FORM 2
THE PATENT ACT 1970
(39 OF 1970)
&
THE PATENT RULES, 2003
COMPLETE SPECIFICATION
(SEE SECTION 10 AND RULE 13)
1 TITLE OF THE INVENTION :
Composition of proton pump inhibitor, prokinetic agent and alginic acid and a method of making it.
2 APPLICANT (S)
Name : Geno Pharmaceuticals Pvt. Ltd.
Nationality :
Indian Company
Address : plot no. 4 Pharmaceutical Complex Tivim Industrial Estate, Karaswada, Mapusa, Goa-403526, India
3 PREAMBLE TO THE DESCRIPTION
COMPLETE
The following specification particularly describes the invention and the manner in which it is
to be performed.

Title
[0001] Composition of proton pump inhibitor, prokinetic agent and alginic acid and a method of making it.
Field of Invention
[0002] The present invention relates to a composition of proton pump inhibitor, prokinetic agent and alginic acid for treatment of (GERD), Zollinger-Ellison syndrome, and stomach ulcers, and a method of making it.
Background
[0003] Gastroesophageal reflux disease (GERD) occurs when stomach acid repeatedly flows back into the tube connecting mouth and stomach (esophagus). This backwash (acid reflux) can irritate the lining of the esophagus, and also cause symptoms such as heartburn, a painful, burning feeling in the middle of the chest, behind breastbone, rising from the lower tip of the breastbone toward the throat; regurgitation, or stomach contents coming back up through esophagus and into the throat or mouth, which may cause the subject to taste food or stomach acid.
[0004] Another Zollinger-Ellison syndrome a digestive disorder where subject is likely to have one or more tumors in the first part of the small

intestine, the pancreas, or both. These tumors, called gastrinomas, release the hormone gastrin. This causes the stomach to release too much acid.
[0005] The aims of gastroesophageal reflux disease (GERD) treatment are symptom relief and healing of oesophagitis. This treatment using single component/ drug is quite prevalent and effective but its overuse gives certain limitations in several GERD patients. These limitation includes decrease in potency of drugs at low dose with delay in onset of action, an increase in a side effect, and a decrease in potency of drugs to give symptomatic relief in GERD. Thus to overcome the limitation, there is a need to develop new formulations that have higher potency, greater tolerance, and synergistic action to give fast relief to GERD patients.
Summary
[0006] The present invention relates to a composition for treatment of GERD, Zollinger-Ellison syndrome, and stomach ulcers, comprising a first component being proton pump inhibitor; a second component being antiemetic and prokinetic agent; a third component being alginic acid; additives, coating (seal and enteric) and lubricants; and purified water in q.s. In the said composition the first component proton pump inhibitor is Esomeprazole ranging between150 mg to 350 mg in weight; the second component antiemetic and prokinetic agent is Domperidone Maleate

ranging between 6.365mg to 19.10 mg in weight; and the third component alginic acid is Sodium Alginate ranging between 150mg to 350mg in weight.
[0007] The present invention relates to a method of making the composition as claimed in claimed 1, comprising steps:
A. Granulation of Domperidone and Sodium Alginate Granules
involving:
i. sifting of Sodium Alginate, Domperidone Maleate, Mannitol,
Sodium Carbonate Decahydrate and Mannitol through
suitable sieve; ii. dry mixing of sifted components; iii. preparing of binder by dissolving Povidone in preferred
amount of purified water without any lumps formation; iv. adding binder to the dry mixed mass in RMG and granulate
at slow speed with purified water till a wet mass of suitable
consistency is formed; v. discharging the wet mass through Dutch weaved wire of FBD
bowl and drying wet granules; and vi. sizing of the granules through sieve, and drying till desired
LOD is obtained.
B. Granulation of Esomeprazole Granules involving:
i. sealing Esomeprazole Magnesium Dihydrate with solution sealing component;
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ii. drying of the granules;
iii. sifting the granules through sieve;
iv. adding Cellulose acetate phthalate and granulate, and further
adding acetone; v. air drying the granules and sizing the granules through sieve.
C. blending & lubrication involving:
i. adding the sodium alginate & Domperidone granules along
with Esomeprazole granules; ii. adding sifted Crospovidone & Purified Talc to Octagonal
Blender & further mix for few minutes; and iii. adding sifted calcium stearate and mix for about few minutes. D. compressing the lubricated granules using suitable punch set.
BRIEF DESCRIPTION OF DRAWINGS:
[0008] None
DETAILED DESCRIPTION
[0009] The present disclosure is best understood with reference to the detailed description set forth herein. Various embodiments have been discussed Those skilled in the art will readily appreciate that the detailed descriptions provided herein are merely for explanatory purposes, as the
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methods and compositions may extend beyond the described embodiments. For instance, the teachings presented and the needs of a particular application may yield multiple alternative and suitable approaches to implement the functionality of any detail described herein. Therefore, any approach may extend beyond certain implementation choices in the following embodiments.
[0010] References to “one embodiment,” “at least one embodiment,” “an embodiment,” “one example,” “an example,” “for example,” “preferred embodiment” and so on indicate that the embodiment(s) or example(s) may include a particular feature, structure, characteristic, property, element, or limitation but that not every embodiment or example necessarily includes that particular feature, structure, characteristic, property, element, or limitation.
[0011] The aims of gastroesophageal reflux disease (GERD) treatment are symptom relief and healing of oesophagitis. Besides proton pump inhibitors (PPIs), prokinetic agents are also commonly prescribed to treat GERD. Domperidone, a well-known antiemetic, is an example of a prokinetic agent. It is a dopaminergic blocker that increases lower oesophagus sphincter pressure and activates gastric motility. A systematic review and meta-analysis to explore the benefits of domperidone in addition to PPI therapy for GERD was carried out. Research made on publications comparing PPI plus domperidone to PPI
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monotherapy in terms of symptom improvement in GERD (until 21 April 2022) on PubMed, Scopus, Google Scholar, Web of Science, Cochrane Library, WHO’s International Clinical Studies Registry Platform, and ClinicalTrials.gov without restricting date, language, or study design. The protocol was registered in PROSPERO (CRD42021242076). This meta-analysis incorporated 11 studies with a total of 841 participants (419 in the PPI plus domperidone group and 422 in the PPI monotherapy group). The combination of a PPI and domperidone resulted in a significant reduction in global GERD symptoms. Adverse events associated with PPI plus domperidone treatment were similar to those associated with PPI monotherapy. In conclusion, the combination of domperidone and a PPI is generally safe and effective in treating GERD as compared with that of PPI alone.
[0012] Monotherapy is effective in most patients, but its overuse gives certain limitations in several GERD patients. Limitation includes decrease in potency of drugs at low dose with delay in onset of action, an increase in a side effect, and a decrease in potency of drugs to give symptomatic relief in GERD. To overcome the limitation of Combination therapy is currently in use to develop new formulations that have higher potency, greater tolerance, and synergistic action to give fast relief to GERD patients. Combinations therapy is more effective than monotherapy and also decreases therapeutic challenges which arise by using monotherapy of these drugs in GERD patients.

[0013] In the present invention a composition for treatment of GERD, Zollinger-Ellison syndrome, and stomach ulcers, comprising a first component being proton pump inhibitor; a second component being antiemetic and prokinetic agent; a third component being alginic acid; additives, coating (seal and enteric) and lubricants; and purified water in q.s.
[0014] In a preferred composition, the first component proton pump inhibitor is Esomeprazole which ranges preferably between150 mg to 350 mg in weight.
[0015] In a preferred composition, the second component antiemetic and prokinetic agent is Domperidone Maleate ranges preferably between 6.365mg to 19.10 mg in weight.
[0016] In another preferred composition the third component alginic acid is Sodium Alginate ranges preferably between 150mg to 350mg in weight.
[0017] In a preferred composition, wherein the additives comprises Mannitol, Sodium Carbonate Decahydrate, Crospovidone (Type-A) and Povidone K-30.
[0017] In a preferred composition the seal coating comprises Hydroxy propyl Methyl Cellulose E6, PEG 400, Titanium Dioxide; and Isopropyl Alcohol.

[0018] In a preferred composition the enteric coat comprises Cellulose Acetate Phthalate; and Acetone
[0019] In a preferred composition the lubricants comprise Crospovidone (Type A), Calcim Stearate and Purified talc.
[0020] A method of making the composition comprising:
A. Granulation 1 of Domperidone and Sodium Alginate Granules comprising
i. Sifting of raw material- Sift Sodium Alginate, Domperidone Maleate, Mannitol, Sodium Carbonate, Decahydrate and Mannitol through suitable sieve.
ii. Dry mixing- Transfer above sifted material (from step A) to Rapid Mixer Granulator (R.M.G) and mix for 7 minutes at fast speed.
iii. Preparation of binder- Dissolve Povidone in sufficient amount of purified water. Ensure that no lumps are formed.
iv. Granulation - Add the binder form step (C) to the dry mixed mass in step (B) in RMG and granulate at slow speed till a mass of suitable consistency is formed. Add additional purified water if necessary to achieve the required end point. Check the integrity of Dutch weaved wire of FBD bowl and discharge the wet mass in the FBD bowl. Scrap the sides of RMG.

v. Drying- Set the temperature at 50 - 60°C. Dry the wet granules
(from step D2) in FBD. Reshuffle and dry further at above
temperature. vi. Sizing- Screen the granules through 20# sieve. vii. Drying- Transfer the granules (from step F) in the FBD bowl
and dry in the FBD with inlet temperature set between 50° -
60°C till desired LOD is obtained.
B. Granulation 2 of Esomeprazole comprising
i. Esomeprazole Magnesium Dihydrate in a container.
ii. Seal coat the above material with the solution.
iii. Air dry for some time & further dry at 500C
iv. Sift the granules through 30# sieve.
v. Transfer the above formed granules in a container, add
Cellulose acetate phthalate and granulate. Add
additional Acetone if required. vi. Air dry the granules for some time and dry further with
inlet temperature set between 50°- 60°C. vii. Size the granules through 30# sieve.
C. Blending & Lubrication, comprising:

i. Add the sodium alginate & Domperidone granules along with Esomeprazole granules to Octagonal Blender and mix the contents for 10mins.
ii. Then add Sifted Crospovidone & Purified Talc to Octagonal Blender & further mix for 10mins.
iii. Then add sifted calcium stearate and mix for 2 minutes.
D. Compression- Compress lubricated granules using suitable punch set.
[0021] Through use of the above composition was given to 10 subjects who were suffering from GERD, and 7 subjects got relief.
[0022] Esomeprazole (Enteric coated pellets) is a proton pump inhibitor that blocks an enzyme called gastric proton pump, responsible for acid production. It works by reducing the amount of acid in the stomach which helps in relief of acid related indigestion and heartburn. Esomeprazole is also used to promote healing of erosive esophagitis (damage of oesophagus caused by stomach acid).
[0023] Domperidone (in tablets as granules) is an antiemetic (anti-sickness) and prokinetic drug that works on the upper digestive tract to increase the movement of the stomach and intestines, allowing the food

to move more easily through the stomach. Domperidone works by blocking dopamine receptors in the gut. It increases the movement or contractions of the muscles in your stomach and intestines, increasing how quickly and easily food moves through your digestive tract. It also acts on the chemoreceptor trigger zone in your brain, which is involved in nausea and vomiting.
[0024] Sodium alginate (in tablets as granules) is the sodium salt of alginic acid. Sodium alginate is a carbohydrate product of a seaweed called Macrocystis pyrifera, extracted from brown seaweed and is most commonly used with calcium lactate or calcium chloride in the spherification process. A hydrophilic colloidal polysaccharide, added to an antacid as protective agent. It forms a gel-like substance when mixed with water and can help to protect the lining of the oesophagus from stomach acid. This may prevent reflux of acid into the oesophagus by keeping the gastric contents in place and reduce the likelihood of reflux irritating the lining of the oesophagus.
[0025] Domperidone is a prokinetic which works on the upper digestive tract to increase the movement of the stomach and intestines, allowing the food to move more easily through the stomach. Esomeprazole is a proton pump inhibitor (PPI) which works by reducing the amount of acid

in the stomach which helps in the relief of acid-related indigestion and heartburn.
[0026] The combination of Domperidone and Esomeprazole is used to treat acidity and heartburn or gastroesophageal reflux disease (GERD); a condition where the acid in the stomach flows back up into the food pipe (esophagus). It is also used to treat gastric and duodenal ulcers. Domperidone helps to control vomiting by increasing the movement of the gut, allowing the food to move more easily through the stomach.
[0027] In addition to the synergistic benefit of Domperidone and Esomeprazol, the G-block structure of an alginate contributes to the gel strength, which results in a reaction between Sodium alginate and the acid present in the stomach, producing a low-density viscous gel that floats on top of the stomach. This forms a physical barrier that protects the delicate esophageal mucosa and the airways from the gastric refluxate.
[0028] Prevention of postprandial reflux. The physical barrier formed by alginate is also very important for eliminating or displacing the acid pocket that has been identified in GERD patients. The acid pocket forms at the gastroesophageal junction after a meal and consists of an unbuffered, highly acidic gastric juice and has pathophysiological

relevance in GERD. A strong alginate raft can cap the acid pocket and reduce or even prevent postprandial acid reflux.
[0029] When consumed first Sodium Alginate will release in the stomach which neutralise the Acid, then Domperidone will control acid reflex and stop the vomiting sensation.
[0030] In small intestine Esomeprazole drug will release at PH 6.8. reducing the amount of acid in the stomach which helps in relief of acid related indigestion and heartburn.
[0031] In a preferred composition is found to have positively affected 70% of subjects.
[0032] In a preferred composition, the stability testing protocol followed is as per GTP for Microbial Examination QC/GTP/003, ICH Guidelines Q1A(R2) and Q1E, WHO Guidelines TRS No. 953, 2009.
[0033] In a preferred composition is stable both under the Accelerated conditions and the Long Term Condition. Accelerated conditions being of Temperature 40°C ± 2°C, Relative Humidity 75%±5%RH stored for 6 months. Long Term condition being of Temperature 30°C ± 2°C, Relative Humidity 75%±5%RH stored for 48 months.
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TABLE -1
TABLE – 2

[0033] In a preferred composition random stability data is drawn from different batches under various temperature and relative humidity, and parameters, shown in the following tables




TABLE – 3

TABLE- 4

TABLE-5

TABLE - 6

WE CLAIM:
1. A composition for treatment of GERD, Zollinger-Ellison syndrome,
and stomach ulcers, comprising:
a. a first component being proton pump inhibitor;
b. a second component being antiemetic and prokinetic agent;
c. a third component being alginic acid;
d. additives, coating (seal and enteric) and lubricants; and
e. purified water in q.s.
2. The composition for treatment of GERD, Zollinger-Ellison syndrome, and stomach ulcers as claimed in claim 1, where in the first component proton pump inhibitor is Esomeprazole.
3. The composition for treatment of GERD, Zollinger-Ellison syndrome, and stomach ulcers as claimed in claim 1, where in the first component proton pump inhibitor ranges between150 mg to 350 mg in weight;
4. The composition for treatment of GERD, Zollinger-Ellison syndrome, and stomach ulcers as claimed in claim 1, where in the second component antiemetic and prokinetic agent is Domperidone Maleate.

5. The composition for treatment of GERD, Zollinger-Ellison syndrome, and stomach ulcers as claimed in claim 1, where in the second component antiemetic and prokinetic agent ranges between 6.365mg to 19.10 mg in weight.
6. The composition for treatment of GERD, Zollinger-Ellison syndrome, and stomach ulcers as claimed in claim 1, where in the third component alginic acid is Sodium Alginate.
7. The composition for treatment of GERD, Zollinger-Ellison syndrome, and stomach ulcers as claimed in claim 1, where in the third component alginic acid ranges between 150mg to 350mg in weight.
8. The composition for treatment of GERD, Zollinger-Ellison syndrome, and stomach ulcers as claimed in claim 1,
wherein the additives comprises: i. Mannitol;
ii. Sodium Carbonate Decahydrate; iii. Crospovidone (Type-A); and iv. Povidone K-30.
wherein the seal coat comprises:
i. Hydroxy propyl Methyl Cellulose E6;

ii. PEG 400;
iii. Titanium Dioxide; and
iv. Isopropyl Alcohol.
wherein the enteric coat comprises:
i. Cellulose Acetate Phthalate; and
ii. Acetone
wherein the lubricants comprises
i. Crospovidone (Type A);
ii. Calcim Stearate; and
iii. Purified talc
9. A method of making the composition as claimed in claimed 1, comprising steps:
A. Granulation of Domperidone and Sodium Alginate Granules
involving:
vii. sifting of Sodium Alginate, Domperidone Maleate, Mannitol,
Sodium Carbonate Decahydrate and Mannitol through
suitable sieve;
viii. dry mixing of sifted components to Rapid Mixer Granulator
(R.M.G) and mix for 7 minutes at fast speed; ix. preparing of binder by dissolving Povidone in preferred amount of purified water without any lumps formation;

x. adding binder to the dry mixed mass in RMG and granulate
at slow speed with purified water till a wet mass of suitable
consistency is formed; xi. discharging the wet mass through Dutch weaved wire of FBD
bowl and drying wet granules; and xii. sizing of the granules through sieve, and drying till desired
LOD is obtained.
B. Granulation of Esomeprazole Granules involving: i. sealing Esomeprazole Magnesium Dihydrate in a container with
solution sealing component; ii. drying of the granules first in air then at a temperature; iii. sifting the granules through sieve; iv. adding Cellulose acetate phthalate and granulate, and further
adding acetone; v. air drying the granules and dry further with an inlet
temperature; and vi. sizing the granules through sieve.
C. blending & lubrication involving: i. adding the sodium alginate & Domperidone granules along with Esomeprazole granules to Octagonal Blender and mix the contents for few minutes;

ii. adding sifted Crospovidone & Purified Talc to Octagonal Blender
& further mix for few minutes; and iii. adding sifted calcium stearate and mix for about 2 minutes.
D. compressing the lubricated granules using suitable punch set.
10. The composition for treatment of GERD, Zollinger-Ellison syndrome, and stomach ulcers as claimed in claim 1, wherein the Esomeprazole is released at pH 6.8