaceutically acceptable excipients selected from the group consisting of binders, diluents, glidants, lubricants, etc.
Examples of suitable binders include, but not limited to, starch, gums, pregelatinized starch, polyvinyl prrolidone (PVP), copovidone, cellulose derivatives, such as hydroxypropylmethyl cellulose (HPMC), hydroxypropyl cellulose (HPC) and carboxymethyl cellulose (CMC) and their salts.
Examples of suitable diluents include, but not limited to one or more of lactose, lactose monohydrate, mannitol, sucrose, maltodextrin, dextrin, maltitol, sorbitol, xylitol, powdered cellulose, cellulose gum, microcrystalline cellulose, powdered cellulose, silicified cellulose, cellulose acetate and celluloses, starch, calcium phosphate, dibasic calcium phosphate or metal carbonate.
Suitable glidants include but not limited to, colloidal silica, silica gel, precipitated silica, or combinations thereof.
Suitable lubricants include, but are not limited to, one or more talc, magnesium stearate, calcium stearate, polyethylene glycol, hydrogenated vegetable oils, stearic acid, sodium stearyl fumarate, talc, colloidal silicon dioxide and sodium benzoate.

Suitable inert barrier coating polymers selected from the group consisting of one or more of cellulose derivatives; polyhydrik, Alcohols, vinyl derivatives, polymers, copolymers or mixtures thereof; polyalkylene oxides or copolymers thereof; acrylic acid polymers and acrylic acid derivatives; or any combinations thereof
Suitable enteric coating polymers selected from acrylic acid polymers include any suitable polyacrylic acid polymers or carboxyvinyl polymers such as those available under the brand name carbopol, Eudagrit. Pharmaceutically acceptable acrylic polymer may include one or more, acrylic acid and methacrylic acid copolymers, methyl methacrylate copolymers, ethoxyethyl methacrylates, cyanoethyl methacrylate, aminoalkyl methacrylate copolymer, poly(acrylic acid), poly(methacrylic acid), methacrylic acid alkylamide copolymer, poly(methyl methacrylate), poly(methacrylic acid) (anhydride), methyl methacrylate, polymethacrylate, poly(methyl methacrylate), poly(methylmethacrylate) copolymer, polyacrylamide, aminoalkyl methacrylate copolymer, poly(methacrylic acid anhydride).
The composition of the present invention may be used for the treatment of various conditions requiring reduction in gastric acid secretion. Such conditions include, but are not limited to gastroesophageal reflux disease, maintenance treatment of patients with reflux esophagitis, non-erosive reflux disease (i.e. heartburn and regurgitation), Nonsteroidal anti-inflammatory drug associated gastric ulcers, risk of NSAID-associated gastric ulcers treatment of pathological hyper secretory conditions (including Zollinger-Ellison Syndrome), Helicobacter pylori (H. pylori) infection.
The present invention is further illustrated by the following examples which are provided merely to be exemplary of the invention and do not limit the scope of the invention. Certain modifications and equivalents will be apparent to those skilled in the art and are intended to be included within the scope of the present invention.

EXAMPLES
Table 1: Esomeprazole enteric coated tablet

Name of ingredients Qty /Tablet [mg]
Core Tablet
Dry Mix
Esomeprazole Magnesium Trihydrate IP 44.5
Macrocrystalline Cellulose IP q.s. to 250.0
Light Magnesium Oxide IP 45.0
Crospovidone IP 6.0
Binder
Hydroxy Propyl Cellulose IP 5.0
Isopropyl Alcohol IP q.s.
Lubrication
Crospovidone IP 6.0
Magnesium Stearate IP 2.5
Weight of core tablet 250.0
Barrier coating
Opadry Clear 06A59037 7.3
Light Magnesium Oxide IP 0.1
Purified Water IP q.s.
Enteric coating
Acryl - Eze Pink 930540057 30.9
Purified Water IP q.s.

Procedure: Esomeprazole magnesium trihydrate, microcrystalline cellulose, light magnesium oxide, crospovidone were sifted. Sifted materials were transferred into RMG & mixed at slow speed. Hydroxypropyl cellulose was dissolved in isopropyl alcohol under continuous stirring to get a clear solution. Binder Solution was added Into RMG and mixed properly. The wet mass was sifted and transferred into FBD bowl. The drying was continued till desired LOD was achieved. The dried granules were sifted and pre-lubricated using crospovidone and magnesium stearate in a blender and compressed into tablets.
Inert barrier Coating: Prepared tablets were coated by using aqueous solution of Opadry Clear 06A59037 and light magnesium oxide.
Enteric Coating: Barrier coated tablets were further coated with enteric coating by using aqueous solution of Acryl - Eze Pink 930540057.
The formulation was prepared by the procedure as described above and is evaluated for various parameters.
The formulation of above example was subjected to different stability conditions (30°C/75%RHand 40°C/75%RH) for 6 months and evaluated for various parameters at 1 month, 3 months and 6 months
Table 2: Stability studies of esomeprazole tablets (1 month)

Test Specification Initial 1st Month

30°C/75 40°C/75
%RH %RH
Dissolution 0.1M HCL NMT10%of the labelled amount released in 120min Complies Complies Complies

pH 6.8 phosphate buffer NLT 75% ( D=70% of labelled amount) 92.69-95.56 100.82-103.34 98.10-103.60
- Assay (%) NLT 90.0 % and NMT 110.0% of the labelled amount 100.16 100.90 100.40 —
Related substances 5
Omeprazole N-Oxide Impurity N.A. N.A. N.A.
Omeprazole related compound A N.A. N.A. N.A.
Any Single Impurity NMT 0.5% 0.09 0.10 0.17
Total Impurity NMT 2.0% 0.22 0.34 0.45
Conclusion: From up to 1 month the above results, it is concl uded that t he product is stable
Table 3: Stability studies of esomeprazole tablets (3 months)

Test Specification Initial 3rd Month

30°C/75 40°C/75
%RH %RH
Dissolution 0.1MHCLNMT 10% of the labelled amount released in 120 min Complies Complies Complies

pH 6.8 phosphate buffer NLT 75% ( D=70% of labelled amount) 92.69-95.56 101.63-103.35 93.18-100.78
- Assay (%) NLT 90.0 % and NMT 110.0% of the labelled amount 100.16 101.59 99.23
Related substances
Omeprazole N-Oxide Impurity N.A. 0.03 0.03
Omeprazole related compound A N.A. 0.08 0.10
Any Single Impurity NMT 0.5% 0.09 0.07 0.15
Total Impurity NMT 2.0% 0.22 0.43 0.65
Conclusion: From the above results, it is conclu to 3 months ded that the product is stable up
Table 4: Stability studies of esomeprazole tablets (6 months)

Test Specification Initial 6th Month

30°C/75 40°C/75
%RH %RH
Dissolution 0.1M HCL
NMT 10% of the labelled amount released in 120 min Complies Complies Complies

pH 6.8 phosphate buffer 92.69- 93.55- 94.40 -
NLT 75% (D=70% of labelled amount) 95.56 99.15 96.57
Assay (%) NLT 90.0 % and NMT 100.16 100.79 100.20
"110.0% of the labelled amount
Related substances
Omeprazole N- N.A. 0.02 0.01
Oxide Impurity
Omeprazole N.A. 0.11 0.11
related compound
A
Any Single NMT 0.5% 0.09 0.14 0.22
Impurity
Total Impurity NMT 2.0% 0.22 0.56 0.92
Conclusion: From the above results, it is concl uded that the : product is stable up
to 6 months
The stability study results of above example indicate that, the formulation remains stable for a period of at least 6 months at 30°C and 75% relative humidity and 40°C and 75% relative humidity. Further, total related substances were within the specified limits.

WE CLAIM:
1. A stable pharmaceutical composition comprising a core tablet consisting of a therapeutically effective amount of esomeprazole magnesium trihydrate, an inert barrier coating surrounding the core tablet and an outer enteric coating surrounding the inert barrier coating, where in the core tabtet~and inert~barrier coating comprises light magnesium oxide as an alkalizing agent.
2. The composition of claim 1, wherein the core tablet is prepared by wet granulation process.