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

IMPROVED PHARMACEUTICAL COMPOSITIONS OF ESOMEPRAZOLE
TECHNICAL FIELD OF THE INVENTION
The present invention relates to the pharmaceutical composition of Esomeprazole. More particularly, the present invention relates to the pharmaceutical composition of gastric resistant multiple unit esomeprazole swallowable dosage form comprising of enteric coated pellets, one or more pharmaceutically acceptable excipients and segregation suppressor and process for manufacture thereof.
BACKGROUND OF THE INVENTION
Esomeprazole is the S-isomer of Omeprazole, which is a mixture of the S- and R-isomers. Magnesium salt esomeprazole is chemically bis(5-methoxy-2-[(S)-[(4-methoxy-3,5-dimethyl-2- pyridinyl)methyl] sulfinyl] -lH-benzimidazole-1-yl) magnesium trihydrate. Its molecular formula is (C17H]gN3O3S)2Mg x 3 H2O with molecular weight of 767.2 as a trihydrate and 713.1 on an anhydrous basis.
The magnesium salt is a white to slightly colored crystalline powder. It contains 3 moles of water of solvation and is slightly soluble in water. The stability of esomeprazole magnesium is a function of pH; it rapidly degrades in acidic media, but it has acceptable stability under alkaline conditions. At pH 6.8 (buffer), the half-life of the esomeprazole magnesium salt is about 19 hours at 25°C and about 8 hours at 37°C.
Esomeprazole is a proton pump inhibitor that suppresses gastric acid secretion by specific inhibition of the H+/K+ - ATPase in the gastric parietal cell. The S- and R-isomers of omeprazole are protonated and converted in the acidic compartment of the parietal cell forming the active inhibitor, the achiral sulphenamide. By acting specifically on the proton pump, esomeprazole blocks the final step in acid production, thus reducing gastric acidity. This effect is dose-related up to a daily dose of 20 to 40 mg and leads to inhibition of gastric acid secretion.
After oral administration peak plasma levels (Cmax) occur at approximately 1.5 hours (Tmax). The Cmax increases proportionally when the dose is increased, and there is a three-

fold increase in the area under the plasma concentration-time curve (AUC) from 20 to 40 mg. At repeated once-daily dosing with 40 mg, the systemic bioavailability is approximately 90% compared to 64% after a single dose of 40 mg. The mean exposure (AUC) to esomeprazole increases from 4.32 umol*hr/L on Day 1 to 11.2 umol*hr/L on day 5 after 40 mg once daily dosing. The AUC after administration of a single 40 mg dose of esomeprazole is decreased by 43% to 53% after food intake compared to fasting conditions. Esomeprazole should be -taken at least one hour before meals.
Esomeprazole is 97% bound to plasma proteins. Plasma protein binding is constant over the concentration range of 2 to 20 umol/L. The apparent volume of distribution at steady state in healthy volunteers is approximately 16 L. Esomeprazole is extensively metabolized in the liver by the cytochrome P450 (CYP) enzyme system. The metabolites of esomeprazole lack antisecretory activity. The major part of esomeprazole's metabolism is dependent upon the CYP 2C19 isoenzyme, which forms the hydroxy and desmethyl metabolites. The remaining amount is dependent on CYP 3A4 which forms the sulphone metabolite. CYP 2C19 isoenzyme exhibits polymorphism in the metabolism of esomeprazole, since some 3% of Caucasians and 15 to 20% of Asians lack CYP 2C19 and are termed poor metabolizers. At steady state, the ratio of AUC in poor metabolizers to AUC in the rest of the population (extensive metabolizers) is approximately 2.
The plasma elimination half-life of esomeprazole is approximately 1 to 1.5 hours. Less than 1% of parent drug is excreted in the urine. Approximately 80% of an oral dose of esomeprazole is excreted as inactive metabolites in the urine, and the remainder is found as inactive metabolites in the feces.
Esomeprazole is commercially available as, delayed release systems in the form of capsules as well as tablets of 20 & 40 mg strengths, suspension for oral administration of in 2,5 mg. 5 mg, 10 mg, 20 mg or 40 mg - unit dose packet containing a fine yellow powder, consisting of white to pale brownish esomeprazole granules and pale yellow inactive granules. It is also available as esomeprazole I.V. Injection and is supplied as a freeze-dried white to off-white powder containing 20 mg or 40 mg of esomeprazole per single-use vial.

Although, similar drug release profiles can be obtained with unit dosage forms, multiple-unit dosage forms offer several advantages over single-unit systems such as tablets or capsules.
1. Multiple unit pellet system (MUPS) preparations distribute readily over a large surface area in the gastrointestinal tract and these small particles (< 2 mm) behave like liquids leaving the stomach within a short period of time.
2. Their small size also enables them to be well distributed along the gastrointestinal tract that could improve the bioavailability, which potentially could result in a reduction in local drug concentration, risk of toxicity, and side-effects.
3. Inter and intra-individual variations in bioavailability caused by, for example food effects, are reduced.
4. Premature drug release from enteric-coated dosage forms in the stomach, potentially resulting in degradation of drug or irritation of gastric mucosa, can be reduced with coated pellets because of more rapid transit time when compared to enteric-coated tablets.
5. In the multiple-unit system, the total drug is divided into many units. Failure of few units may not be as consequential as failure of a single-unit system, This is apparent in sustained-release single-unit dosage form, where a failure may lead to dose-dumping of the drug.
6. Other advantages of this divided dose include ease of adjustment of the strength of a dosage unit, administration of incompatible drugs in a single dosage unit by separating them in different multi-particulates and combination of multi-particulates with different drug-release rates to obtain the desired overall release profile.
7. With regards to the final dosage form, multi-particulates can be filled into hard gelatin capsules or be compressed into tablets of which the former is more common.
MUPS when compressed into tablets provides added advantage over capsules:
1. Unfortunately, the production costs for capsules are high and their production rate is low compared with those of tablets. This is due to the lower output of capsule filling machines and to the higher cost of capsules themselves.

2. Capsules cannot be divided into subunits in the same way as tablets. These disadvantages make compression of subunits into rapidly disintegrating tablets an interesting issue.
3. Tableting of multiparticulates include a reduced risk of tampering and lower tendency of adhesion of dosage form to esophagus during swallowing.
4. Tablets from pellets can be prepared at low cost when compared to pellet-filled capsules because of the higher production rate of tablet process. The expensive control of capsule integrity after filling is also eliminated.
5. Tablets containing multi-particulates can be scored without losing modified-release properties thus allowing a more flexible dosage regimen.
6. Tableting of pellets as opposed to that of powder also results in reduction of dust.
Compaction of pellets is a challenging area.
The major challenges involved in compression of pellets into tablets are:
1. Compacted pellets should disintegrate rapidly.
2. The drug release pattern should not be affected by the compression force involved
3. Segregation of the pellets during compression cycle.
EP 1072257 (Tsuchida Kazutaka et al., January 2001) discloses a multi-unit sustained release tablets consisting of a granular part and a powdery part. The granular part comprises a core particle coated with matrix layer composed of water insoluble polymer ethyl cellulose of viscosity more than 15 cps and an active ingredient. The weight ratio of water insoluble polymer to active ingredient is 07:1 to 3:1. These matrix granules are further coated with water insoluble release controlling polymer that controls release of the drug over a period of time. These coated matrix granules are blended with powdery part in the ratio of 1:0.5 or more to ensure disintegration into sub units. Though such compositions solve the problems related to breakdown of coating when compressed into tablets, it fails to prevent the drug from being appreciably released in acidic medium.
PCT publication WO03/103637 (Kumar Pratik et al, December 2003) discloses modified release multiple unit system and their method of preparation. Modified release multiple

unit comprises inert core coated with first coating layer that includes one or more active pharmaceutical ingredients and one or more rate controlling polymers, second layer includes one or more rate controlling polymer and an outer layer on the outer surface of unit which comprising a material that is elastic and/or compressible waxy material such as polyethylene glycol's (PEGS). The rate controlling membrane controls release of the drug over a period of 24 hours. The outer waxy layer provides protection to the rate controlling membrane to withstand the compression force during tabletting. The process requires an additional coating with waxy material (PEG) by using organic solvents making the product relatively more expensive.
WO03/103637 and EP 1072257 do not teach methods to provide protection to the acid labile drugs in stomach or to prevent the release of the drug in the acidic pH and to provide immediate release of the drug in pH above 5.5.
WO 97/25029 (Newton John et al., 3 997) .teaches a disintegrating tablet preparation comprising of drug pellets, deformable soft pellets and disintegrating pellets. The drug pellets are coated with a controlled release binder, soft pellets contain an ester of fatty acid and the disintegratable pellets preferably comprise of a water insoluble inorganic powder. The soft pellets deform during the tabletting process that minimize damage to drug pellets while the disintegratable pellets ensure break down of the tablets into individual subunits which minimizes the variation in release characteristic from drug pellets. The process is expensive and time consuming as it requires preparation of 3 different types of pellets.
U.S. Pat. No. 6,328,994 (Toshihiro Shimizu et al., May 1999) discloses orally disintegratable tablets comprising lansoprazole granules having an average diameter of 400 microns or less having superior acid resistance property after compression. Lansoprazole core was coated with an enteric coating layer which comprises a first component which is an enteric coating agent and a second component which is a sustained release agent. An enteric coating layer is further coated by a water soluble sugar alcohol layer. The process necessarily requires granules that the average particle diameter of the granules should be less than 400 microns for tablets to retain acid resistance property after compression.

U.S. Pat. No. 6,923,984 (Jean Paul Remon, August 2005) disclose compatible biologically inactive cushioning beads essentially consisting of microcrystalline hydrocarbon wax or natural wax at least about 30% by weight of the biologically inactive cushioning beads. These beads are useful for making solid shaped articles containing biologically active ingredients in the form of biologically active ingredient loaded beads with brittle coating by compression. The size of biologically inactive cushioning beads is about 0.5 to 2 mm to protect brittle coating over active beads during compression. The biologically inactive cushioning beads comprise at least one compressible cushioning component and optionally another biologically inactive compressible cushioning component or pharmaceutically acceptable excipient. The weight ratio of the biologically active cushioning beads to the coated biologically active ingredient loaded beads is between 30:70 and 70:30. The process is expensive and time consuming as it requires preparation of 2 types of beads as well as the productivity of the process is low.
U.S. Pat. No. 5,817,338 (Pontus John AB et al, 1998), U.S. Pat. No. 5,753,265 (Pontus John AB et al., 1998), disclose oral pharmaceutical multiple unit tablet compositions comprising at least one tablet excipient and multiple of pellets or granules comprising ranging between 0.1 mm and 2 mm and active ingredient is acid-labile omeprazole. The pellets or granules are covered with at least one enteric coating layer comprising a plasticizing compound, which is more than 20% but less than 50% by weight of the enteric coating polymer to retain acid resistance property after compression.
US patent application 2009/0068263 (Amit Krishna Antarkar et al., 2009) discloses a multiple unit tablet comprising of enteric coated pellets and at least one tablet excipient. Enteric coated pellets are prepared with at least two enteric layers comprising of enteric polymers and plasticizer either coated on the core or on the separating layer to obtain enteric coated pellets, such that the last enteric layer is formed from a solution comprising of enteric polymer and plasticizer in organic solvent(s), resulting in no appreciable change in release profile of active ingredient on compression of enteric coated pellets into tablets. The process involves multiple coatings and using organic solvent increases the cost as well as it is time consuming. The US 2009/0068263 does not teach method to achieve uniform distribution of pellets in to the tablets during an entire compression cycle.

Disclosures in prior art to protect the desired layer from cracking during compression involve the use of: a) Powdery part to granular part at least in the ratio of 0.5:1, or b) Elastic and compressible outer layer comprising waxy materials such as PEG to protect inner rate controlling polymer layer, or c) Soft pellets or deformable pellets or biologically inactive cushioning beads, or d) Sustained release agent in combination with enteric coating agent, or e) Plasticizer of more than 20% w/w of enteric polymer in enteric layer or f)At least two enteric layers in which last enteric layer is formed from a solution comprising of enteric polymer and plasticizer in organic solvent(s)
Considering these reported facts, there is a long standing need to provide swallowable dosage form such as tablet comprising multiple unit pellets that are appropriately distributed through out the dosage form during entire manufacturing process to achieve content uniformity and to ensure that the acid labile drug is prevented from being released in the gastric region.
OBJECT OF THE INVENTION
The objective of the present invention is to provide pharmaceutical gastric resistant tablet compositions of esomeprazole or its pharmaceutically acceptable salts, solvates, enantiomers or mixtures thereof.
Another objective of the present invention is to provide pharmaceutical gastric resistant tablet compositions of esomeprazole or its pharmaceutically acceptable salts, solvates, mixtures thereof comprising of multiple unit pellets that are appropriately distributed through out the dosage form during entire manufacturing process to achieve uniformity of contents and to ensure that the acid labile drug is prevented from being released in the gastric region.
Another objective of the invention is to provide a composition comprising multiple unit particles and a tablet excipient such that the multiple unit particles are not segregated and remain appropriately distributed through out the dosage form during entire manufacturing process.

Further, object of the present invention is to provide an improved, simple and effective pharmaceutical composition of Esomeprazole or its pharmaceutically acceptable salt(s), solvate(s), or mixtures thereof.
Another object of the present invention is to provide an improved process for the manufacture of stable, solid, oral pharmaceutical composition of Esomeprazole or its pharmaceutical ly acceptable salt(s), solvate(s), or mixtures thereof.
SUMMARY OF THE INVENTION
In one aspect, the present invention provides a multiple unit tablet composition comprising of enteric coated pellets wherein each pellet comprises:
a. an inert core coated with first layer of active ingredient(s);
b. a second separating layer coated on the surface of first layer;
c. a third enteric layer comprising of enteric polymers and plasticizer coated on the
separating layer to obtain enteric coated pellets, the total enteric polymers being at
least 30% by weight of the enteric coated pellets and plasticizer up to 45% by
weight of enteric polymers;
d. optionally a top coating of 2-5% to enteric coated pellet to improve
compressibility.
the pellets are compressed in to tablets which results in no appreciable change in release profile of active ingredient, wherein the tablets comprises of at least one pharmaceutical excipient and one or more segregation suppressors;
e. coating on the tablet.
In another aspect, the present invention provides a multiple unit tablet composition comprising of enteric coated pellets wherein each pellet comprises:
a. an inert core coated with first layer of esomeprazole;
b. a second separating layer coated on the surface of first layer;

c. a third enteric layer comprising of enteric polymers and plasticizer coated on the
separating layer to obtain enteric coated pellets, the total enteric polymers being at
least 30% by weight of the enteric coated pellets and plasticizer up to 45% by
weight of enteric polymers;
d. optionally a top coating of 2-5% to enteric coated pellet to improve
compressibility.
the pellets are compressed in to tablets which results in no appreciable change in release profile of active ingredient, wherein the tablets comprises of at least one pharmaceutical excipient and one or more segregation suppressors;
e, coating on the tablet.
In one another aspect, the present invention provides use of segregation suppressors in the tablet comprising multiple unit pellets, coated with first layer of active ingredient, to distribute the pellets appropriately through out the dosage form and to optimize the inter-particulate bonding and reduce the segregation of the pellets during entire manufacturing process to achieve content uniformity of active ingredient in a dosage forms.
DETAILED DESCRIPTION OF THE INVENTION
In accordance with the present invention, the pharmaceutical composition is in the form multiple unit pellets compressed into tablets.
By "pharmaceutically acceptable" as used in the invention is meant to cover a carrier comprised of a material that is not biologically or otherwise undesirable.
The term "esomeprazole" as used in the invention is meant to cover esomeprazole in the form of free base or its pharmaceutically acceptable salt(s), hydrate(s), solvate(s) and physiologically functional derivative(s) and precursors thereof. The term also includes all polymorphic forms, whether crystalline or amorphous.
The term "segregation suppressor" as used in the invention is meant to cover an inactive ingredient which optimizes the inter-particulate bonding and reduce the segregation of the pellets during compression of pellets in to tablets.

The term "content uniformity or uniformity of dosage unit" as used in the invention, is meant to cover degree of uniformity in the amount of the drug substance among dosage units.
The term "segregation" as used in the invention is meant to cover the action or state of setting someone or something apart from other, more preferably "segregation" refers to the separation of particles because of particle size and shape due to mechanical agitation.
The term "inter-particulate bonding" as used in the invention is meant to cover, van der waals forces of attraction present amongst the particles.
In one embodiment the present invention provides, a multiple unit tablet composition comprising of enteric coated pellets wherein each pellet comprises:
a. an inert core coated with first layer of active ingredient(s);
b, a second separating layer coated on the surface of first layer;
c. a third enteric layer comprising of enteric polymers and plasticizer coated on the
separating layer to obtain enteric coated pellets, the total enteric polymers being at
least 30% by weight of the enteric coated pellets and plasticizer up to 45% by weight of enteric polymers;
d. optionally a top coating of 2-5% to enteric coated pellet to improve
compressibility.
the pellets are compressed in to tablets which results in no appreciable change in release profile of active ingredient, wherein the tablets comprises of at least one pharmaceutical excipient and one or more segregation suppressors;
e. coating on the tablet.
In one another embodiment the present invention provides a multiple unit tablet composition comprising of enteric coated pellets wherein each pellet comprises:
a. an inert core coated with first layer of esomeprazole;
b. a second separating layer coated on the surface of first layer;
c. a third enteric layer comprising of enteric polymers and plasticizer coated on the separating layer to obtain enteric coated pellets, the total enteric polymers being at

least 30% by weight of the enteric coated pellets and plasticizer up to 45% by weight of enteric polymers; d. optionally a top coating of 2-5% to enteric coated pellet to improve compressibility,
the pellets are compressed in to tablets which results in no appreciable change in release profile of active ingredient, wherein the tablets comprises of at least one pharmaceutical excipient and one or more segregation suppressors;
e. coating on the tablet.
An inert core may be made up of sugar, starch, microcrystalline cellulose (MCC), carbohydrates, cellulose, resins, wax, different oxides and other materials. Inert core may further be coated by applying a layer comprising active ingredient.
According to present invention the term "active ingredients" includes any physiologically or pharmacologically active substance that produces a local or systemic effect, in animals, including warm blooded mammals, humans.
Exemplary active ingredients includes esomeprazole, pantoprazole, diphenidol, meclizine hydrochloride, prochlorperazine rnaleate, phenoxybenzamine, thiethylperazine maleate, anisindone, diphenadione erythrityl tetranitrate, isoflurophate, acetazolamide, methazolamide, bendroflumethiazide, chlorpropamide, tolazamide, chlormadinone acetate, phenaglycodol, allopurinol, aluminum aspirin, methotrexate, acetyl sulfisoxazole. erythromycin, progestins, esterogenic, progestational, corticosteroids, hydrocortisone, hydrocorticosterone acetate, cortisone acetate, triamcinolone, methyltesterone, ethinyl estradiol, pednisolone, aspirin, indomethacin, naproxen, fenoprofen, sulindac, indoprofen. nitroglycerin, isosorbide dinitrate, propranolol, timolol, atenolol, alprenolol, cimetidine, clonidine, imipramine, levodopa, chloropromazine, methyldopa, dihydroxyphenylalanine, pivaloyloxyethyl ester of alpha-methyldopa hydrochloride, theophylline, calcium gluconate, ketoprofen, ibuprofen,- cephalexin, erythromycin, haloperidol, zomepirac, , diazepam, phenoxybenzamine, diltiazem, milrinone, captopril, madol, quanbenz, hydrochlorothiazide, ranitidine, flurbiprofen, fenbufen, fluprofen, tolmetin, alolofenac, mefenamic, flufenamic. difuninal, nimodipine, nitrendipine, nisoldipine, nicardipine, felodipine, lidoflazine, tiapamil, gallopamil, amlodipine,

mioflazine, lisinolpril, enalapril, captopril, ramipril, endlapriat, famotidine, nizatidine, sucralfate, etintidine. tertatolol, minoxidil, chlordiazepoxide, chlordiazepoxide hydrochloride, diazepan, amitriptylin hydrochloride, imipramine pamoate, and the like
In one another embodiment the present invention provides use of segregation suppressors in the tablet comprising multiple unit pellets, coated with first layer of active ingredient, to distribute the pellets appropriately through out the dosage form and to optimize the inter-particulate bonding and reduce the segregation of the pellets during entire manufacturing process to achieve content uniformity of active ingredient in a dosage forms.
In one another embodiment, the one or more segregation suppressors being used are same or different.
In one another embodiment, segregation suppressors being used are grades of microcrystalline cellulose, more preferably segregation suppressors being used are microcrystalline cellulose commercially available as Avicel PH 101, microcrystalline cellulose commercially available as Avicel PH 200, microcrystalline cellulose commercially available as Ceolus KG 802, silicified microcrystalline cellulose commercially available as Prosolv SMCC 90HD and microcrystalline cellulose commercially available as Celphere CP 102.
In one another embodiment, one or more segregation suppressors being used are microcrystalline cellulose commercially available as Avicel PH 101: microcrystalline cellulose commercially available as Avicel PH 200: microcrystalline cellulose commercially available as Ceolus KG 802 in a ratio from about 0.3:1.1:0.3 to 3:10.1:3.
In preferred embodiment, one or more segregation suppressors being used are microcrystalline cellulose commercially available as Avicel PH 101: microcrystalline cellulose commercially available as Avicel PH 200: microcrystalline cellulose commercially available as Ceolus KG 802 in a ratio of 1:3.37:1.
In one another embodiment, one or more segregation suppressors being used are silicified microcrystalline cellulose commercially available as Prosolv SMCC : microcrystalline

cellulose commercially available as Celphere CP 102 in a ratio from about 2.5:0.4 to 12,5:2.5.
In preferred embodiment, one or more segregation suppressors being used are silicified . microcrystalline cellulose commercially available as Prosolv SMCC : microcrystalline cellulose commercially available as Celphere CP 102 in a ratio of 5 :1.
A segregation suppressor will optimize the inter-particulate bonding and reduce the segregation of the pellets. Flow problem may be observed if the inter-particulate bonding is high and if the inter-particulate bonding is less then the problem of segregation may be observed. So. there is long standing need to have segregation suppressor in the tablet comprising multiple unit pellets to distribute the pellets appropriately through out the dosage form during entire manufacturing process to achieve content uniformity.
In one another embodiment the present invention provides a content uniformity acceptance value less than 15.
The active ingredient layering process on the inert core may involve binder, stabilizer and optionally other pharmaceutically acceptable ingredients along with active ingredient. The application of layer comprising active ingredient can be done simultaneous with binder or alternating with binder.
The drug layered core is coated with a separating layer comprising of binder and optionally other pharmaceutical ingredients. Separating layer may be prepared by spraying either dispersion or solution on to the drug layered cores.
The cores or separating layer coated cores of the present invention are coated with enteric layer comprising of enteric polymers and plasticizer.
The tablets in the present invention are formed from enteric coated pellets from above step and at least one tablet excipient from diluent, binder, disintegrant, lubricating agent, cushioning agent and segregation suppressor.
In accordance with the present invention one or more diluent used may be combination of two or more excipients, and these excipient granules can be manufactured by any conventional manufacturing processes well known to those of skill in the art by wet

granulation technique or dry granulation technique of two or more of pharmaceutically acceptable excipients.
In accordance with present invention method of manufacturing of gastro resistant tablets may be by direct compression includes mixing of enteric coated pellets with other pharmaceutically acceptable excipients, or excipient granulates, lubrication and then compression into core tablets.
In accordance with the present invention, pharmaceutical composition of gastric resistant multiple unit tablet comprises, esomeprazole or its pharmaceutically acceptable salt, solvate, enantiomers or mixtures thereof and at least one or more pharmaceutically acceptable excipients like diluents, disintegrants, binders, lubricants, glidants, cushioning agents, segregation suppressor agents, stabilizer, buffers, surfactants, anti-foaming agents, polymers, plasticizer, anti-adherent agents and one or more of coating agents for film coating.
Diluents used in the present invention are at least one or more of microcrystalline cellulose, silicified microcrystalline cellulose, lactose monohydrate, starch, calcium phosphate (dibasic/tribasic), calcium sulphate, calcium sulphate dihydrate. fructose, sucrose, sorbitol, mannitol, xylitol, dextrose, compressible sugar, dextrates, dextrin, powdered cellulose, cellulose acetate, polymethacrylates, sodium alginate and tragacanth.
Disintegrants used in the present invention are at least one or more of the croscarmellose sodium, crospovidone, sodium starch glycollate, pregelatinized starch, microcrystalline cellulose, emcosoy (Soya polysaccharide) and potassium polacrilin.
Binders used in the present invention may be at least one or more of polyvinyl pyrrolidone (polyplasdone), co-povidone, polyethylene oxide, cellulose derivatives like ethyl cellulose, methyl cellulose, carboxymethyl cellulose sodium, hydroxypropyl cellulose, hydroxypropylmethyl cellulose (Hypromeilose E5 LV), hyroxyethyl cellulose etc., acacia gum, guar gum, xanthan gum, karaya gum, gellan gum, hupu gum. carob gum, caramania gum, gelatin, glucose, sugar, dextrin, sorbitol, maltose, pregelatinised starch, agar, alginic acid, sodium alginate, carbomers, carrageenan, ceratonia, chitosan, poloxamer, magnesium aluminum silicate, glyceryl monostearate, glyceryl behenate, gelyceryl monooleate, glyceryl palmitostearate, microcrystalline wax, stearyl alcolhol,

cetyl alcohol, cetostearyl alcohol, hydrogenated caster oil, tristearin, waxes, ethylene glycol palmitostearate and Kollicoat protect.
Lubricants used in the present invention are one or more of magnesium stearate, calcium stearate, stearic, acid, sodium stearyl fumerate, talc, hydrogenated vegetable oils, magnesium lauryl sulfate, wax, polyethylene glycol, glyceryl behenate, glyceryl palmitostearate, palmitic acid, poloxamer, sodium bervzoate and sodium lauryl sulfate.
Glidants used in the present invention may be at least one or more of colloidal silicon dioxide, talc, stearic acid, magnesium stearate, calcium stearate, hydrogenated castor oil, sodium lauryl sulfate, precipitated silicon dioxide, starch and like.
Cushioning agent used in the present invention may be at least one or more of microcrystalline cellulose, silicified microcrystalline cellulose, lactose monohydrate, starch, admixture of lactose and cellulose, polyethelene glycol, microcrystalline wax, hydrogenated oil, carnauba wax, beeswax, glyceryl monostearate, colloidal silicon dioxide, glyceryl behenate, glyceryl monooleate, glyceryl palmitostearate, hydroxypropyl cellulose and like.
Segregation suppressor used in the present invention may be at least one or more of microcrystalline cellulose commercially available as Avicel PH 200, Ceolus KG 802 and Avicel PH 101, silicified microcrystalline cellulose, lactose monohydrate, starch, admixture of lactose and cellulose, polyethelene glycol, microcrystalline wax, hydrogenated oil, carnauba wax, beeswax, glyceryl monostearate colloidal silicon dioxide, glyceryl behenate, glyceryl monooleate, glyceryl palmitostearate and hydroxypropyl cellulose.
Stabilizer is selected from the group consisting of alkali and alkaline earth metals. Alkalizing agents used in the present invention are at least one or more of aluminum salts such as magnesium aluminum silicate ; magnesium salts such as magnesium carbonate, magnesium trisilicate, magnesium aluminum silicate, magnesium stearate; calcium salts such as calcium carbonate; bicarbonates such as calcium bicarbonate and sodium bicarbonate; phosphates such as monobasic calcium phosphate, dibasic calcium phosphate, dibasic sodium phosphate, tribasic sodium phosphate (TSP), dibasic potassium phosphate, tribasic potassium phosphate; metal hydroxides such as aluminum

hydroxide, sodium hydroxide, potassium hydroxide and magnesium hydroxide; metal oxides such as magnesium oxide; N-methyl glucamine; arginine and salts thereof; amines such as monoethanolamine, diethanolamine, triethanolamine, meglumine and tris (hydroxy methyl) amino methane (TRIS).
Buffers such as acetate, phosphate, borate, bicarbonate, carbonate, succinate, tris buffer, organic acid buffer and mixtures thereof may also be used. Preferably alkaline substance from monobasic sodium phosphate, dibasic sodium phosphate, tribasic sodium phosphate, sodium hydroxide, potassium hydroxide, sodium lauryl sulphate, magnesium carbonate, calcium carbonate, magnesium oxide and mixtures thereof are used.
Surfactants are selected from the group of cationic surfactant, non-ionic surfactant and anionic surfactant and is preferably selected from sodium lauryl sulfate, polysorbates such as polysorbate 80, sorbitan esters, poloxamers, fatty acid esters and ethers of polyethylene glycol, alkyl phenoxy polyethylene glycols, block polymers of polyethylene and polypropylene oxides, oleic acid and its salt, bile salts and their conjugates, octoxynol, polyoxyethylene and its derivatives such as castor oil derivatives polyoxyethylene monoalkyl ethers, sucrose esters, lanolin esters and ethers, lauric acid and its salts, alkyl sulfate and its salts, fatty acid and its salts and mixtures thereof.
Antifoaming agents used in the present invention are one or more of polyether surfactant, polyhydric alcohol fatty acid ester, silicone dioxide, silicone derivatives and organopolysiloxane polymers, simethicone emulsion and dimethicone.
Enteric polymer in the enteric layers is selected from methacrylic acid copolymers. cellulosic polymers, polyvinyl alcohol phthalate, polyvinyl acetate phthalate, shellac and mixtures thereof.
Methacrylic acid copolymers is selected from Eudragit L30D55 (Type C), Eudragit LI0055 (Type C), Eudragit LI00 (Type A), Eudragit LI2.5, (Type A), Eudragit Si00 (Type B), Eudragit S 12.5 (Type B) and Eudragit FS30D.
Cellulosic polymer is selected from cellulose acetate phthalate (CAP), cellulose acetate trimelliate (CAT), hydroxypropylmethylcellulose phthalate (HPMCP), cellulose

propionate phthalate, hydroxypropylmethylcellulose acetate succinate (HPMCAS), cellulose acetate maleate and hydroxypropylmethylcellulose hexahydrophthalate.
Plasticizer is selected from the group of hydrophilic and/or hydrophobic plasticizers and is selected from polyethylene glycol, triacetin, triethylcitrate, acetyl triethylcitrate, miglyol, cetyl alcohol, acetyltributylcitrate, diethyl phthalate, dibutyl phthalate. propylene glycol, hydrogenated oils, dibutylsebacate, meglumine and mixtures thereof and is preferably dibutyl sebacate.
Anti-adherent in the enteric layers is selected from talc, colloidal silicon dioxide, glyceryl monostearate, stearic acid, kaolin, magnesium stearate, calcium stearate, sodium stearyl fumarate, glyceryl behenate. starch and mixtures thereof.
Coating agents used are polyvinyl pyrrolidone (polyplasdone), co-povidone. polyethylene oxide, cellulose derivatives like ethyl cellulose, methyl cellulose, carboxymethyl cellulose sodium, hydroxypropyl cellulose, hydroxypropylmefhyl cellulose (Hypromellose E5 LV), hyroxyethyl cellulose or Opadry (a ready mix for coating) along with these coating agents it may or may not contain plasticizer. opacifier (titanium dioxide), colorant (FD and C colours) and like.
Enteric coated pellets and excipient granules prepared above are compressed into swallowable dosage form such as tablets.
In accordance with the present invention, the tablet is coated, wherein coating is applied for elegance.
The gastric resistant pharmaceutical composition of the present invention may be administered to the mammals. Preferably the mammal is a human, and the composition is administered as gastric resistant tablet. Preferably, the pharmaceutical composition of present invention containing esomeprazole may be used in the treatment of gastroesophageal reflux disease (GERD), risk reduction of NSAID-associated gastric ulcer. The amount of the esomeprazole in the delayed release pharmaceutical composition of present invention is preferably an amount that provides a therapeutically effective amount of esomeprazole.

Although the present invention has been described with reference to specific embodiments, this description is not meant to be construed in a limiting sense. Various modifications of the disclosed embodiments, as well as alternate embodiments of the invention, will become apparent to persons skilled in the art upon reference to the description of the invention. It is therefore contemplated that such modifications can be made without departing from the spirit or scope of the present invention as defined.
The following examples illustrate preferred embodiments in accordance with the present
invention without limiting the scope or spirit of the invention.
Dosage: 44.500 mg of esomeprazole magnesium (equal to 40 mq of esomeprazole base)
per tablet
Example 1

Sr.
No. Ingredients Quantity per tablet in mg

Example 1A Example IB
Drug loading
1 Esomeprazole magnesium eq. to 40 mg Esomeprazole 44.500 44.500
2 Hypromellose E5 LV 16.160 16.160
3 Sodium hydroxide 0.600 0.600
4 Sugar spheres (#40/60) 28.300 26.400
5 Simethicon emulsion 0.890 0.890
6 Polysorbate 80 0.950 0.950
7 Purified water q.s. q.s
Barrier coating
8 Opadry clear 9.100 9.000
9 Purified water q.s. q.s.
Enteric coating
10 Methyl methacrylate copolymer (EudragitL30D55) 47.830 58.600
11 Triethyl citrate 14.350 17.580
12 Talc 6.000 7.325

13 Sodium hydroxide 0.370 0.358
14 Glyceryl monostearate 11.950 14.650
15 Purified water q.s. q.s.
Unit weight of enteric coated pellets 181.00 197.00
Brief Manufacturing Procedure: Enteric coated pellet preparation A) Drug loading
1. Purified water was divided in two equal parts. To one part hypromellose E5 LV was dissolved.
2. To the second part sodium hydroxide, polysorbate 80 and simethicon emulsion were added. Esomeprazole magnesium was added to the resulting solution and stirred continuously to get uniform dispersion.
3. Solution in step 1 and step 2 were mixed together and stirred continuously.
4. Sugar spheres were loaded into the chamber of pellet coater and loaded with solution in step 3. After complete drug loading pellets were dried.
B). Barrier coating
5. Drug loaded pellets were further barrier coated with the opadry clear solution.
which was prepared by dissolving the opadry clear powder in purified water.
Barrier coated pellets were dried.
C) Enteric coating
6. Purified water for enteric coating solution preparation was divided into four parts
7. Methyl methacrylic acid dispersion (Eudragit L 30 D55) was added to one part of purified water containing triethyl citrate under continuous stirring.
8. Sodium hydroxide was dissolved in second part of purified water
9. Solution in step 7 and 8 were added together and stirred continuously.
10. Third part of purified water was heated up to 80°C. To the heated water glyceryl monostearate was added and resulting solution was kept aside till the temperature below 35°C is attained.
11. To the fourth part of purified water talc was added and stirred continuously.

12. Dispersions in step 10 and 11 were added to the dispersion in step 9 and stirred
continuously. Resulting dispersion was filtered through #60 mesh.
13. Barrier coated pellets of step 5 were enteric coated with the dispersion in step 12.
Resulting pellets were compressed into tablets based on the drug content of enteric
coated pellets
Example 2

Sr.
No. Ingredients Quantity per tablet in mg
1 Enteric coated pellets of Esomeprazole magnesium eq. to 40mg Esomeprazole 181.000
2 Placebo granules of Microcrystalline cellulose and 2 % Hypromellose E5 LV (#24/35 mesh) 353.000
3 Ceolus KG 802 100.00
4 Polyplasdone 80.000
5 Crospovidone 42.500
6 Polyethylene glycol 6000 85.000
7 Sodium stearyl fumarate 8.500
Weight of core tablet 850.000
8 Opadry pink 25.000
9 Purified water q.s.
Weight of coated tablet 875.000
Brief Manufacturing Procedure:
1. Microcrystalline cellulose was spray granulated with 2 % solution of hypromellose E5 LV. Granules were dried and sifted through #24 mesh and fraction in between #24 and #35 mesh was selected for compression.
2. Crospovidone, polyethylene glycol and polyplasdone were added together and sifted through sieve #40.

3. Placebo granules in step 1 and blend in step 2 were mixed together and to that mixture enteric coated pellets of esomeprazole were added and mixed together and blended for 10 min
4. Blend in step 3 was lubricated with sodium stearyl fumarate. which was previously sifted through # 60 mesh.
5. Resulting lubricated blend was compressed into tablets with suitable punches.
6. Opadry pink was dispersed into purified water and stirred continuously.
7. Compressed tablets were coated with the dispersion in step 6.
Example 3

Sr.
No. Ingredients Quantity per tablet in mg
1 Enteric coated pellets of Esomeprazole magnesium eq. to 40mg Esomeprazole 197.000
2 Microcrystalline cellulose (Avicel PH 101) 75.000
3 Microcrystalline cellulose (Avicel PH 200) 154.82
4 Microcrystalline cellulose (Ceolus KG 802) 75.000
5 Polyplasdone 61.18
6 Crospovidone 32.500
7 Polyethylene glycol 6000 . 65.000
8 Sodium stearyl fumarate 6.500
Weight of core tablet 667.000
9 Opadry pink 20.000
10 Purified water q.s.
Weight of coated tablet 687.000
Brief Manufacturing Procedure:
1. Microcrystalline cellulose (Avicel PH 101, Avicel PH 200.. Ceolus KG 802), polyplasdone, crospovidone and polyethylene glycol 6000 were added together and sifted through #40 mesh,
2. Enteric coated pellets of esomeprazole were added to the above blend.

3. Blend in step 2 was lubricated with sodium stearyl fumarate, which was previously sifted through # 60 mesh.
4. Resulting lubricated blend was compressed into tablets with suitable punches.
5. Opadry pink was dispersed into purified water and stirred continuously.
Compressed tablets were coated with the dispersion in step 5.
Example 4

Sr. No. Ingredients Quantity tablet in per rag
1 Enteric coated pellets of Esomeprazole magnesium eq. to 40mg Esomeprazole 197.00
2 Microcrystalline cellulose (Avicel PH 101) 65.000
3 Microcrystalline cellulose (Avicel PH 200) 219.000
4 Microcrystalline cellulose (Ceolus KG 802) 65.000
5 Polyplasdone (Kollidone VA 64) 32.500
6 Crospovidone XL 10 32.500
7 Polyethylene glycol 32.500
8 Sodium stearyl fumarate 6.500
Weight of core tablet 650.000
9 Opadry pink 19.500
10 Purified water q.s.
Weight of coated tablet 669.500
Brief Manufacturing Procedure;
1. Microcrystalline celluloses (Avicel PH 101, Avicel PH 200 and Ceolus KG 802), crospovidone, polyethylene glycol and polyplasdone were added together and sifted through sieve #40.
2. Mixture.in step 1 and enteric coated pellets of esomeprazole were mixed together and blended for 10 min
3. Blend in step 2 was lubricated with sodium stearyl fumarate., which was previously sifted through # 60 mesh.

4. Resulting lubricated blend was compressed into tablets with suitable punches.
5. Opadry pink was dispersed into purified water and stirred continuously.
6. Compressed tablets were coated with the dispersion in step 5.
Example 5

Sr. No. Ingredients Quantity per tablet in mg
Drug loading
1 Esomeprazole magnesium eq. to 40 mg Esomeprazole 44.500
2 Hypromellose E5 LV 20.410
3 Sodium hydroxide 0.540
4 Polysorbate 80 1.15
5 Sugar spheres (#60/70) 13.57
6 Isopropyl Alcohol q.s.
7 Purified water q.s.
Barrier coating
8 Opadry clear 24.06
9 Isopropyl Alcohol q.s.
10 Purified water q.s.
Enteric coating
11 Methacrylic acid copolymer (Eudragit L 100) 55.92
12 Triethyl citrate 5.59
13 Talc 13.99
14 Sodium hydroxide 0.34
15 Glyceryl monostearate 7.54
16 Isopropyl Alcohol q.s.
17 Purified water q.s.
Top coating
18 Hydroxy propyl cellulose (Klucel LF)
■ 7.22

19 Poly ethylene glycol 6000 2.16
20 Isopropyl Alcohol q.s.
21 Purified water q.s.
Unit weight of enteric coated pellets 197.00
Brief Manufacturing Procedure: Enteric coated pellet preparation
D) Drug loading
14. Purified water and isopropyl alcohol was mix and divided in two equal parts. To one part hypromellose E5 LV was dissolved.
15. To the second part sodium hydroxide was added. Esomeprazole magnesium was added to the resulting solution and stirred continuously to get uniform solution,
16. Solution in step 1 and step 2 were mixed together and stirred continuously.
17. Polysorbate 80 was added to step 3 and stirred continuously to get uniform solution; solution was filtered through ASTM #60.
18. Sugar spheres were loaded into the chamber of pellet coater and loaded with solution in step 3. After complete drug loading pellets were dried.
E) Barrier coating
19. Drug loaded pellets were further barrier coated with the opadry clear solution,
which was prepared by dissolving the opadry clear powder in mixture of purified
water & Isopropyl alcohol. Barrier coated pellets were dried.
F) Enteric coating
20. Purified water and isopropyl alcohol for enteric coating was mix and divided into four parts.
21. Methacrylic acid copolymer (Eudragit L 100) was added to the one part of purified & Isopropyl alcohol mix,, under continuous stirring.
22. Sodium hydroxide was dissolved in second part of purified water & Isopropyl alcohol mix, were added to step 8 solution and stirred continuously.
23. Glycerol mono stearate was heated up to 80°C. To the heated glycerol mono stearate, isopropyl alcohol was added and resulting solution was kept aside till the temperature below 40°C is attained.

24. To the fourth part of purified water & Isopropyl alcohol, talc was added and stirred continuously.
25. Triethyl citrate was added to step 9 followed by addition of step 10 & step 11 solution with continuous stirring.
26. Barrier coated pellets of step 6 were enteric coated with the dispersion in step 12. After complete enteric coating pellets were dried.
D) Top coating
27. Polyethylene glycol 6000 was dissolved in Purified water and isopropyl alcohol mix and stirred continuously.
28. Hydroxy propyl cellulose (Klucel LF) wae added to step 14 solution and stirred continuously to get uniform solution.
29. Enteric coated pellets were further top coated with step 15 solution. After top coating pellets were dried.
Resulting pellets were compressed into tablets based on the drug content of enteric coated pellets
Example 6

Sr. No. Ingredients Quantity per tablet in mg
1 Enteric coated pellets of Esomeprazole magnesium eq. to 40mg Esomeprazole 197.000
2 Silicified Microcrystalline Cellulose, NF (Prosolv SMCC 90HD) 400.00
3 Micro crystalline cellulose (Celphere CP 102) 80.00
4 Copovidone (Kolliodon VA 64) 40.00
5 Crosspovidone XL 40.00
6 Polyethylene Glycol 6000 40.00
7 Sodium stearyl fumarate 8.00
Weight of core tablet 805.00
8 Opadry pink 25.000
9 Purified water q.s.

10 Isopropyl alcohol q.S.
Weight of coated tablet 830.000
Brief Manufacturing Procedure:
8. Silicified Microcrystalline Cellulose (Prosolv SMCC 90HD), Micro crystalline cellulose (Celphere CP 102), Copovidone (Kolliodon VA 64), Crosspovidone XL and Polyethylene Glycol 6000 was sifted together through #18 mesh.
9. Mixture in step 1 and enteric coated pellets of esomeprazole were mixed together and blended for 10 min
10. Blend in step 2 was lubricated with sodium stearyl fumarate, which was previously sifted through # 40 mesh.
11. Resulting lubricated blend was compressed into tablets with suitable punches.
12. Opadry pink was dispersed into mixture of purified water and Isopropyl alcohol and stirred continuously.
13. Compressed tablets were coated with the dispersion in step 5.
The results of content uniformity from the example numbers 2, 3 and 4 are presented in the table below.

Example Content Uniformity range (minimum-maximum) Acceptance value (Limit as per pharmacopoeia < 15)
Example 2 112.4-160.1% 66.8
Example 3 91.0-114.8% 20.75
Example 4 86.5-101.0% 13.39
Example 6 94.7-105.3% 9.7

We claim:
1. A multiple unit tablet composition comprising of enteric coated pellets wherein each
pellet comprises:
a. an inert core coated with first layer of active ingredient(s);
b. a second separating layer coated on the surface of first layer;
c. a third enteric layer comprising of enteric polymers and plasticizer coated on the
separating layer to obtain enteric coated pellets, the total enteric polymers being at
least 30% by weight of the enteric coated pellets and plasticizer up to 45% by
weight of enteric polymers;
d. optionally a top coating of 2-5% to enteric coated pellet to improve
compressibility.
the pellets are compressed in to tablets which results in no appreciable change in release profile of active ingredient, wherein the tablets comprises of at least one pharmaceutical excipient and one or more segregation suppressors.
e. coating on the tablet
2. Use of segregation suppressors in the tablet comprising multiple unit pellets coated with first layer of active ingredient, to distribute the pellets appropriately through out the dosage form and to optimize the inter-particulate bonding and reduce the segregation of the pellets during entire manufacturing process to achieve content uniformity of active ingredient in a dosage forms.
3. A multiple unit tablet composition comprising of enteric coated pellets wherein each pellet comprises:
a. an inert core coated with first layer of esomeprazole;
b. a second separating layer coated on the surface of first layer;
c. a third enteric layer comprising of enteric polymers and plasticizer coated on the
separating layer to obtain enteric coated pellets, the total enteric polymers being at
least 30% by weight of the enteric coated pellets and plasticizer up to 45% by
weight of enteric polymers;
d. optionally a top coating of 2-5% to enteric coated pellet to improve
compressibility.

the pellets are compressed in to tablets which results in no appreciable change in release profile of active ingredient wherein the tablets comprises of at least one pharmaceutical excipient and one or more segregation suppressors e. coating on the tablet.
4. The multiple unit tablet composition claimed in claim 1, 2 and 3, wherein segregation suppressor optimizes the inter-particulate bonding and reduces the segregation of the pellets.
5. The multiple unit tablet composition claimed in claim 1, 2 and 3, wherein one or more segregation suppressors are selected from a group comprising of microcrystalline cellulose commercially available as Avicel PH 101, Avicel PH 102, Avicel PH 200, Ceiphere CP 102 and Ceolus KG 802, silicified microcrystalline cellulose of different particle size, lactose monohydrate, starch, admixture of lactose and cellulose, polyethylene glycol, microcrystalline wax, hydrogenated oil, carnauba wax, beeswax, glycerol monostearate colloidal silicon dioxide, glyceryl behenate, glyceryl monosterate, glyceryl palmitostearate and hydroxypropyl cellulose.
6. The multiple unit tablet composition claimed in claim 1, 2 and 3, wherein segregation suppressor being used are different grade of microcrystalline cellulose.
7. The multiple unit tablet composition claimed in claim 1, 2 and 3, wherein segregation suppressors being used are microcrystalline cellulose commercially available as Avicel PH 101: microcrystalline cellulose commercially available as Avicel PH 200: microcrystalline cellulose commercially available as Ceolus KG 802 in a ratio from about 0.5:2:0.5 to 2:4.5:2.
8. The multiple unit tablet composition claimed in claim 7, wherein segregation suppressors being used are silicified microcrystalline cellulose commercially available as Prosolv SMCC: microcrystalline cellulose commercially available as Ceiphere CP 102 in a ratio of 2.5:0.4 to 12.5:2.5.
9. The multiple unit tablet composition claimed in claim 1, 2 and 3 wherein a content uniformity acceptance value obtained is less than 15.