DESC:FIELD OF THE INVENTION
The invention relates to a pharmaceutical composition comprising esomeprazole or pharmaceutically acceptable salt thereof. Specifically the invention relates to a pharmaceutical composition providing a biphasic release of esomeprazole or a salt thereof. The invention also relates to a process of preparation of such composition.
BACKGROUND OF INVENTION
Many active pharmaceutical agents, including drugs and prodrugs, have been formulated as orally deliverable dosage forms providing sustained release (otherwise known as slow release or extended release) of such agents over a period of time effective to permit once daily administration. In particular, number of drug delivery and release systems have been developed that influence the control of drug release.
Proton pump inhibitors (PPIs) are highly effective gastric secretion inhibitors. They are a group of acid-unstable physiologically active antisecretory compounds that do not exhibit anticholinergic or histamine H2 -receptor antagonist properties. Examples of PPIs include omeprazole, esomeprazole, lansoprazole, rabeprazole, pantoprazole, pariprazole, lemiprazole, tenatoprazole, nepaprazole, and ilaprazole. Worldwide clinical experience with PPIs in recent years has established their effectiveness in treating acid reflux-related diseases, including gastric and duodenal ulcers, gastroesophageal reflux disease (GERD), and even erosive esophagitis.
Extended-release dosage forms for once-daily oral administration of PPIs are available, though such dosage forms do not effectively control gastroesophageal symptoms over the full course of a day. Due to the short plasma half-lives of PPIs, a single "pulse" or release of a PPI from a dosage form (even extended release) typically does not provide relief over 24 hours. This shortcoming of currently available PPI dosage forms allows gastro-esophageal symptoms to "breakthrough" when PPI plasma levels drop below therapeutic range.

Esomeprazole,(S)-(-)-5-Methoxy-2-[(4-methoxy-3,5-dimethylpyridin-2yl) methyl sulfinyl]-3H-benzoimidazole is a proton pump inhibitor which reduces stomach acid secretion through inhibition of the H+/K+-ATPase in the parietal cells of the stomach. By inhibiting the functioning of this transporter, the drug prevents formation of stomach acid. It is used in the treatment of dyspepsia, peptic ulcer disease, gastroesophageal reflux disease, and Zollinger-Ellison syndrome

U.S. Publication No. 20060165797 discloses oral forms of PPI wherein PPI (omeprazole) is present in outer coat and inner delayed release coat. The outer coat is not enteric coated and quickly dissolves in the stomach of a patient immediately after ingestion (60 min). PCT Publication No. WO1999/032093 discloses enteric coated dosage forms of PPI (omeprazole) with pulsed delayed release and instant release fraction wherein the portions are released in time by from 0.5 up to 4 or 8 or 12 hours interval. WO 2006/049565 discloses solid forms of PPI (esomeprazole) comprising delayed and immediate release tablets with lag time of 1-10 hours. WO 2004/071374 discloses pharmaceutical compositions for once a day oral administration, comprising at least one delayed release component, wherein said delayed release component comprises a proton pump inhibitor (esomeprazole), said composition further including at least one immediate release and/or a sustained release prokinetic agent. US 20120128764 discloses a pharmaceutical composition comprising a first population and second population comprising controlled release PPI (esomeprazole) composition provides a lag time of from about 1 hour to about 6 hours, followed by release of said proton pump inhibitor over a period of from about 2 hours to about 6 hours.
All proton pump inhibitors found in conventional gastroresistant (Delayed release) type of dosage forms, which requires to take medicine before meal every time. The inventors of the invention have surprisingly found that preparation of a pharmaceutical composition comprising pulsatile delivery of proton pump inhibitors having two pulse deliveries wherein first pulse is conventional and second pulse releases medicines after 6-10 hours lag time which reduces frequency of administration as well as provide patient compliance.

SUMMARY OF THE INVENTION
In one general aspect, there is provided a pharmaceutical composition comprising esomeprazole or pharmaceutically acceptable salt thereof.
In another general aspect, there is provided a pharmaceutical composition comprising esomeprazole or pharmaceutically acceptable salt thereof and one or more pharmaceutically acceptable excipients.
In another general aspect, there is provided a pharmaceutical composition providing a biphasic release of esomeprazole or a salt thereof; said composition comprises (a) a first component comprising about 17 % w/w to about 27 % w/w esomeprazole or a salt thereof, sodium chloride and one or more pharmaceutically acceptable excipients; and (b) a second component comprising about 15 % w/w to about 25 % w/w esomeprazole or a salt thereof, sodium chloride, a pulsatile release coat; and one or more pharmaceutically acceptable excipients; wherein the second component provides release of esomeprazole or salt thereof after a lag period of about 6 hours to about 10 hours from release of the first component, when tested in USP Type I Dissolution Test Apparatus containing 900 ml of phosphate buffer having pH 6.8 to 7.4 at about 37ºC. In one embodiment of this aspect, weight ratio of esomeprazole or a salt thereof to sodium chloride is about 1:0.1 or about 1:0.15 present in the first component and the second component. In another embodiment of this aspect, the first and second component further comprises an alkaliser seal coat of about 0.55 % to about 0.65% w/w or about 0.60 % w/w of sodium bicarbonate. In another embodiment of this aspect a pulsatile release coat in the second component comprises about 5% to about 10% of ethyl cellulose. In another embodiment of this aspect, the pulsatile release coat in the second component comprises about 7.1% of ethyl cellulose surrounding the alkaliser seal coat. In another embodiment of this aspect, the second component further comprises a delayed release coat surrounding the pulsatile release coat, containing about 7.1% w/w of methacrylic acid copolymer.

In another general aspect, there is provided A pharmaceutical composition providing a biphasic release of esomeprazole or a salt thereof; said composition comprises (a) a first component comprising (i) 20.65 mg of esomeprazole or a salt thereof, (ii) 0.1 mg polysorbate 80, (iii) 6 mg croscarmellose sodium, (iv) 2mg sodium chloride; and (v) an alkaliser seal coat that comprises 0.6 mg of sodium bicarbonate; and b) a second component comprising (i) 20.65 mg of esomeprazole or a salt thereof, (ii) 0.1 mg polysorbate 80, (iii) 6mg croscarmellose sodium, (iv) 2mg sodium chloride; (v) an alkaliser seal coat that comprises 0.6 mg of sodium bicarbonate; (vi) a pulsatile release coat that comprises 7.2mg ethyl cellulose, and 0.96 mg polysorbate 80; and (vii) a delayed release coat that comprises 7.20 mg methacrylic acid copolymer. In another embodiment of this aspect, the composition is in the form of a tablet, capsule, bilayer tablet, trilayer tablet, multilayer tablet, tablet in capsule, tablets in capsule or tablet in tablet.

In another general aspect, there is provided a pharmaceutical composition; wherein the composition is present in the form of powder, tablets, dispersible tablet, pellets, capsules, granules or pellets filled in capsule, tablet in capsule, multilayer tablet, bilayer tablet, trilayer tablet, minitablets or premixed powder filled in capsule.

In another general aspect, there is provided a pharmaceutical composition; wherein the composition is present in the form of tablet filled in capsule
In another general aspect, there is provided a pharmaceutical composition for treatment of dyspepsia, peptic ulcer disease, gastroesophageal reflux disease, and Zollinger-Ellison syndrome.
In another general aspect, there is provided a process of preparation of pharmaceutical composition comprising esomeprazole or pharmaceutically acceptable salt thereof.
DETAILED DESCRIPTION OF THE INVENTION
The term "esomeprazole" used throughout the specification refers to not only esomeprazole per se, but also their other pharmaceutically acceptable salts, pharmaceutically acceptable solvates, pharmaceutically acceptable hydrates, pharmaceutically acceptable enantiomers, pharmaceutically acceptable derivatives, pharmaceutically acceptable polymorphs or pharmaceutically acceptable prodrugs thereof.
“Pharmaceutical composition” or “pharmaceutical formulation” or “pharmaceutical dosage form” can be used interchangeably and refers to the combination of one or more active ingredients and one or more excipients.
“Pharmaceutically acceptable salt” refers to salts derived from a variety of organic and inorganic counter ions well known in the art and includes any pharmaceutically acceptable salt soluble in water to form an aqueous solution.
“Pharmaceutically acceptable excipient” refers to non-active pharmaceutical ingredient substances which are within the scope of sound medical judgment suitable for use in formulating pharmaceutical products.
The term biphasic release or pulsatile release refers to a system having release of active in two pulses, where the first pulse releases active in a conventional delayed release manner that is immediately after passing stomach and second pulse releases active after about 6 hours to about 10 hours lag time from the first release.
The term lag time or lag period refers to a time period between the release of active from first pulse and release of active from the second pulse.
The compositions of the invention can be prepared together with at least one pharmaceutically acceptable excipient or as oral, parental, inhalation dosage forms comprising the active agent. The pharmaceutical compositions of the invention can be prepared in solid forms comprising tablet; capsule; enterically coated or modified-release tablets; controlled-release tablet, extended-release tablet; delayed-release tablet; slow or fast-release tablet; fast soluble tablet; effervescent tablet; effervescent granule; fast soluble powder mixture; water-soluble powder, tablet, or granule; granule; pellet; mini tablet; micro tablet; granule in capsule; pellet in capsule; mini tablet in capsule; micro tablet in capsule or dry powder mixture to prepare syrup; orodispersible tablet; film tablet or combinations thereof; or in any one of liquid forms such as syrup or suspension.
In general embodiment there is provided a solid pharmaceutical composition comprising esomeprazole or pharmaceutically acceptable salt thereof.
In another embodiment, there is provided a pharmaceutical composition comprising esomeprazole or pharmaceutically acceptable salt thereof and one or more pharmaceutically acceptable excipients.
In another embodiment, there is provided a pharmaceutical composition providing a biphasic release of esomeprazole or a salt thereof; said composition comprises, (a) a first component comprising a core, said core comprises esomeprazole or a salt thereof and one or more pharmaceutically acceptable excipients; wherein the first component provides release of esomeprazole or salt thereof at about 2 hours to about 3 hours; (b) a second component comprising a core, said core comprises esomeprazole or a salt thereof and one or more pharmaceutically acceptable excipients; wherein the second component provides release of esomeprazole or salt thereof after a lag of about 6 hours to about 10 hours from release of first component; wherein a weight ratio of esomeprazole or a salt thereof present in the first component to the second component is about 1:1
In another embodiment there is provided, a pharmaceutical composition providing a biphasic release of esomeprazole or a salt thereof; said composition comprises (a) a first component comprising (i) about 17 % w/w to about 27 % w/w esomeprazole or a salt thereof, (ii) sodium chloride and, (iii) one or more pharmaceutically acceptable excipients; and (b) a second component comprising (i) about 15 % w/w to about 25 % w/w esomeprazole or a salt thereof (ii) sodium chloride; and (iii) a pulsatile release coat and one or more pharmaceutically acceptable excipients; wherein the second component provides release of esomeprazole or salt thereof after a lag period of about 6 hours to about 10 hours from release of the first component, when tested in USP Type I Dissolution Test Apparatus containing 900 ml of phosphate buffer having pH 6.8 to 7.4 at about 37ºC.
In another embodiment, the first component comprising about 18 % w/w to about 25 % w/w, or about 20% w/w to about 23% w/w esomeprazole or a salt thereof and one or more pharmaceutically acceptable excipients.
In another embodiment, the second component comprising about 15 % w/w to about 25 % w/w or about 18% w/w to about 24% w/w, or about 20% w/w to about 22% w/w of esomeprazole or a salt thereof and one or more pharmaceutically acceptable excipients.
In another embodiment, a weight ratio of esomeprazole or a salt thereof to sodium chloride is about 1:0.1 or about 1:0.15 present in the first component and the second component.

In another embodiment, a weight ratio of esomeprazole or a salt thereof contained in the first component to that of the second component is about 1:1.
In another embodiment, the first and second component further comprises an alkaliser seal coat containing about 0.55 % to about 0.65% w/w or about 0.60 % w/w of sodium bicarbonate.
In another embodiment, the alkaliser seal coat further comprises of about 0.80% w/w to about 1.2% w/w of hypromellose, about 0.15% w/w to about 0.25% w/w of polyethylene glycol, and one or more pharmaceutically acceptable excipients.
In another embodiment, the second component further comprises a pulsatile release coat and one or more pharmaceutically acceptable excipients.
In another embodiment, the pulsatile release coat in the second component comprises about 5% to about 10%, or about 6% to about 8%, or about 7.1% of ethyl cellulose surrounding the alkaliser seal coat.
In another embodiment, the pulsatile release coat further comprises of about 1.7% w/w to about 2.3% w/w of hypromellose, about 3.7% w/w to about 4.3% w/w of glyceryl behenate, about 0.7%w/w to about 1.3% w/w of polysorbate 80, and one or more pharmaceutically acceptable excipients.
In another embodiment, a weight ratio of ethyl cellulose to glyceryl behenate present in the pulsatile release coat is about 1:0.55.
In another embodiment, the second component further comprises a delayed release coat surrounding the pulsatile release coat, containing about 5% to about 10%, or about 6% to about 8%, or about 7.1% w/w of methacrylic copolymer.
In another embodiment, the delayed release coat further comprises of about 6.8% w/w to about 7.3% w/w of triethyl citrate, and one or more pharmaceutically acceptable excipients.
In another embodiment, the first component provides release of esomeprazole or salt thereof after 2 hours of administration in a delayed release manner, when tested in USP Type I Dissolution Test Apparatus containing 900 ml of phosphate buffer having pH 6.8 at about 37ºC.
In another embodiment, the second component provides release of esomeprazole or salt thereof after a lag period of about 6 hours to about 10 hours, or about 7 hours to about 9 hours, or about 8 hours to about 9 hours from release of the first component, when tested in USP Type I Dissolution Test Apparatus containing 900 ml of phosphate buffer having pH 7.4 at about 37ºC.

In another embodiment, the first component provides about 90 % to about 100% release of contained esomeprazole or salt thereof at about 3 hours when tested in USP Type I Dissolution Test Apparatus containing 900 ml of phosphate buffer having pH 6.8 at about 37ºC; and the second component provides about 75% release of contained esomeprazole or salt thereof at about 13 hours when tested in USP Type I Dissolution Test Apparatus containing 900 ml of phosphate buffer having pH 7.4 at about 37ºC.
In another embodiment, there is provided a pharmaceutical composition providing a biphasic release of esomeprazole or a salt thereof; said composition comprises (a) a first component comprising (i) 20.65 mg of esomeprazole or a salt thereof, (ii) 0.1 mg polysorbate 80, (iii) 6 mg croscarmellose sodium, (iv) 2mg sodium chloride; and (v) an alkaliser seal coat that comprises 0.6 mg of sodium bicarbonate; and (b) a second component comprising (i) 20.65 mg of esomeprazole or a salt thereof, (ii) 0.1 mg polysorbate 80, (iii) 6mg croscarmellose sodium, (iv) 2mg sodium chloride; (v) an alkaliser seal coat that comprises 0.6 mg of sodium bicarbonate; (vi) a pulsatile release coat that comprises 7.2mg ethyl cellulose, and 0.96 mg polysorbate 80; and (vii) a delayed release coat that comprises 7.20 mg methacrylic acid copolymer.
In another embodiment the pharmaceutical composition is stable for six months at 40ºC with 75% related humidity.
In another embodiment, the composition is in the form of a tablet, capsule, bilayer tablet, trilayer tablet, multilayer tablet, tablet in capsule, tablets in capsule or tablet in tablet
The pharmaceutically acceptable excipients for composition can be selected from a group comprising one or more binding agents (binders), disintegrants, lubricants, one or more diluents, glidants, wetting agents, coating agents, anti-adhesive agents, swelling agent, viscosity enhancing agents, filling agents, drying agents, rate controlling polymer agent, surfactants, cosolvents, acidifier, alkaliser, stabilizing agents, pH regulators, flavouring agent, sweeteners, emulgators, antifoaming agents, antioxidants, protective agents, solvents or solvent combinations, colouring agents and complexing agents or the combinations thereof.
The disintegrants that can be used in the pharmaceutical compositions of the invention can be selected from a group comprising carboxymethyl cellulose, carboxymethyl cellulose calcium, carboxymethyl cellulose sodium, croscarmellose sodium, crospovidone, hydroxypropyl cellulose, microcrystalline cellulose, methyl cellulose, chitosan, starch, sodium starch glycolate or combinations thereof. Preferably the disintegrant is croscarmellose sodium in the range of about 5.5% w/w to about 6.5% w/w.
The binders that can be used in the pharmaceutical compositions of the invention can be selected from a group comprising carboxymethyl cellulose sodium, ethyl cellulose, gelatin, hydroxyethyl cellulose, hydroxymethyl cellulose, hydroxypropyl cellulose, hypromellose, magnesium aluminum silicate, maltodextrin, methyl cellulose, povidone, copovidone, starch or combinations thereof. Preferably the binder is povidone in the range of about 1.25% w/w to about 1.75% w/w.
The diluents that can be used in the pharmaceutical compositions according to the invention can be selected from a group comprising calcium carbonate, dibasic calcium phosphate, tribasic calcium phosphate, calcium sulphate, microcrystalline cellulose, dextrose, fructose, lactitol, lactose, magnesium carbonate, magnesium oxide, maltitol, maltodextrin, maltose, mannitol, simethicone, sorbitol, starch and starch derivatives, sodium chloride, sucrose, talc, xylitol or the combinations thereof. Preferably the diluent is microcrystalline cellulose in the range of about 20% w/w to about 27% w/w.
The lubricants that can be used in the pharmaceutical compositions of the invention can be selected from a group comprising calcium stearate, magnesium stearate, polyethylene glycol, sodium benzoate, potassium benzoate, sodium lauryl sulphate, talc, stearic acid, zinc stearate or combinations thereof. Preferably the lubricant is magnesium stearate in the range of 1.25% w/w to about 1.5% w/w.
The glidants that can be used in the pharmaceutical compositions according to the invention can be selected from but not limited to colloidal silicon dioxide, calcium silicate, magnesium silicate, silicon hydrogel, silicified microcrystalline cellulose magnesium trisilicate, cornstarch, talc and the like or combinations thereof. Preferably the glidant is colloidal silicon dioxide in the range of 0.35% w/w to about 0.5% w/w of and/or silicified microcrystalline cellulose in the range of about 9.5% w/w to about 11.5% w/w.
The alkalizer are selected, but not limited to sodium hydroxide, potassium hydroxide, calcium hydroxide, magnesium hydroxide, sodium carbonate, sodium bicarbonate, calcium carbonate, magnesium oxide, magnesium carbonate, magnesium hydrogen carbonate, aluminum hydroxide, magnesium hydroxide, magnesium silicate, magnesium aluminate or aluminum magnesium hydroxide, sodium citrate, pharmaceutically acceptable salt of phosphoric acid such as tribasic calcium phosphate or mixtures thereof. Preferably the alkalizer is sodium bicarbonate in the range of about 0.55% w/w to about 0.65% w/w.
The film forming polymers are selected from the group comprising cellulose derivatives such as methylcellulose, hydroxymethyl cellulose, hydroxyethyl cellulose, hydroxypropyl cellulose, hydroxymethyl ethylcellulose, hydroxypropyl methylcellulose, sodium carboxymethyl cellulose, and ethyl cellulose; vinyl polymers such as polyvinylpyrrolidones; acrylic polymers; and mixtures thereof. Alternatively, commercially available coating compositions comprising film forming polymers marketed under various trade names.
In another embodiment, there is provided a pharmaceutical composition; wherein the composition is present in the form of powder, tablets, dispersible tablet, pellets, capsules, granules or pellets filled in capsule, tablet in capsule, multilayer tablet, bilayer tablet, trilayer tablet, minitablets or premixed powder filled in capsule.

In another embodiment, there is provided a pharmaceutical composition; wherein the composition is present in the form of tablet in capsule.
In another general embodiment, there is provided a process of preparation of solid composition comprising esomeprazole or pharmaceutically acceptable salt thereof.
The pharmaceutical compositions of the invention are prepared by wet or dry processing methods. In general aspect of the invention the pharmaceutical compositions are prepared by dry mix processing methods. In another general aspect the pharmaceutical compositions are prepared by dry processing methods. In a class of this aspect the pharmaceutical compositions are prepared by direct compression or dry granulation methods.
In another embodiment, there is provided a process of preparation of a pulsatile release pharmaceutical composition comprising esomeprazole or salt thereof; wherein said process comprises steps of: A) preparing a pulsatile release esomeprazole tablet, B) preparing a delayed release esomeprazole tablet, and C) filing the tablet of step (A) and (B) in a capsule to obtain the pulsatile release pharmaceutical composition.
In another embodiment, the pulsatile release esomeprazole tablet is obtained by following steps:
a) preparing a dry mixture blend of esomeprazole or salt thereof with other pharmaceutical excipients,
b) granulating the dry mixture of step (a) with a binder solution,
c) drying, lubricating and compressing the granules obtained from step (b) to obtain a tablet,
d) coating the tablet of step (c) with an alkaliser seal coat comprising sodium bicarbonate, hypromellose and polyethylene glycol (6000) in purified water followed by a protective seal coat,
e) coating the protective seal coat of step (d) with a pulsatile release coat comprising ethyl cellulose, hypromellose, polysorbate 80 and glyceryl behenate in isopropyl alcohol and dichloromethane,
f) coating the pulsatile release coat of step (e) with a delayed release coat comprising Eudragit S-100 and triethyl citrate in isopropyl alcohol and purified water, and
g) film coating over the coat of step (f) to obtain the pulsatile release esomeprazole tablet.
In another embodiment, there is provided a process of preparation of the delayed release esomeprazole tablet; wherein said process comprises steps of:
a) preparing of a dry mixture blend of esomeprazole with other pharmaceutical excipients,
b) granulating the dry mixture of step (a) with a binder solution,
c) drying, lubricating and compressing the granules obtained from step (b) to obtain a tablet
d) coating the tablet obtained from step (c) with alkaliser seal coat comprising sodium bicarbonate, hypromellose and polyethylene glycol (6000) in purified water followed by a protective seal coat, and an enteric coat,
e) film coating over the coat of step (d) to obtain the delayed release esomeprazole tablet.
In another embodiment, the pulsatile release esomeprazole capsule is prepared by following steps:
a) filling capsule size ‘0’ with one pulsatile release esomeprazole tablet and one delayed release esomeprazole tablet using capsule filling machine, and
b) packaging the capsule obtained in step (a) in Alu-Alu blister pack to obtain the pulsatile release esomeprazole capsule.
The pharmaceutical compositions obtained by the dry or wet processing methods and may be compressed into tablets, encapsulated, or metered into sachets.
The term "tablet" as used herein is intended to encompass compressed pharmaceutical dosage formulations of all shapes and sizes, whether coated or uncoated.
In another embodiment, there is provided a method of treating dyspepsia, peptic ulcer disease, gastroesophageal reflux disease, and Zollinger-Ellison syndrome in a patient which method comprising administering the pharmaceutical composition in accordance with the invention.
In another embodiment, the pharmaceutical composition is packed in Alu-Alu blister pack.
The 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 invention.
EXAMPLES
Example 1A: Pulsatile Release Esomeprazole Tablet 20 mg:
Sr. No. Name of Ingredients Unit qty. (mg) %W/W
Dry mixing
1. Esomeprazole Magnesium Trihydrate 20.65 20.45
2. Microcrystalline cellulose 23.35 23.12
3. Colloidal silicon dioxide (Aerosil 200) 0.40 0.40
4. Light magnesium oxide 4.00 3.96
Granulating solution
5. Polysorbate 80 0.10 0.10
6. Povidone K-30 1.50 1.49
7. Isopropyl alcohol 18.35 18.17
Lubrication
8. Croscarmellose sodium 6.00 5.94
9. Prosolv SMCC 50 10.60 10.50
10. Sodium chloride 2.00 1.98
11. Magnesium stearate 1.40 1.39
Total 70.00 69.31
COATING FORMULA
ALKALIZER SEAL COAT
12. Hypromellose (6cps) 1.00 0.99
13. Polyethylene glycol (6000) 0.20 0.20
14. Sodium bicarbonate 0.60 0.59
15. Purified Talc 0.20 0.20
16. Purified water 8.00 -
PROTECTIVE SEAL COAT
17. Instamoistshield White IJ-MS-1031 2.00 1.98
18. Isopropyl alcohol 15.2 -
19. Dichloromethane 22.8 -
PULSATILE RELEASE COAT
20. Ethyl Cellulose (10cps) 7.20 7.13
21. Hypromellose (6cps) 1.92 1.90
22. Glyceryl behenate 4.00 3.96
23. Polysorbate 80 0.96 0.95
24. Purified Talc 1.92 1.90
25. Isopropyl alcohol 106.40 -
26. Dichloromethane 197.60 -
DELAYED RELEASE COAT
27. Eudragit S-100 (methacrylic acid copolymer) 7.20 7.13
28. Triethyl citrate 0.90 0.89
29. Purified Talc 0.90 0.89
30. Isopropyl alcohol 117.50 -
31. Purified water 6.20 -
TOP COAT
32. Instamoistshield White IJ-MS-1031 2.00 1.98
33. Isopropyl alcohol 15.2 -
34. Dichloromethane 22.8 -
TOTAL 101.00 100.00

Example 1B: Delayed Release Esomeprazole Tablet 20 mg:
Sr. No. Name of Ingredients Unit qty. (mg) %W/W
Dry mixing
1. Esomeprazole Magnesium Trihydrate 20.65 21.97
2. Microcrystalline cellulose 23.35 24.84
3. Colloidal silicon dioxide (Aerosil 200) 0.40 0.43
4. Light magnesium oxide 4.00 4.26
Granulating solution
5. Polysorbate 80 0.10 0.11
6. Povidone K-30 1.50 1.60
7. Isopropyl alcohol 18.35 19.52
Lubrication
8. Croscarmellose sodium 6.00 6.38
9. Prosolv SMCC 50 10.60 11.28
10. Sodium chloride 2.00 2.13
11. Magnesium stearate 1.40 1.49
Total 70.00 74.47
COATING FORMULA
ALKALIZER SEAL COAT
12. Hypromellose (6cps) 1.00 1.06
13. Polyethylene glycol (6000) 0.20 0.21
14. Sodium bicarbonate 0.60 0.64
15. Purified Talc 0.20 0.21
16. Purified water 8.00 -
PROTECTIVE SEAL COAT
17. Instamoistshield White IJ-MS-1031 2.00 2.13
18. Isopropyl alcohol 15.2 -
19. Dichloromethane 22.8 -
ENTERIC COATING
20. Instacoat EN HPMCP A34D00159 (Pink) 17.00 18.09
21. Isopropyl alcohol 113.05 -
22. Dichloromethane 209.95 -
TOP COATING
23. Instamoistshield Pink (A21D00984) 3.00 3.19
24. Isopropyl alcohol 22.80 -
25. Dichloromethane 34.20 -
TOTAL 94.00 100.00

Example 1C: Composition of Pulsatile Release Esomeprazole Capsule
CAPSULE FILLING
Sr. No. Ingredients mg/cap
1. Esomeprazole Delayed Release Tablet 20 mg 94.00
2. Esomeprazole Pulsatile Release Tablet 20 mg 101.00
3. EHG Capsule size '0' 96.00
Filled capsule weight 291.00

Manufacturing Process:
Preparation of Pulsatile Release Esomeprazole Tablet 20mg:
Dry Mix Blend Preparation:
1. Sifted and co-sifted Esomeprazole Magnesium Trihydrate, Microcrystalline cellulose, Colloidal silicon dioxide and Light magnesium oxide through sieve 40mesh (ASTM 425µ).
2. Material obtained in step 1 was mixed in Rapid mixer granulator for 5 minutes.
Binder solution preparation and granulation:
3. Dissolved Polysorbate 80 and Povidone K 30 in Isopropyl alcohol under mechanical stirrer.
4. Granulated dry mix blend with step 3 prepared binder solution in Rapid mixer granulator till suitable consistent granulate formed.
Drying, sizing and Prelubrication:
5. Drying of granulate done in fluidized bed dryer till desired percentage loss on drying is achieved.
6. Size dried granules though sieve 25 mesh (ASTM 710µ).
7. Sifted Croscarmellose sodium and Prosolv SMCC 50 through sieve 40mesh (425µ). Sifted sodium chloride through sieve 60mesh (300µ).
8. Prelubricated step 6 material with step 7 material in octagonal blender for 20 minutes at slow speed.
Lubrication:
9. Sifted magnesium stearate through sieve 60mesh (300µ) and lubricated step 8 material with sifted magnesium Stearate octagonal blender for 5 minutes at slow speed.
Compression:
10. Compressed the Lubricated blend on rotary compression machine using 4.8mm circular, standard concave Punch plain on both sides.
Coating:
Alkaliser seal coat:
11. Prepared coating solution by dispersing sodium bicarbonate, Hypromellose, Polyethylene glycol (6000) and Talc in purified water under stirring for 45minutes.
12. Coated the core Esomeprazole tablet of step 10 with coating solution prepared in step 11 till desired weight gain achieved.
Protective seal coat:
13. Prepared coating solution by dispersing Instamoistshield White IJ-MS-1031 in Isopropyl alcohol and Dichloromethane mixture under stirring for 45minutes.
14. Coated the coated tablet of step 12 with coating solution prepared in step 13 till desired weight gain achieved.
Pulsatile Release coat:
15. Prepared coating solution by dispersing Ethyl cellulose, Hypromellose, Polysorbate 80, Glyceryl behenate and Talc in Isopropyl alcohol and Dichloromethane mixture under stirring for 45minutes.
16. Coated the seal coated tablet of step 14 with coating solution prepared in step 15 till desired weight gain achieved.
Delayed Release coat:
17. Prepared coating solution by dispersing Eudragit S-100, Triethyl citrate and Talc in Isopropyl alcohol and Purified water mixture under stirring for 45minutes.
18. Coated the coated tablet of step 16 with coating solution prepared in step 17 till desired weight gain achieved.
Top coat:
19. Prepared coating solution by dispersing Instamoistshield White IJ-MS-1031 in Isopropyl alcohol and Dichloromethane mixture under stirring for 45minutes.
20. Coated the tablet of step 18 with coating solution prepared in step 19 till desired weight gain achieved.
Preparation of Delayed Release Esomeprazole Tablet 20mg:
Dry Mix Blend Preparation:
1. Sifted and Co-sifted Esomeprazole Magnesium Trihydrate, Microcrystalline cellulose, Colloidal silicon dioxide and Light magnesium oxide through sieve 40mesh (ASTM 425µ).
2. Material obtained in step 1 was mixed in Rapid mixer granulator for 5 minutes.
Binder solution preparation and granulation:
3. Dissolved Polysorbate 80 and Povidone K 30 in Isopropyl alcohol under mechanical stirrer.
4. Granulated dry mix blend with step 3 prepared binder solution in Rapid mixer granulator till suitable consistent granulate formed.
Drying, sizing and Prelubrication:
5. Drying of granulate done in fluidized bed dryer till desired percentage loss on drying is achieved.
6. Size dried granules though sieve 25 mesh (ASTM 710µ).
7. Sifted Croscarmellose sodium and Prosolv SMCC 50 through sieve 40mesh (425µ). Sifted sodium chloride through sieve 60mesh (300µ).
8. Prelubricated the step 6 material with step 7 materials in octagonal blender for 20 minutes at slow speed.
Lubrication:
9. Sifted magnesium stearate through sieve 60mesh (300µ) and lubricate step 8 material with sifted magnesium Stearate octagonal blender for 5 minutes at slow speed.
Compression:
10. Compressed the Lubricated blend on rotary compression machine using 4.8mm circular, standard concave punch plain on both sides.
Coating:
Alkaliser seal coat:
11. Prepared coating solution by dispersing sodium bicarbonate, Hypromellose, Polyethylene glycol (6000) and Talc in purified water under stirring for 45minutes.
12. Coated the core Esomeprazole tablet of step 10 with coating solution prepared in step 11 till desired weight gain achieved.
Protective seal coat:
13. Prepared coating solution by dispersing Instamoistshield White IJ-MS-1031 in Isopropyl alcohol and Dichloromethane mixture under stirring for 45minutes.
14. Coated the tablet of step 12 with coating solution prepared in step 13 till desired weight gain achieved.
Enteric coat:
15. Prepared coating solution by dispersing Instacoat EN HPMCP A34D00159 (Pink) in Isopropyl alcohol and Dichloromethane mixture under stirring for 45minutes.
16. Coated the tablet of step 14 with coating solution prepared in step 15 till desired weight gain achieved.
Top coat:
17. Prepared coating solution by dispersing Instamoistshield Pink (A21D00984) in Isopropyl alcohol and Dichloromethane mixture under stirring for 45minutes.
18. Coated the tablet of step 16 with coating solution prepared in step 17 till desired weight gain achieved.

Preparation of Pulsatile Release Esomeprazole Capsule:
1. Fill the capsules size ‘0’ with one Esomeprazole Pulsatile Release Tablet 20mg and one Esomeprazole Delayed Release Tablet 20mg using capsule filling machine.
Packaging:
1. Packaging of Capsules done in Alu-Alu blister pack.

Table 1: Dissolution Profile of Example 1C
Pulsatile Release Esomeprazole Capsule 40 mg
Dissolution parameters
Parameters Acid Stage Buffer stage-I Buffer stage-II
Apparatus USP-I (Basket) 10mesh USP-I (Basket) 10mesh USP-I (Basket) 10mesh
Medium 0.1N HCl pH 6.8 phosphate buffer pH 7.4 phosphate buffer
Volume 900 ml 900 ml 900 ml
Basket RPM 100 100 50
Temperature 37ºC 37ºC 37ºC
Time points 2 hrs 10, 20, 30, 45 and 60 min after acid stage 2,4,6,8,10 & 12 hrs after buffer stage -I
Dissolution Results
Time points % Drug Release in Acid stage % Drug Release in Buffer stage-I % Drug Release in Buffer stage-II
2 hrs 0 - -
10 min - 29 0
20 min - 50 0
30 min - 51 0
45 min - 51 0
60 min - 51 0
2 hrs - - 0
4 hrs - - 0
6 hrs - - 0
8 hrs - - 0
10 hrs - - 39
12 hrs - - 43

Example 2: Stability Data for Example 1C
Condition %Assay Acid stage Buffer
stage -I Buffer Stage-II
2hrs 60min 2hrs 4hrs 6hrs 8hrs 10hrs 12hrs
1M 40ºC/75%RH 98 8 48 0 0 0 0 34 45
2M 40ºC/75%RH 96.30 0 49 0 0 0 6 38 41
3M 40ºC/75%RH 94.30 0 49 0 0 0 0 10 37
6M 40ºC/75%RH 94.10 0 49 0 0 0 0 0 39

Example 3A: Pulsatile Release Esomeprazole Tablet 20 mg:
Sr. No. Name of Ingredients Unit qty. (mg) %W/W
Dry mixing
1. Esomeprazole Magnesium Trihydrate 20.65 18.77
2. Microcrystalline cellulose 24.35 22.14
3. Colloidal silicon dioxide (Aerosil 200) 0.50 0.45
4. Light magnesium oxide 4.50 4.09
Granulating solution
5. Polysorbate 80 0.10 0.09
6. Povidone K-30 1.70 1.55
7. Isopropyl alcohol 19.66 -
Lubrication
8. Croscarmellose sodium 6.70 6.09
9. Prosolv SMCC 50 12.00 10.91
10. Sodium chloride 2.50 2.27
11. Magnesium stearate 2.00 1.82
Total 75.00 -
COATING FORMULA
ALKALIZER SEAL COAT
12. Hypromellose (6cps) 1.10 1.00
13. Polyethylene glycol (6000) 0.25 0.23
14. Sodium bicarbonate 0.70 0.64
15. Purified Talc 0.20 0.18
16. Purified water 9.00 -
PROTECTIVE SEAL COAT
17. Instamoistshield White IJ-MS-1031 3.50 3.18
18. Isopropyl alcohol 17.31 -
19. Dichloromethane 25.96 -
PULSATILE RELEASE COAT
20. Ethyl Cellulose (10cps) 7.50 6.82
21. Hypromellose (6cps) 2.00 1.82
22. Glyceryl behenate 4.00 3.64
23. Polysorbate 80 1.00 0.91
24. Purified Talc 2.20 2.00
25. Isopropyl alcohol 111.05 -
26. Dichloromethane 206.25 -
DELAYED RELEASE COAT
27. Eudragit S-100 (methacrylic acid copolymer) 7.50 6.82
28. Triethyl citrate 1.00 0.91
29. Purified Talc 1.00 0.91
30. Isopropyl alcohol 124.03 -
31. Purified water 6.54 -
TOP COAT
32. Instamoistshield White IJ-MS-1031 3.05 1.98
33. Isopropyl alcohol 23.56 -
34. Dichloromethane 35.34 -
TOTAL 101.00 110.00

Example 3B: Delayed Release Esomeprazole Tablet 20 mg:
Sr. No. Name of Ingredients Unit qty. (mg) %W/W
Dry mixing
1. Esomeprazole Magnesium Trihydrate 20.65 18.77
2. Microcrystalline cellulose 24.35 22.14
3. Colloidal silicon dioxide (Aerosil 200) 0.50 0.45
4. Light magnesium oxide 4.50 4.09
Granulating solution
5. Polysorbate 80 0.10 0.09
6. Povidone K-30 1.70 1.55
7. Isopropyl alcohol 19.66 -
Lubrication
8. Croscarmellose sodium 6.70 6.09
9. Prosolv SMCC 50 12.00 10.91
10. Sodium chloride 2.50 2.27
11. Magnesium stearate 2.00 1.82
Total 75.00 -
COATING FORMULA
ALKALIZER SEAL COAT
12. Hypromellose (6cps) 1.10 1.00
13. Polyethylene glycol (6000) 0.25 0.23
14. Sodium bicarbonate 0.70 0.64
15. Purified Talc 0.20 0.18
16. Purified water 9.00 -
PROTECTIVE SEAL COAT
17. Instamoistshield White IJ-MS-1031 3.50 3.18
18. Isopropyl alcohol 17.31 -
19. Dichloromethane 25.96 -
ENTERIC COATING
20. Instacoat EN HPMCP A34D00159 (Pink) 25.00 22.73
21. Isopropyl alcohol 166.25 -
22. Dichloromethane 308.75 -
TOP COATING
23. Instamoistshield Pink (A21D00984) 4.25 3.86
24. Isopropyl alcohol 31.92 -
25. Dichloromethane 47.88 -
TOTAL 110.00 100.00

Example 3C: Composition of Pulsatile Release Esomeprazole Capsule
CAPSULE FILLING
Sr. No. Ingredients mg/cap
1. Esomeprazole Delayed Release Tablet 20 mg of Example 3A 110.00
2. Esomeprazole Pulsatile Release Tablet 20 mg of Example 3B 110.00
3. EHG Capsule size '0' 96.00
Filled capsule weight 316.00

Manufacturing Process:
Manufacturing process is as mentioned in Example 1 ,CLAIMS:1. A pharmaceutical composition providing a biphasic release of esomeprazole or a salt thereof; said composition comprises (a) a first component comprising: (i) 17 % w/w to 27 % w/w of esomeprazole or a salt thereof, (ii) sodium chloride, and (iii) one or more pharmaceutically acceptable excipients; and (b) a second component comprising: (i) 15 % w/w to 25 % w/w of esomeprazole or a salt thereof, (ii) sodium chloride, (iii) a pulsatile release coat, and (iv) one or more pharmaceutically acceptable excipients; wherein the second component provides release of esomeprazole or salt thereof after a lag period of about 6 hours to about 10 hours from release of the first component, when tested in USP Type I Dissolution Test Apparatus containing 900 ml of phosphate buffer having pH 6.8 to 7.4 at about 37ºC.

2. The pharmaceutical composition of claim 1, wherein esomeprazole or a salt thereof and sodium chloride are present in a weight ratio of about 1:0.1 in the first component and the second component.

3. The pharmaceutical composition of claim 1, wherein the first and second component further comprises an alkaliser seal coat containing about 0.55 % to about 0.65% w/w of sodium bicarbonate.

4. The pharmaceutical composition of claim 3, wherein the first and second component comprises an alkaliser seal coat containing about 0.60 % w/w of sodium bicarbonate.

5. The pharmaceutical composition of claim 1, wherein the pulsatile release coat in the second component comprises about 5% to about 10% of ethyl cellulose.

6. The pharmaceutical composition of claim 5, wherein the pulsatile release coat in the second component comprises about 7.1% of ethyl cellulose surrounding the alkaliser seal coat.

7. The pharmaceutical composition of claim 1, wherein the second component further comprises a delayed release coat surrounding the pulsatile release coat, containing about 7.1% w/w of methacrylic acid copolymer.

8. A pharmaceutical composition providing a biphasic release of esomeprazole or a salt thereof; said composition comprises (a) a first component comprising (i) 20.65 mg of esomeprazole or a salt thereof, (ii) 0.1 mg polysorbate 80, (iii) 6 mg croscarmellose sodium, (iv) 2mg sodium chloride; and (v) an alkaliser seal coat that comprises 0.6 mg of sodium bicarbonate; and (b) a second component comprising (i) 20.65 mg of esomeprazole or a salt thereof, (ii) 0.1 mg polysorbate 80, (iii) 6mg croscarmellose sodium, (iv) 2mg sodium chloride; (v) an alkaliser seal coat that comprises 0.6 mg of sodium bicarbonate; (vi) a pulsatile release coat that comprises 7.2 mg ethyl cellulose, and 0.96 mg polysorbate 80, and (vii) a delayed release coat that comprises 7.20 mg methacrylic acid copolymer.
9. The pharmaceutical composition of claim 1 or 8, wherein the composition is in the form of a tablet, capsule, bilayer tablet, trilayer tablet, multilayer tablet, tablet in capsule, tablets in capsule or tablet in tablet.
10. The pharmaceutical composition of claim 8, wherein the first component provides about 90 % to about 100% release of contained esomeprazole or salt thereof at about 3 hours when tested in USP Type I Dissolution Test Apparatus containing 900 ml of phosphate buffer having pH 6.8 at about 37ºC; and the second component provides about 75% release of contained esomeprazole or salt thereof at about 13 hours when tested in USP Type I Dissolution Test Apparatus containing 900 ml of phosphate buffer having pH 7.4 at about 37ºC.