DESC:FIELD OF INVENTION:
The present invention relates to orally disintegrating Tablets comprising amorphous dexlansoprazole and process of preparation thereof.
BACKGROUND OF INVENTION:
Dexlansoprazole is a proton pump inhibitor and and it is widely used for the treatment of stomach ulcer and duodenal ulcer. US patent numbers 6,664,276 and 7,737,282 disclose crystalline and amorphous forms of dexlansoprazole respectively.
Dexlansoprazole is approved as capsule as well as orally disintegarting tablets marketed by Takeda under Brand name Dexilant® and Dexilant SoluTab® respectively.
Orally disintegrating tablets are capable of being administered without water and is more convinient for administering to aging patients.
US patent no. 9,241,910 discloses orally disintegrating composition of dexlansoprazole comprising two types of enteric coated granules wherein at least one type of granule has the average particle size 500 µm or below. However, preparing composition with two types of granules involve complex process of praparation which can be costly as well as time consuming.
There continues to be a need to provide stable orally disintegrating tablets of amorphous dexlansoprazole which can be easily prepared by using conventional means.
OBEJECTIVES OF INVENTION:
The main objective of the invention is to provide orally disintegrating tablets comprising amorphous dexlansoprazole and process of preparation thereof.
Another object of the invention is to provide orally disintegrating tablets comrpising enteric coated granules of amorphous dexlansoprazole, wherein average particle size of the granules is greater than 500 µm.
Another object of the invention is to provide orally disintegrating tablets comprising enteric coated granules of average particle size greater than 500 µm and one or more pharmaceutically acceptable excipients, wherein enteric coated granules comprises: a core granule comprising amorphous dexlansoprazole and one or more pharmaceutically acceptable excipients, a barrier coating layer surrounding the core granule and an enteric coating layer surrounding the barrier coating layer.
Another object of the invention is to provide orally disintegrating tablets comprising enteric coated granules of average particle size greater than 500 µm and one or more pharmaceutically acceptable excipients, wherein enteric coated granules comprise: a core granule comprising amorphous dexlansoprazole and one or more pharmaceutically acceptable excipients, a barrier coating layer surrounding the core granule and an enteric coating layer surrounding the barrier coating, wherein enteric coating layer comprises methacrylic acid copolymer and at least one polymer selected from the group consisting of ethyl acrylate and methyl methacrylate copolymer, methacrylic acid-methyl acrylate-methyl methacrylate copolymer.
Another object of the invention is to provide orally disintegrating tablets comprising enteric coated granules of average particle size greater than 500 µm and one or more pharmaceutically acceptable excipients, wherein enteric coated granules comprise: a core granule comprising amorphous dexlansoprazole and one or more pharmaceutically acceptable excipients, a barrier coating layer surrounding the core granule, a sustained release coating layer surrounding the barrier coating layer and an an enteric coating layer surrounding the sustained release coating layer.
Another object of the invention is to provide orally disintegrating tablets comprising enteric coated granules of average particle size greater than 500 µm and one or more pharmaceutically acceptable excipients, wherein enteric coated granules comprise: a core granule comprising amorphous dexlansoprazole and one or more pharmaceutically acceptable excipients, a barrier coating layer surrounding the core granule, a sustained release coating surrounding the barrier coating layercomprising copolymers of methyl methacrylate and methacrylic acid ester with quaternary ammonium groups and an enteric coating layer surrounding the barrier coating, wherein enteric coating layer comprises methacrylic acid copolymer and at least one polymer selected from the group consisting of ethyl acrylate and methyl methacrylate copolymer, methacrylic acid-methyl acrylate-methyl methacrylate copolymer.
Another object of the invention is to provide orally disintegrating tablets comprising enteric coated granules of average particle size greater than 500 µm and one or more pharmaceutically acceptable excipients, wherein enteric coated granules comprise: a core granule comprising amorphous dexlansoprazole and one or more pharmaceutically acceptable excipients, a barrier coating layer surrounding the core granule and an enteric coated layer surrounding the barrier coating, wherein core comprises one or more non-toxic bases or basic salts in an amount less than 0.2 part by weight based on one part by weight of dexlansoprazole.
Another object of the invention is to provide a stable orally disintegrating tablets of amorphous dexlansoprazole which is stable throughout shelf life.
Another object of the invention is to provide a stable orally disintegrating tablets of dexlansoprazole which has comparable in-vitro dissolution profile with marketed orally disintegrating composition of dexlansoprazole (Dexilant SoluTab®).
Another object of the invention is to provide a stable orally disintegrating tablets of dexlansoprazole which is bioequivalent to the marketed orally disintegrating composition of dexlansoprazole (Dexilant SoluTab®).
Another object of the invention is to provide orally disintegrating tablets of amorphous dexlansoprazole comprising enteric coated granules of average particle size greater than 500 µm, wherein rate of release of dexlansoprazole from the composition is more than 10% for 5 hours in a solution of pH 6.0, and more than 5% for one hour and less than 60% for 8 hours in a solution of pH 6.8 using USP dissolution apparatus.
Another object of the invention is to provide orally disintegrating tablets of amorphous dexlansoprazole comprising enteric coated granules of average particle size greater than 500 µm, wherein composition has Cmax and AUC within the limit of 80% to 125% of Cmax and AUC of marketed orally disintegrating tablets of dexlansoprazole (Dexilant SoluTab®).
In another embodiment, a process of preparing stable orally disintegrating tablets comprising enteric coated granules of average particle size greater than 500 µm and one or more pharmaceutically acceptable excipients, wherein the process comprises steps of
(i) preparing core granule comprising amorphous dexlansoprazole by spraying dispersion of dexlansoprazole and one or more pharmaceutically acceptable excipients in a solvent, on an inert core,
(ii) preparing the dispersion of pharmaceutically acceptable excipients in a solvent and spraying it on core granules of step (i) to get barrier coated granules,
(iii) preparing the dispersion of pharmaceutically acceptable excipients in a solvent and spraying it on barrier coated granules of step (ii) to get enteric coated granules,
(iv) blending the enteric coated granules of step (iii) with extragranular portion comprising one or more pharmaceutically acceptable excipients,
(v) compressing the blend of step (iv) to get a tablet.
BRIEF DESCRIPTION OF ACCOMPANYING DRAWINGS
Figure 1: XRD pattern for Example 1 (XRD pattern of enteric coated pellets granules)

DETAILED DESCRIPTION OF THE INVENTION
The present invention relates to orally disintegrating tablets comprising amorphous dexlansoprazole and process of preparation thereof. The pharmaceutical compositions of the invention are preferably tablets.
Dexlansoprazole used in the present invention is in the form of base or pharmaceutically acceptable salt(s) thereof. Preferably dexlansoprazole is in the form of base and more preferably it is amorphous base.
The term "amorphous" is intended to mean a non-crystalline form of dexlansoprazole having X-ray diffraction (XRD) pattern as depicted in Figures 1.
In one embodiment, an orally disintegrating tablet comrpising enteric coated granules of amorphous dexlansoprazole and one or more pharmaceutically accpetable excipients, wherein average particle size of the granules is greater than 500 µm.
In another embodiment, an orally disintegrating tablet comprising enteric coated granules of average particle size more than 500 µm and one or more pharmaceutically acceptable excipients, wherein enteric coated granules comprise: a core granule comprising amorphous dexlansoprazole and one or more pharmaceutically acceptable excipients, a barrier coating layer surrounding the core granule and an enteric coating layer surrounding the barrier coating layer.
In another embodiment, an orally disintegrating tablet comprising enteric coated granules of average particle size greater than 500 µm and one or more pharmaceutically acceptable excipients, wherein enteric coated granules comprise: a core granule comprising amorphous dexlansoprazole and one or more pharmaceutically acceptable excipients, a barrier coating layer surrounding the core granule and an enteric coating layer surrounding the barrier coating layer, wherein enteric coating layer comprises two or more polymers.
The pH-dependent polymer comprises but not limited to hypromellose phthalate, cellulose acetate phthalate, hydroxypropyl methylcellulose acetate succinate, shellac, polyvinyl acetate phthalate, Eudragit® polymers such as methacrylic acid-methyl acrylate-methyl methacrylate copolymer (Eudragit FS 30D), methacrylic acid copolymer (Eudragit L30 D55) methacrylic acid-ethyl acrylate copolymer (L100-55) methyl methacrylate-methacrylic acid copolymer (Eudragit L 100), wherein the most preferable polymers are methacrylic acid-methyl acrylate-methyl methacrylate copolymer and methacrylic acid copolymer.
In another embodiment, enteric coating layer further comprises one or more polymers comprising but not limited to Eudragit polymers such as copolymer of ethyl acrylate, methyl methacrylate and a low content of methacrylic acid ester with quaternary ammonium groups (Eudragit RL 30 D, RL 100, RS 30 D), methyl methacrylate ethyl acrylate copolymer (Eudragit NE 30D), polyvinyl acetate, Kollidon SR (which is a mixture of 8 parts w/w of polyvinyl acetate and 2 parts w/w of polyvinylpyrrolidone), cellulose derivatives such as ethyl cellulose, triglycerides, waxes such as compritol, lubritab, peceol, gelucires, wherein the most preferable polymer is methyl methacrylate ethyl acrylate copolymer.
In another embodiment, an orally disintegrating tablet comprising enteric coated granules of average particle size greater than 500 µm and one or more pharmaceutically acceptable excipients, wherein enteric coated granules comprise: a core granule comprising amorphous dexlansoprazole one or more pharmaceutically acceptable excipients, a barrier coating layer surrounding the core granule and an enteric coating layer surrounding the barrier coating layer, wherein enteric coating layer comprises methacrylic acid copolymer and at least one polymer selected from the group consisting of ethyl acrylate and methyl methacrylate copolymer, methacrylic acid-methyl acrylate-methyl methacrylate copolymer.
In another embodiment, an orally disintegrating tablet comprising enteric coated granules of average particle size greater than 500 µm and one or more pharmaceutically acceptable excipients, wherein enteric coated granules comprise: a core granule comprising amorphous dexlansoprazole and one or more non-toxic bases or basic salts, a barrier coating layer surrounding the core granule and an enteric coating layer surrounding the barrier coating layer.
The non-toxic bases or basic salts comprises but not limited to, magnesium hydroxide, potassium hydroxide, magnesium carbonate, calcium carbonate, , magnesium oxide, sodium carbonate, sodium bicarbonate, sodium hydroxide, meglumine, alkali metal salts such as sodium salt and potassium salt; alkaline earth metal salts such as calcium salt and magnesium salt; ammonium salt and the like, alkylamine (trimethylamine, triethylamine and the like), a heterocyclic amine (pyridine, picoline, arginine and the like), an alkanolamine (ethanolamine, diethanolamine, triethanolamine and the like), dicyclohexylamine, N,N'-dibenzylethylenediamine; ; wherein the most preferable base is potassium hydroxide.
In another embodiment, an orally disintegrating tablet comprising enteric coated granules of average particle size greater than 500 µm and one or more pharmaceutically acceptable excipients, wherein enteric coated granules comprise: a core granule comprising amorphous dexlansoprazole and one or more non-toxic bases or basic salts, a barrier coating layer on the core granule and an enteric coating layer on the barrier coating layer, wherein core comprises a non-toxic base or basic salt in an amount less than 0.2 part by weight based on one part by weight of dexlansoprazole.
In another embodiment, an orally disintegrating tablet comprising enteric coated granules of average particle size greater than 500 µm and one or more pharmaceutically acceptable excipients, wherein enteric coated granules comprise: a core granule comprising amorphous dexlansoprazole and potassium hydroxide, a barrier coating layer surrounding the core granule and an enteric coating layer surrounding the barrier coating layer.
In another embodiment, an orally disintegrating tablet comprising enteric coated granules of average particle size greater than 500 µm and one or more pharmaceutically acceptable excipients, wherein enteric coated granules comprise: a core granule comprising amorphous dexlansoprazole and one or more pharmaceutically acceptable excipients, a barrier coating layer surrounding the core granule, a sustained release coating layer surrounding the barrier coating layer and an an enteric coating layer surrounding the sustained release coating layer.
In another embodiment, an orally disintegrating tablet comprising enteric coated granules of average particle size greater than 500 µm and one or more pharmaceutically acceptable excipients, wherein enteric coated granules comprise: a core granule comprising amorphous dexlansoprazole and one or more pharmaceutically acceptable excipients, a barrier coating layer surrounding the core granule, a sustained release coating surrounding the barrier coating and an an enteric coating layer surrounding the barrier coating wherein, enteric coating layer comprises at least two polymers.
In another embodiment, an orally disintegrating tablet comprising enteric coated granules of average particle size greater than 500 µm and one or more pharmaceutically acceptable excipients, wherein enteric coated granules comprise: a core granule comprising amorphous dexlansoprazole and one or more pharmaceutically acceptable excipients, a barrier coating layer on the core granule, a sustained release coating layer on the barrier coating layer comprising copolymers of methyl methacrylate and methacrylic acid ester with quaternary ammonium groups and an enteric coating layer on the sustained release coating layer, wherein enteric coating layer comprises methacrylic acid copolymer dispersion and at least one polymer selected from the group consisting of ethyl acrylate and methyl methacrylate copolymer dispersion, methacrylic acid-methyl acrylate-methyl methacrylate copolymer.
In another embodiment, an orally disintegrating tablet comprising enteric coated granules of average particle size more than 500 µm and one or more pharmaceutically acceptable excipients, wherein enteric coated granules comprise: a core granule comprising amorphous dexlansoprazole and one or more non-toxic bases or basic salts, a barrier coating layer surrounding the core granule, a sustained release coating layer surrounding the barrier coating layer and an an enteric coating layer surrounding the sustained release coating wherein, core comprises a non-toxic base or basic salt in an amount less than 0.2 part by weight based on part by weight of dexlansoprazole.
In another embodiment, an orally disintegrating tablet comprising enteric coated granules of average particle size greater than 500 µm and one or more pharmaceutically acceptable excipients, wherein enteric coated granules comprises: a core granule comprising amorphous dexlansoprazole and one or more non-toxic bases or basic salts, a barrier coating layer surrounding the core granule, a sustained release coating layer surrounding the barrier coating layer and an an enteric coating layer surrounding the sustained release coating layer wherein, core comprises potassium hydroxide in an amount less than 0.2 part by weight based on part by weight of dexlansoprazole.
The term "average particle size" is defined as volume median diameter (median diameter: a particle diameter corresponding to 50% of cumulative distribution).
The particle size can be measured using various commonly available methods such as laser diffraction particle size distribution measuring method, Malvern Zeta sizer, measurement using light (eg. light-scattering methods or turbidimetric methods), sedimentation methods (eg. pipette analysis using an Andreassen pipette, sedimentation scales, photo-sedimentometers or sedimentation in a centrifugal force), pulse methods (eg. Coulter counter), sieving method or sorting by means of gravitational or centrifugal force.
In another embodiment, orally disintegrating tablets of the present invention comprises enteric coated granules, wherein granules can be prepared by using one or more techniques such as wet, dry granulation, direct compression, fluidized bed processor or any other technique known in the art.
In another embodiment granules can be prepared by wet granulation, wherein granulation liquid can be aqueous, non-aqueous or hydroalcoholic.
In another embodiment, orally disintegrating tablets of the present invention comprises extragranular portion, wherin extragranular portion comprises pharmaceutical acceptable excipients but not limited to diluents, disintegrants, glidants, lubricants, flavouring agents, sweetening agents.
The term ‘pharmaceutically acceptable excipient(s)’ used in the orally disintegrating tablets of the present invention comprise but not limited to diluents, binders, disintegrants, glidants, lubricants, flavouring agents, sweetening agents.
The amount of excipient(s) employed will depend upon how much active agent is to be used. One excipient(s) can perform more than one function.
Binders as used in the present invention comprise but are not limited to, starches such as potato starch, wheat starch, corn starch; microcrystalline cellulose such as products known under the registered trademarks Avicel, Filtrak, Heweten or Pharmacel; celluloses such as hydroxypropyl cellulose, hydroxyethyl cellulose, hydroxypropylmethyl cellulose (HPMC), ethyl cellulose, Low Substituted Hydroxypropyl Cellulose, sodium carboxy methyl cellulose; natural gums like acacia, alginic acid, guar gum; liquid glucose, dextrin, povidone, syrup, polyethylene oxide, polyvinyl pyrrolidone, poly-N-vinyl amide, polyethylene glycol, gelatin, poly propylene glycol, tragacanth, combinations thereof and other materials known to one of ordinary skill in the art and mixtures thereof.
Fillers or diluents as used in the present invention comprise but not limited to microcrystalline cellulose, dextrin, dextrose, mannitol, sucrose, starch, lactose, xylitol, sorbitol and other materials known to one of ordinary skill in the art.
Lubricants as used in the present invention comprise but not limited to Mg, Al ,Ca or Zn stearate, polyethylene glycol, glyceryl behenate, mineral oil, sodium stearyl fumarate, stearic acid, hydrogenated vegetable oil, talc and other materials known to one of ordinary skill in the art.
Glidants as used in the present invention comprise but not limited to silicon dioxide; magnesium trisilicate, powdered cellulose, starch, talc and tribasic calcium phosphate, calcium silicate, magnesium silicate, colloidal silicon dioxide, silicon hydrogel and other materials known to one of ordinary skill in the art.
Disintegrants as used in the present invention comprise but not limited to starches; clays; celluloses; alginates; gums; cross-linked polymers, e.g., cross-linked polyvinyl pyrrolidone or crospovidone, e.g., POLYPLASDONE XL, cross-linked sodium carboxymethylcellulose or crosscarmellose sodium, e.g., AC-DI-SOL from FMC; cross-linked calcium carboxymethylcellulose; soy polysaccharides, sodium starch glycolate, guar gum and other materials known to one of ordinary skill in the art.
Examples of sweetening agents and flavouring agents comprises but not limited to sugar alcohols, sugars, liquid glucose, sucrose, sachharine sodium, aspartame, banana flavouring, vanilla flavouring, tutti frutty flavor, xylitol, sorbitol, mannitol, erythritol and other materials known to one of ordinary skill in the art.
Solvents as used in the present invention comprise but not limited to aqueous solvents such as water, non-aqueous such as inorganic sovents or hydroalcoholic such as ethanol, methanol.
The amount of dexlansoprazole in orally disintegrating tablets of the present invention will be suitable amount as known in the art; preferably the amount is 30 mg.
In another embodiment, orally disintegrating tablets according to the present invention is intended to be used for maintaining healing of erosive esophagitis and relief of heartburn and treating heartburn associated with (gastroesophageal reflux disease) GERD.
In another embodiment oral disintegration time for orally disintegrating tablets of the present invention is within 1 minute, preferably within 30 seconds.
In another embodiment orally disintegrating tablets of the present invention are uncoated.
In another embodiment orally disintegrating tablets of the present invention are stable throughout shelf life. Further, orally disintegrating tablets of the present invention have comparable in-vitro dissolution profile with marketed orally disintegrating tablets of dexlansoprazole (Dexilant SoluTab).
In another embodiment, orally disintegrating tablets of the present invention, wherein rate of release of dexlansoprazole from the composition is more than 10% for 5 hours in a solution of pH 6.0, and more than 5% for one hour and less than 60% for 8 hours in a solution of pH 6.8 using USP dissolution apparatus.
In another embodiment, orally disintegrating tablets of the present invention are bioequivalent to the marketed orally disintegrating tablets of dexlansoprazole which is DEXILANT SOLUTAB®.
In another embodiment, orally disintegrating tablets of the present invention have Cmax and AUC within the limit of 80% to 125% of Cmax and AUC of marketed orally disintegrating tablets of dexlansoprazole, wherein Cmax and AUC of marketed orally disintegrating tablets of dexlansoprazole is 688 ng/ml and 2866 ng.h/ml respectively.
The term "Cmax" as used herein, means maximum plasma concentration of Dexlansoprazole produced by the ingestion of the pharmaceutical composition of invention or the marketed Dexilant SoluTab. (Orally disintegrating tablets of Dexlansoprazole) composition. Cmax or peak plasma level may be used interchangeably.
The term "AUC" as used herein, means area under the plasma concentration-time curve of Dexlansoprazole produced by the ingestion of the pharmaceutical composition of invention or the marketed Dexilant SoluTab (Orally disintegrating tablets of Dexlansoprazole).
In another embodiment, a process of preparing stable orally disintegrating tablets comprising enteric coated granules of average particle size greater than 500 µm and one or more pharmaceutically acceptable excipients, wherein the process comprises steps of
(i) preparing core granule comprising amorphous dexlansoprazole by spraying dispersion of dexlansoprazole and one or more pharmaceutically acceptable excipients in a solvent, on an inert core,
(ii) preparing the dispersion of pharmaceutically acceptable excipients in a solvent and spraying it on core granules of step (i) to get barrier coated granules,
(iii) preparing the dispersion of pharmaceutically acceptable excipients in a solvent and spraying it on barrier coated granules of step (ii) to get enteric coated granules,
(iv) blending the enteric coated granules of step (iii) with extragranular portion comprising one or more pharmaceutically acceptable excipients,
(v) compressing the blend of step (iv) to get a tablet.
In another embodiment, a process of preparing stable orally disintegrating tablets comprising enteric coated granules of average particle size greater than 500 µm and one or more pharmaceutically acceptable excipients, wherein the process comprises steps of
(i) preparing core granules comprising amorphous dexlansoprazole by spraying dispersion of dexlansoprazole and one or more pharmaceutically acceptable excipients in a solvent, on an inert core,
(ii) preparing the dispersion of pharmaceutically acceptable excipients in a solvent and spraying it on core granules of step (i) to get barrier coated granules,
(iii) preparing the dispersion of pharmaceutically acceptable excipients in a solvent and spraying it on barrier coated granules of step (ii) to get sustained release coated granules,
(iv) preparing the dispersion of pharmaceutically acceptable excipients in a solvent and spraying it on sustained release coated granules of step (iii) to get barrier coated granules,
(v) preparing the dispersion of pharmaceutically acceptable enteric excipients in a solvent and spraying it on barrier coated granules of step (iv) to get enteric coated granules,
(vi) blending the enteric coated granules of step (v) with extragranular portion comprising one or more pharmaceutically acceptable excipients,
(vii) compressing the blend of step (vi) to get a tablet.
The following examples are illustrative of the present invention, and the examples should not be considered as limiting the scope of this invention in any way, as these examples and other equivalents thereof will become apparent to those versed in the art, in the light of the present disclosure, and the claims.
Examples:
Example 1 –
Formula for enteric coated granules:
Sr. No. Ingredients %w/w

Stage I: Drug loading
1 Microcrystalline Cellulose NF 11.175
2 Dexlansoprazole 9.579
3 Hydroxypropyl Cellulose NF 4.789
4 Potassium Hydroxide 1.277
5 Crosscarmellose 1.916
6 Solvent Q.S.
Stage II: Barrier coating (25%w/w)
7 Drug loaded granules
8 Hypromellose 2910 USP 4.023
9 Sodium Starch Glycolate NF 1.437
10 Talc USP 0.862
11 Titanium Dioxide USP 0.862
12 Solvent Q.S.
Stage III: Eudragit RL 30D coating (16%w/w)
13 Barrier coated granules
14 Eudragit RL 30D 3.382
15 Triethyl Citrate NF 0.675
16 Talc USP 1.690
17 Purified Water USP Q.S.
Stage IV: Barrier coating (20%w/w)
18 Eudragit RL 30D coated granules
19 Hypromellose 2910 USP 4.667
20 Croscarmellose Sodium NF 1.667
21 Talc USP 1.000
22 Titanium Dioxide USP 1.000
23 Purified Water USP Q.S.
Stage V: Enteric coating (100%w/w)
24 Barrier coated pellets
25 Methacrylic Acid Copolymer dispersion (Eudragit L30D55) 41.259

26 1 N NaOH to adjust pH Q.S.
27 Ethyl acrylate and Methyl Methacrylate Copolymer dispersion (Eudragit NE30D) 2.172

28 20%w/w Citric Acid solution to adjust pH Q.S.
29 Plasacryl HTP 20 (emulsion of Glycerol Monostearate, Triethyl Citrate and Polysorbate 80) 6.515
30 Ferric Oxide Yellow NF 0.027
31 Ferric Oxide Red NF 0.027
32 Purified Water USP Q.S.
Total weight of enteric coated pellets 100.000

Procedure:
Stage I: Drug loading:
1. Dissolve Dexlansoprazole, Potassium Hydroxide, Hydroxypropyl Cellulose in solvent.
2. Disperse Croscarmellose Sodium in step 1 solution under stirring.
3. Load Celphere in wurster coater bowl. Fluidize the material and spray entire dispersion of step 2 under proper atomization and bed temperature.
Stage II: Barrier coating:
1. Dissolve Hypromellose in solvent.
2. Disperse disintegrant, Talc, Titanium Dioxide in step 1 solution.
3. Load drug loaded pellets in wurster coater bowl. Fluidize the material and spray entire dispersion of step 2 under proper atomization and bed temperature.
Stage III: Eudragit RL 30D coating:
1. Homogenize Triethyl Citrate and Talc in Purified Water and add to Eudragit RL 30D dispersion under stirring.
2. Load barrier coated pellets in wurster coater bowl. Fluidize the material and spray entire dispersion of step 1 under proper atomization and bed temperature.
Stage IV: Barrier coating:
1. Dissolve Hypromellose in solvent.
2. Disperse disintegrant, Talc, Titanium Dioxide in step 1 solution.
3. Load Eudragit RL 30D coated pellets in wurster coater bowl. Fluidize the material and spray entire dispersion of step 2 under proper atomization and bed temperature.
Stage 5: Enteric coating:
1. Adjust pH of Eudragit L30 D 55 dispersion to 5 using 1 N NaOH solution.
2. Adjust pH of Eudragit NE30D dispersion to 5 using 20%w/w Citric Acid solution.
3. Add step 2 dispersion to step 1 dispersion under stirring.
4. Add Plasacryl HTP 20 to step 2 dispersion.
5. Homogenize Ferric Oxide Yellow and Ferric Oxide Red in Purified Water and add to step 4 dispersion.
6. Add remaining quantity of Purified Water to step 5 dispersion.
7. Load Barrier coated pellets in wurster coater bowl. Fluidize the material and spray entire dispersion of step 6 under proper atomization and bed temperature.

Example 2 –
Formula for enteric coated granules:
Sr. No. Ingredients %w/w

Stage I: Drug loading
1 Microcrystalline Cellulose NF 15.556
2 Dexlansoprazole 13.333
3 Hydroxypropyl Cellulose NF 6.667
4 Potassium Hydroxide 1.778
5 Croscarmellose Sodium NF 2.667
6 Solvent Q.S.
Weight of drug loaded pellets
Stage II: Barrier coating (25%w/w)
7 Drug loaded pellets
8 Hypromellose USP 5.600
9 Croscarmellose Sodium NF 2.000
10 Talc USP 1.200
11 Titanium Dioxide USP 1.200
12 Solvent 0.000
Weight of barrier coated pellets
Stage V: Enteric coating (100%w/w)
13 Barrier coated pellets
14 Methacrylic Acid Copolymer dispersion (Eudragit L30D55) 26.058
15 1 N NaOH to adjust pH Q.S.
16 Ethyl acrylate and Methyl Methacrylate Copolymer dispersion (Eudragit NE30D) 17.372
17 20%w/w Citric Acid solution to adjust pH 0.000
18 Plasacryl HTP 20 (emulsion of Glycerol Monostearate, Triethyl Citrate and Polysorbate 80) 6.515
19 Ferric Oxide Yellow NF 0.028
20 Ferric Oxide Red NF 0.028
21 Purified Water USP Q.S.
Total weight of enteric coated pellets 100.000

Procedure:
Stage I: Drug loading:
1. Dissolve Dexlansoprazole, Potassium Hydroxide, Hydroxypropyl Cellulose in Ethanol/Methanol.
2. Disperse Croscarmellose Sodium in step 1 solution under stirring.
3. Load Celphere in wurster coater bowl. Fluidize the material and spray entire dispersion of step 2 under proper atomization and bed temperature.
Stage II: Barrier coating:
1. Dissolve Hypromellose in solvent.
2. Disperse disintegrant, Talc, Titanium Dioxide in step 1 solution.
3. Load drug loaded pellets in wurster coater bowl. Fluidize the material and spray entire dispersion of step 2 under proper atomization and bed temperature.
Stage 3: Enteric coating:
1. Adjust pH of Eudragit L30 D 55 dispersion to 5 using 1 N NaOH solution.
2. Adjust pH of Eudragit NE30D dispersion to 5 using 20%w/w Citric Acid solution.
3. Add step 2 dispersion to step 1 dispersion under stirring.
4. Add Plasacryl HTP 20 to step 2 dispersion.
5. Homogenize Ferric Oxide Yellow and Ferric Oxide Red in Purified Water and add to step 4 dispersion.
6. Add remaining quantity of Purified Water to step 5 dispersion.
7. Load Barrier coated pellets in wurster coater bowl. Fluidize the material and spray entire dispersion of step 6 under proper atomization and bed temperature.
Example for compression:
Sr. No. Ingredients %w/w
1. Enteric coated pellets of example 1 or 2 62.640
2. Mannitol USP 19.129
3. Crospovidone NF 8.400
4. Microcrystalline Cellulose NF 5.682
5. Colloidal Silicon Dioxide NF 0.840
6. Aspartame NF 1.729
7. Strawberry Flavor 0.530
8. Magnesium Stearate NF 1.050
Total weight of tablet 100.000

Procedure:
1. Mix and sift Mannitol, disintegrant, Microcrystalline Cellulose, Colloidal Silicon Dioxide, Aspartame, Strawberry Flavor through 40 mesh s.s. sieve and mix again.
2. Mix step 1 material with enteric coated pellets in blender for 25 minutes at 5 rpm.
3. Sift Magnesium Stearate through 60 mesh s.s. sieve and mix with step 2 material in blender for 3 minutes at 5 rpm.
4. Compress blend of step 3 in to tablets using suitable punch.
,CLAIMS:1. A stable orally disintegrating tablet comprising enteric coated granules of average particle size greater than 500 µm and one or more pharmaceutically acceptable excipients, wherein the enteric coated granule comprises
(i) core granule comprising amorphous dexlansoprazole and one or more non-toxic bases or basic salts,
(ii) a barrier coating layer surrounding the core granule of step (i)
(iii) an enteric coating layer surrounding the barrier coating of step (ii), wherein enteric coating layer comprises methacrylic acid copolymer and at least one polymer selected from the group consisting of ethyl acrylate and methyl methacrylate copolymer, methacrylic acid-methyl acrylate-methyl methacrylate copolymer;

2. The composition of claim 1, wherein core comprises non-toxic base included in an amount less than 0.2 part by weight based on one part by weight of dexlansoprazole.

3. The composition of claim 1, wherein core comprises non-toxic base or basic salts comprises magnesium hydroxide, potassium hydroxide, alkali metal salts such as sodium salt and potassium salt; alkaline earth metal salts such as calcium salt and magnesium salt; ammonium salt and the like, alkylamine, a heterocyclic amine, an alkanolamine, dicyclohexylamine, N,N' dibenzylethylenediamine.

4. The composition of claim 1, wherein the rate of release of dexlansoprazole from the composition is 10% or more for 5 hours in a solution of pH 6.0, and 5% or more for one hour and 60% or less for 8 hours in a solution of pH 6.8 using USP dissolution apparatus.
5. The composition of claim 1, wherein the composition has Cmax and AUC are within the limit of Cmax and AUC of orally disintegrating tablet of dexlansoprazole.

6. A stable orally disintegrating tablet comprising enteric coated granules of average particle size greater than 500 µm and one or more pharmaceutically acceptable excipients, wherein the enteric coated granule comprises
(i) core granule comprising amorphous dexlansoprazole and one or more non-toxic bases or basic salts,
(ii) a barrier coating layer on the core granule,
(iii) a sustained release coating on the barrier coating comprising copolymers of methyl methacrylate and methacrylic acid ester with quaternary ammonium groups and
(iv) an enteric coating layer on the barrier coating, wherein enteric coating layer comprises methacrylic acid copolymer dispersion and at least one polymer selected from the group consisting of ethyl acrylate and methyl methacrylate copolymer dispersion, methacrylic acid-methyl acrylate-methyl methacrylate copolymer;
and extragranular part comprising pharmaceutically acceptable excipients.

7. The composition of claim 5, wherein base comprises a base included in an amount less than 0.2 part by weight based on one part by weight of dexlansoprazole.

8. The composition of claim 5, wherein the rate of release of dexlansoprazole from the composition is 10% or more for 5 hours in a solution of pH 6.0, and 5% or more for one hour and 60% or less for 8 hours in a solution of pH 6.8 using USP dissolution apparatus.

9. The composition of claim 6, wherein the composition has Cmax and AUC are within the limit of Cmax and AUC of orally disintegrating tablet of dexlansoprazole.

10. The composition of claim 1, has disintegration time of 30 seconds or less.

11. The process of preparing stable orally disintegrating tablet comprising enteric coated granules of average particle size greater than 500 µm of claim 1, wherein the process comprises steps of
(i) preparing core granule comprising amorphous dexlansoprazole by spraying dispersion of dexlansoprazole on an inert core,
(ii) preparing the dispersion of pharmaceutically acceptable polymers and spraying it on core granules of step (i) to get barrier coated granules,
(iii) preparing the dispersion of pharmaceutically acceptable enteric polymers and spraying it on barrier coated granules of step (ii) to get enteric coated granules,
(iv) blending the enteric coated granules of step (iii) with extragranular portion comprising one or more pharmaceutically acceptable excipients,
(v) compressing the blend of step (iv) to get a tablet.

12. A stable orally disintegrating tablet comprising enteric coated granules of average particle size greater than 500 µm, wherein enteric coated granule comprises
(i) core granule comprising amorphous dexlansoprazole comprising hydrophilic polymers and non-toxic inorganic base
(ii) a barrier coating layer on the core granule and
(iii) an enteric coating layer on the barrier coating, wherein enteric coating layer comprises methacrylic acid copolymer dispersion and ethyl acrylate and methyl methacrylate copolymer dispersion;
and extragranular part comprising one or more pharmaceutically acceptable excipients.

13. A stable orally disintegrating tablet comprising enteric coated granules of average particle size greater than 500 µm, wherein enteric coated granule comprises
(i) core granule comprising amorphous dexlansoprazole comprising hydrophilic polymers and non-toxic inorganic base
(ii) a barrier coating layer on the core granule and
(iii) an enteric coating layer on the barrier coating, wherein enteric coating layer comprises methacrylic acid copolymer dispersion and methacrylic acid-methyl acrylate-methyl methacrylate copolymer.