FORM 2
THE PATENTS ACT, 1970 (39 of 1970)
&
THE PATENTS RULES, 2003
COMPLETE SPECIFICATION
(See section 10 and rule 13)
1. Title of the invention:
"PHARMACEUTICAL COMPOSITION CONTAINING
COMBINATION OF A POTASSIUM-COMPETITIVE ACID BLOCKER (P-CAB) AGENT OR PHARMACEUTICALLY ACCEPTABLE SALT THEREOF AND PROKINETIC AGENT"
2. Macleods Pharmaceuticals Ltd., an Indian Company, having its Registered Office at 304 - Atlanta Arcade, Opp. Leela Hotel, Marol Church Road, Andheri (East), Mumbai - 400 059, Maharashtra, India.
3. The following specification particularly describes the invention and the manner in which it is to be performed.

FIELD OF THE INVENTION 200326345
The present invention relates to a novel pharmaceutical composition comprising combination of an therapeutically effective amount of a potassium-competitive acid blocker (P-CAB) agent or its pharmaceutical^ acceptable salt, and a prokinetic agent; for the effective treatment, prevention and/or reduction of symptoms of gastro-intestinal disease, gastro-esophageal disease and gastro-esophageal reflux disease (GERD) such as non-erosive reflux disease (NERD), erosive esophagitis (EE), Barrett esophagus (BE) or erosive reflux disease.
BACKGROUND OF THE INVENTION
Gastro-esophageal reflux disease (GERD) is one of the commonly diagnosed digestive disorders. The GERD is a gastrointestinal disorder or a medical condition wherein the regurgitation of gastric contents into the esophagus. Other esophageal or extra-esophageal symptoms of GERD includes heartburn, nausea, vomiting epigastric pain, dental erosions, chronic cough, dyspepsia, laryngitis, dysphagia and odynophagia. The intrinsic or structural mechanisms can cause GERD, may contribute to disruption of the esophagogastric junction barrier leading into exposure of the esophagus to acidic gastric contents. The GERD is commonly classified into non-erosive reflux disease (NERD), erosive esophagitis (EE), Barrett esophagus (BE) and erosive reflux disease.
Potassium-competitive acid blockers (P-CAB) agents represent a heterogeneous group of drug compounds that bind reversibly to K+ ions and block the H+, K+ ATPase enzyme, thus preventing acid production. P-CABs have a fast onset of action and have dose-dependent effects on acid production. P-CABs act at the H+/K+ ATPase transporter on the luminal membrane of gastric parietal cells. Upon systemic absorption, P-CABs are immediately protonated and accumulate at a much higher concentration in parietal cell canaliculi and ionically bond to H+/K+ ATPase transporters to prevent acidifying proton secretion. After binding, the P-CAB blocks K+ ion access to the proton pump. Evidently, because of the selective mechanism P-CABs facilitate more rapid attainment of peak plasma levels and onset of action.

There are several known potassium-Competitive Acid Blocker (P-CAB) agents such as Tegoprazan, Vonoprazan, Linaprazan, Soraprazan, Revaprazan, Fexuprazan, Zastaprazan and Keverprazan, that are useful for preventing symptoms of GERD. The pharmacodynamics and pharmacokinetics of P-CAB convey several potentially clinically beneficial properties. Precisely, the longer half-lives of P-CABs allow prolonged inhibition of newly synthesized proton pumps and thus longer durations of action than Proton pump inhibitors (PPIs).
Vonoprazan, chemically know as l-[5-(2-fluorophenyl)-l-pyridin-3-ylsulfonylpyrrol-3-yl]-N-methylmethanamine, and represented by the structure of Formula-II as below and marketed as its fumarate salt;
^ o?s JO
F \ H
V
Formula-II
U.S. Pat. No. 7,977,488 (hereinafter US'488) provides 1-heterocyclylsulfonyl, 2-aminomethyl, 5-(hetero-) aryl substituted 1-H-pyrrole derivatives as acid secretion inhibitors including Vonoprazan that are useful in the treatment of gastro-oesophageal reflux disease. The drug containing Vonoprazan fumarate is marketed under the brand TAKECAB® and VOCINTI® in some countries, in oral dosage form as Tablet lOmg and 20mg for the treatment of gastroesophageal disease. Vonoprazan is an acid-stable and fast absorbing drug approved for the treatment of reflux esophagitis for prevention of relapse. In GERD, vonoprazan improves epigastric pain, postprandial distress, constipation, and diarrhea. Vonoprazan is used for treating acid-related diseases having mechanism of action called potassium-competitive acid blockers (P-CABs) which competitively inhibits the binding of potassium ions to H+,K+-ATPase in the final step of gastric acid secretion in gastric parietal cells. Vonoprazan fumarate has fast-acting, strong and sustained acid secretion inhibitory effects. Some of the commonly reported

adverse effects of the Vonoprazan includes diarrhoea, nausea and vomiting, constipation, abdominal pain, skin rash, and heartburn.
Tegoprazan, chemically know as (-)-4-[((4S)-5,7-Difluoro-3,4-dihydro-2H-chromen-4-yl)oxy]-N,N,2-trimethyl-lH-benximidazole-6-carboxamide, and represented by the structure of Formula-I as below;
o
F
Formula-I
U.S. Pat. No. 7,723,321 (hereinafter US'321) provides chromane substituted benzimidazole derivatives including Tegoprazan that are useful in the treatment of gastroesophageal reflux disease. The drug containing Tegoprazan is marketed under the brand K-CAB® in some countries, in oral dosage form as Tablet 25mg and 50mg for the treatment of gastroesophageal dieseas. Tegoprazan is a gastric acid secreation inhibitor works as a high-selective potassium-competitive acid blocker (P-CAB) agent that inhibits Gastric H+/K+-ATPase in a Potassium-Competitive and Reversible Manner. Some of the commonly reported adverse effects of the Tagoprazan are Nausea, diarrhea, dyspepsia and chest discomfort.
Dopamine D2-receptor antagonists has been widely used as gastrointestinal prokinetic agents. The prokinetic agents such as Domperidone, Itopride Benzamide, Cisapride, Mosapride, Metoclopramide, Prucalopride, Renzapride, Tegaserod, Mitemcinal, Levosulpiride, Cinitapride or Linaclotide; antagonizes the inhibitory effect of dopamine, resulting in stimulation of gastric muscle contraction. This provides a mechanism for

the gastrokinetic effect of domperidone. The dopamine inhibits gastric muscle contraction evoked by electric field stimulation by inhibiting cholinergic transmission. This is mediated by DA2 receptors located on the postganglionic cholinergic neurons, and the pathway involves a pertussis toxin-sensitive G protein. Precisely, Domperidone acts as a peripherally selective antagonist of the dopamine D2 and D3 receptors and provides relief from nausea by blocking receptors at the chemoreceptor trigger zone at the floor of the fourth ventricle.
It is evident that, medically, refractory GERD is becoming increasingly common, therefore, there is a need of a tailored approach in the effective management of GERD and other gastrointestinal disorders without or with reduced reported adverse effects. It is thus an objective of the present invention to employ suitable pharmaceutical combination comprising of therapeutically effective amount of a potassium-competitive acid blocker (P-CAB) agent or salt thereof, and a prokinetic agent such as Domperidone; for the effective treatment, prevention and/or reduction of symptoms of gastro-esophageal reflux disease (GERD) such as non-erosive reflux disease (NERD), erosive esophagitis (EE), Barrett esophagus (BE) or erosive reflux disease; that show significant control over adverse effects and hence the enhanced therapeutic efficacy.
SUMMARY OF THE INVENTION
In one aspect, the present invention relates to a pharmaceutical composition comprising a combination of therapeutically effective amount of,
(i) a potassium-competitive acid blocker (P-CAB) agent or its pharmaceutically acceptable salt, and (ii) a prokinetic agent.
In one aspect, the present invention relates to a pharmaceutical composition comprising a combination of therapeutically effective amount of,
(i) a potassium-competitive acid blocker (P-CAB) agent or its pharmaceutically acceptable salt, and (ii) a prokinetic agent; for the effective treatment, prevention and/or reduction of symptoms of gastro-intestinal disease, gastro-esophageal disease and gastro-esophageal reflux disease (GERD).

In one aspect, the present invention relates to a pharmaceutical composition comprising
a combination of therapeutically effective amount of,
(i) a potassium-competitive acid blocker (P-CAB) agent or its pharmaceutically
acceptable salt, and (ii) a prokinetic agent;
wherein, the potassium-competitive acid blocker (P-CAB) agent or its pharmaceutically
acceptable salt, and the prokinetic agent in the pharmaceutical composition are present
in a weight ratio within the range of 1:9 to 9:1, for the effective treatment, prevention
and/or reduction of symptoms of gastro-intestinal disease, gastro-esophageal disease
and gastro-esophageal reflux disease (GERD).
In one aspect, the present invention relates to pharmaceutical composition comprising a combination of therapeutically effective amount of a potassium-competitive acid blocker (P-CAB) agent or its pharmaceutically acceptable salt and a prokinetic agent in a single dosage form, together with one or more pharmaceutically acceptable excipients.
In one aspect, the present invention relates to pharmaceutical composition comprising a combination of therapeutically effective amount of a potassium-competitive acid blocker (P-CAB) agent or its pharmaceutically acceptable salt and a prokinetic agent in a single dosage form, together with one or more pharmaceutically acceptable excipients, wherein the potassium-competitive acid blocker (P-CAB) is present in an amount of 1 to 80 % w/w of total weight of composition and a prokinetic agent is present in an amount of 1 to 80 % w/w of total weight of composition.
In one aspect, the present invention relates to pharmaceutical composition comprising a combination of therapeutically effective amount of a potassium-competitive acid blocker (P-CAB) agent or its pharmaceutically acceptable salt and a prokinetic agent in a single dosage form, together with one or more pharmaceutically acceptable excipients, wherein the potassium-competitive acid blocker (P-CAB) is present in an amount from about 1 mg to about 100 mg. and a prokinetic agent is present in an amount from about 1 mg to about 100 mg.

In one aspect, the present invention relates to pharmaceutical composition comprising a combination of therapeutically effective amount of vonoprazan or its pharmaceutically acceptable salt and Domperidone in a single dosage form, together with one or more pharmaceutically acceptable excipients; for the effective treatment, prevention and/or reduction of symptoms of gastro-intestinal disease, gastro-esophageal disease and gastro-esophageal reflux disease (GERD).
In one aspect, the present invention relates to pharmaceutical composition comprising a combination of therapeutically effective amount of vonoprazan fumarate and Domperidone; wherein, vonoprazan fumarate and Domperidone are present in a weight ratio within the range of 1:9 to 9:1, for the effective treatment, prevention and/or reduction of symptoms of gastro-intestinal disease, gastro-esophageal disease and gastro-esophageal reflux disease (GERD).
BRIEF DESCRIPTION OF THE DRAWINGS OF THE INVENTION
Figure-1: represents dissolution profile of the formulation obtained according to Example-1.
DETAILED DESCRIPTION OF THE INVENTION
It should be understood that the following specific embodiments are to be construed as merely illustrative, and not limitative of the remainder of the disclosure in any way whatsoever, in the detailed description and examples. A person of ordinary skill in the art, based upon the definitions herein, may utilize the present invention to its fullest extent. Unless otherwise as defined herein, all the technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which the invention relates.
For the purpose of present invention, the term 'gastro-intestinal disease5 and 'gastro-esophageal disease' refers to the medical condition that covers, but not limited to chronic or acute gastroesophageal reflux disease (GERD), peptic ulcer, gastric ulcer,

duodenal ulcer, NSAID-induced ulcers, gastritis, infection of Helicobacter pylori, dyspepsia, functional dyspepsia, Zollinger-Ellison syndrome, non-erosive reflux disease (NERD), visceral pain, heartburn, nausea, esophagitis, dysphagia, erosive esophagitis (EE), Barrett esophagus (BE) or erosive reflux disease.
For the purpose of present invention, the term 'therapeutically effective amount' refers to an amount of active pharmaceutical ingredient sufficient or composition to treat desired disease or disorder when administered alone or in combination at a reasonable effect to any medical treatment. Therefore, the term "therapeutically effective" as relates to a dose or an amount refers to that quantity of a compound or corresponding pharmaceutical composition that is sufficient to result in a desired activity upon administration to a mammal in need thereof. Thus, the term "therapeutically effective amount" refers to the quantity or dose of a compound or corresponding pharmaceutical composition that is sufficient to produce an effective response upon administration to a mammal.
For the purpose of present invention, the term "excipient(s)" or "'pharmaceutically acceptable excipients" collectively refers to inactive ingredient which is suitable for delivering a therapeutically active agent to the target site without affecting the therapeutic activity of the said active agent. The excipient(s) as used herein may include but not limited to, a diluent, binder, disintegrant, glidant, lubricant, diluent, flavouring agent, coating material, release modifying agents, sweetener, preservative, solvent, co-solvant, stabilizer, colourant, film forming polymer, plasticizer, anti-caking agent, vehicle, surfactants, stabilizers, antioxidants, tonicity agents, suspending agents, filers or their combination.
For the purpose of present invention, the term "Potassium-competitive acid blockers (P-CAB) agents" refers to the class of compounds having mechanism of action as potassium-competitive acid blocker (P-CAB)' such therapeutically active P-CAB agent are selected from, but not limited to Vonoprazan, Tegoprazan, Linaprazan, Soraprazan, Revaprazan, Fexuprazan, Zastaprazan or Keverprazan or its pharmaceutically acceptable salt.; and the like.

For the purpose of present invention, the term "prokinetic agent" refers to the therapeutic prokinetic agent that covers, but not limited to 'Dopamine D2-receptor antagonists' selected from Domperidone, Itopride Benzamide, Cisapride, Mosapride, Metoclopramide, Prucalopride, Renzapride, Tegaserod, Mitemcinal, Levosulpiride, Cinitapride or Linaclotide; and the like.
In one embodiment, the present invention relates to a pharmaceutical composition comprising a combination of therapeutically effective amount of (i) a potassium-competitive acid blocker (P-CAB) agent or its pharmaceutically acceptable salt, and (ii) a prokinetic agent.
In one embodiment, the present invention relates to a pharmaceutical composition comprising a combination of therapeutically effective amount of, (i) a potassium-competitive acid blocker (P-CAB) agent or its pharmaceutically acceptable salt, and (ii) a prokinetic agent; for the effective treatment, prevention and/or reduction of symptoms of gastro-intestinal disease, gastro-esophageal disease and gastro-esophageal reflux disease (GERD).
In an embodiment, the potassium-competitive acid blocker (P-CAB) agent or its pharmaceutically acceptable salt used in the pharmaceutical combination of the present invention is selected from the group consisting of but not limited to Vonoprazan, Tegoprazan, Linaprazan, Soraprazan, Revaprazan, Fexuprazan, Zastaprazan and Keverprazan; or its pharmaceutically acceptable salt.
In an embodiment, the term 'pharmaceutically acceptable salt' used in the contet of a potassium-competitive acid blocker (P-CAB) agent, refers to the pharmaceutically acceptable acid addition salts of the corresponding P-CAB agent, include but are not limited to, those derived from inorganic acids such as hydrochloric acid, nitric acid, phosphoric acid, sulfuric acid and the like, as well as the salts derived from organic acids such as acetic acid, trifluoroacetic acid, propionic acid, oxalic acid, maleic acid, benzoic acid, succinic acid, fumaric acid, phthalic acid, benzenesulfonic acid, p-toluenesulfonic acid, citric acid, tartaric acid, methanesulfonic acid and the like.

In an embodiment, the 'prokinetic agent' used in the pharmaceutical combination of the present invention is selected from the group consisting of but not limited to Domperidone, Itopride Benzamide, Cisapride, Mosapride, Metoclopramide, Prucalopride, Renzapride, Tegaserod, Mitemcinal, Levosulpiride, Cinitapride and Linaclotide, or mixture thereof.
In an embodiment, the pharmaceutical composition of the present invention is useful for the effective treatment treatment, prevention and/or reduction of symptoms of 'gastro-intestinal disease' and 'gastro-esophageal disease' such as chronic or acute gastroesophageal reflux disease (GERD), peptic ulcer, gastric ulcer, duodenal ulcer, NS AID-induced ulcers, gastritis, infection of Helicobacter pylori, dyspepsia, functional dyspepsia, Zollinger-Ellison syndrome, non-erosive reflux disease (NERD), visceral pain, heartburn, nausea, esophagitis, dysphagia, erosive esophagitis (EE), Barrett esophagus (BE) or erosive reflux disease; wherein the composition comprises therapeutically effective amount of: (i) a potassium-competitive acid blocker (P-CAB) agent or its pharmaceutically acceptable salt, and (ii) a prokinetic agent.
In another embodiment, the present invention relates to a pharmaceutical composition
comprising a combination of therapeutically effective amount of,
(i) a potassium-competitive acid blocker (P-CAB) agent or its pharmaceutically
acceptable salt, and (ii) a prokinetic agent;
wherein, the potassium-competitive acid blocker (P-CAB) agent or its pharmaceutically
acceptable salt, and the prokinetic agent in the pharmaceutical composition are present
in a weight ratio within the range of 1:9 to 9:1, for the effective treatment, prevention
and/or reduction of symptoms of gastro-intestinal disease, gastro-esophageal disease
and gastro-esophageal reflux disease (GERD).
In an embodiment, the potassium-competitive acid blocker (P-CAB) agent or its pharmaceutically acceptable salt, and prokinetic agent in the pharmaceutical composition are present in a weight ratio within the range of 1:9 to 9:1.

In the context of the present invention, the term "weight ratio" when used with respect to any element, for instance combination of a potassium-competitive acid blocker (P-CAB) agent or its pharmaceutical^ acceptable salt, and a prokinetic agent; it is intended to mean that the subject element consists of w/w (weight/weight) ratio ranging from 1:9 to 9:1 of the potassium-competitive acid blocker (P-CAB) agent or its pharmaceutical^ acceptable salt and the prokinetic agent; all the possible permutation and combination alternatives of weight ratio (w/w) are intended to be within the scope of the present invention.
For the purpose of present invention, the pharmaceutical composition comprising a combination of the potassium-competitive acid blocker (P-CAB) agent or its pharmaceutical^ acceptable salt, and prokinetic agent in a weight ratio within the range of 1:9 to 9:1 in a single dosage form, wherein all the possible permutation and combination alternatives of weight ratio (w/w) are intended to be within the scope of the present invention, including but not limited to 1:1, 2:1, 3:1, 4:1, 5:1, 6:1, 7:1, 8:1, 9:1, 2:1, 3:1, 4:1, 5:1, 6:1, 7:1, 8:1, 9:1, 3:1, 4:1, 3:2, 4:2, 3:3, 4:4, 6:2, 6:1, 5:1, 5:2 and the like.
In an embodiment, the pharmaceutical composition comprising a combination of the potassium-competitive acid blocker (P-CAB) agent or its pharmaceutical^ acceptable salt, and prokinetic agent in a weight ratio within the range of 1:9 to 9:1 in a single dosage form, wherein all the possible permutation and combination alternatives of weight ratio (w/w) are intended to be within the scope of the present invention, including but not limited to 1:1, 2:1, 3:1, 4:1, 5:1, 2:1, 2:2, 2:3, 2:4, 2:5, 3:1, 3:2, 3:4, 3:4, 4:1, 4:2, 4:3, 4:5, 5:1, 5:2, 5:3, 5:4, 5:5, 6:2, 7:2, 8:3, 9:1 and the like; for treatment, prevention and/or reduction of symptoms of respiratory disorders.
In an embodiment, the potassium-competitive acid blocker (P-CAB) agent or its pharmaceutical^ acceptable salt, and prokinetic agent in the pharmaceutical composition are present in a weight ratio (w/w) within the range of 1:5 to 5:1; wherein all the possible permutation and combination alternatives of weight ratio (w/w) are intended to be within the scope of the present invention, including but not limited to 1:1,

1:2, 1:3, 1:4, 1:5, 2:1, 2:2, 2:3, 2:4, 2:5, 3:1, 3:2, 3:3, 3:4, 3:5, 4:1, 4:2, 4:3, 4:4, 4:5, 5:1, :2, 5:3, 5:3, 5:4 or 5:5
In an embodiment, the potassium-competitive acid blocker (P-CAB) agent or its pharmaceutically acceptable salt, and prokinetic agent in the pharmaceutical composition are present in a weight ratio (w/w) within the range of 1:3 to 3:1; wherein all the possible permutation and combination alternatives of weight ratio (w/w) are intended to be within the scope of the present invention, including but not limited to 1:1, 1:2,1:3,2:1, 2:2, 2:3, 3:1, 3:2 or 3:3.
In yet another embodiment, the potassium-competitive acid blocker (P-CAB) agent or its pharmaceutically acceptable salt, and prokinetic agent in the pharmaceutical composition are present in a weight ratio (w/w) of 1:3.
In yet another embodiment, the potassium-competitive acid blocker (P-CAB) agent or its pharmaceutically acceptable salt, and prokinetic agent in the pharmaceutical composition are present in a weight ratio (w/w) of 1:1.5.
According to a preferred embodiment of the present invention, the pharmaceutical composition comprising a combination of the potassium-competitive acid blocker (P-CAB) agent or its pharmaceutically acceptable salt, and prokinetic agent in a weight ratio (w/w) within the range of, but not limited to 1:1.25, 1:1.5, 1:1.75, 1:2, 1:2.5, 1:2.75, 1:3.25, 1:3.5, 1:3.75, 1:4.25, 1:4.5, 1:4.75, 1:5.25, 1:5.5, 1:5.75, 1:6, 1:6.25, 1:6.5, 1:6.75, 1:7, 1:7.25, 1:7.5, 1:7.75, 1:8, 1: 8.25, 1:8.5, 1:8.75, 1:9, 1:9.25, 1:9.5, 1:9.75 2.75:1, 3.25:1, 3.5:1, 3.75:1, 4.25:1, 4.5:1 or 4.75:1.
In an embodiment, the potassium-competitive acid blocker (P-CAB) agent used in the pharmaceutical combination of the present invention is vonoprazan or its pharmaceutically acceptable salt.
In an embodiment, the potassium-competitive acid blocker (P-CAB) agent used in the pharmaceutical combination of the present invention is vonoprazan fumarate.

In an embodiment, the potassium-competitive acid blocker (P-CAB) agent used in the pharmaceutical combination of the present invention is Tegoprazan. In an embodiment, the prokinetic agent used in the pharmaceutical combination of the present invention is Domperidone.
In an embodiment, the prokinetic agent used in the pharmaceutical combination of the present invention is Itopride.
In an embodiment, the prokinetic agent used in the pharmaceutical combination of the present invention is Prucalopride.
In another embodiment, the present invention relates to a pharmaceutical composition comprising a combination of therapeutically effective amount of, (i) vonoprazan fumarate, and (ii) domperidone;
wherein, the vonoprazan fumarate or vonoprazan base equivalent and domperidone in the pharmaceutical composition are present in a weight ratio within the range of 1:9 to 9:1, for the effective treatment, prevention and/or reduction of symptoms of gastro-intestinal disease, gastro-esophageal disease and gastro-esophageal reflux disease (GERD).
In another embodiment, the present invention relates to a pharmaceutical composition
comprising a combination of therapeutically effective amount of,
(i) tegoprazan, and (ii) domperidone;
wherein, the tegoprazan and domperidone in the pharmaceutical composition are
present in a weight ratio within the range of 1:9 to 9:1, for the effective treatment,
prevention and/or reduction of symptoms of gastro-intestinal disease, gastro-esophageal
disease and gastro-esophageal reflux disease (GERD).
In another embodiment, the present invention relates to a pharmaceutical composition comprising a combination of therapeutically effective amount of, (i) tegoprazan, and (ii) domperidone;

wherein, the tegoprazan and domperidone in the pharmaceutical composition are present in a weight ratio within the range of 1:3 to 3:1, for the effective treatment, prevention and/or reduction of symptoms of gastro-intestinal disease, gastro-esophageal disease and gastro-esophageal reflux disease (GERD).
In one embodiment, the present invention relates to a pharmaceutical composition comprising a combination of therapeutically effective amount of a potassium-competitive acid blocker (P-CAB) agent or its pharmaceutically acceptable salt and a prokinetic agent in a single dosage form, together with one or more pharmaceutically acceptable excipients.
For the purpose of present invention, the potassium-competitive acid blocker (P-CAB) agent or its pharmaceutically acceptable salt and prokinetic agent are present as combination in a single dosage form.
In an embodiment, the present invention relates to pharmaceutical composition comprising a combination of therapeutically effective amount of a potassium-competitive acid blocker (P-CAB) agent or its pharmaceutically acceptable salt and a prokinetic agent in a single dosage form, wherein the potassium-competitive acid blocker (P-CAB) is present in an amount of 1 to 80 % w/w of total weight of composition and a prokinetic agent is present in an amount of 1 to 80 % w/w of total weight of composition.
In an embodiment, the present invention relates to pharmaceutical composition comprising a combination of therapeutically effective amount of a potassium-competitive acid blocker (P-CAB) agent or its pharmaceutically acceptable salt and a prokinetic agent in a single dosage form, together with one or more pharmaceutically acceptable excipients, wherein the potassium-competitive acid blocker (P-CAB) is present in an amount of 1 to 80 % w/w of total weight of composition and a prokinetic agent is present in an amount of 1 to 80 % w/w of total weight of composition.

In an embodiment, the present invention relates to pharmaceutical composition comprising a combination of therapeutically effective amount of a potassium-competitive acid blocker (P-CAB) agent or its pharmaceutically acceptable salt and a prokinetic agent in a single dosage form, wherein the potassium-competitive acid blocker (P-CAB) is present in an amount of 1 to 50 % w/w of total weight of composition.
In an embodiment, the present invention relates to pharmaceutical composition comprising a combination of therapeutically effective amount of a potassium-competitive acid blocker (P-CAB) agent or its pharmaceutically acceptable salt and a prokinetic agent in a single dosage form, wherein the prokinetic agent is present in an amount of 1 to 30 % w/w of total weight of composition.
In an embodiment, the potassium-competitive acid blocker (P-CAB) is present in an amount of 1 to 30 % w/w of total weight of composition.
In an embodiment, the potassium-competitive acid blocker (P-CAB) is present in an amount of 2 to 20 % w/w of total weight of composition.
In an embodiment, the prokinetic agent is present in an amount of 1 to 20 % w/w of total weight of composition.
In an embodiment, the prokinetic agent is present in an amount of 5 to 20 % w/w of total weight of composition.
In an embodiment, the present invention relates to pharmaceutical composition comprising a combination of therapeutically effective amount of a potassium-competitive acid blocker (P-CAB) agent or its pharmaceutically acceptable salt and a prokinetic agent in a single dosage form, together with one or more pharmaceutically acceptable excipients, wherein the potassium-competitive acid blocker (P-CAB) is present in an amount of 2 to 20 % w/w of total weight of composition and a prokinetic agent is present in an amount of 5 to 20 % w/w of total weight of composition.

For the purpose of present invention, the pharmaceutical composition comprising of active ingredients in an amount of % w/w of total weight of composition and one or more of the excipients in an amount of % w/w of total weight of composition as depicted in below Table-1:

Table-l
Ingredient amount % w/w of total composition weight of
potassium-competitive acid blocker (P-CAB) agent or its pharmaceutical^ acceptable salt 1 to 80 % w/w
prokinetic agent 1 to 50 % w/w
Diluent 0.05 to 65% w/w
Binders 1 to 25% w/w
Disintegrants 0.1 to 50% w/w
Glidants 0.1 to 15% w/w
Lubricants 0.1 to 15% w/w
Sweeteners 0.05 to 10% w/w
Preservative 0.05 to 10% w/w
Stabilizers 0.1 to 30% w/w
Plasticizers 0.05 to 20% w/w
Polymers 0.1 to 50% w/w
Flavours 0.01 to 10% w/w
Suspending agent 0.1 to 20% w/w
Buffering agents 0.001 to 5% w/w
Chelating agents 0.01 to 5% w/w
In an embodiment, the present invention relates to pharmaceutical composition comprising a combination of therapeutically effective amount of vonoprazan fumarate or vonoprazan base equivalent and domperidone in a single dosage form, wherein the vonoprazan fumarate or vonoprazan base equivalent is present in an amount of 1 to 80

% w/w of total weight of composition and domperidone is present in an amount of 1 to 80 % w/w of total weight of composition.
In an embodiment, the present invention relates to pharmaceutical composition comprising a combination of therapeutically effective amount of vonoprazan fumarate or vonoprazan base equivalent and domperidone in a single dosage form, wherein the vonoprazan fumarate is present in an amount of 2 to 20 % w/w of total weight of composition and domperidone is present in an amount of 5 to 20 % w/w of total weight of composition.
In an embodiment, vonoprazan fumarate or vonoprazan base equivalent is present in an amount of 1 to 30 % w/w of total weight of composition. More preferably, vonoprazan fumarate is present in an amount of 1 to 20 % w/w of total weight of composition.
In an embodiment, the present invention relates to pharmaceutical composition comprising a combination of therapeutically effective amount of tegoprazan and domperidone in a single dosage form, wherein the tegoprazan is present in an amount of
1 to 80 % w/w of total weight of composition and domperidone is present in an amount
of 1 to 50 % w/w of total weight of composition.
In an embodiment, tegoprazan is present in an amount of 1 to 30 % w/w of total weight of composition. More preferably, tegoprazan is present in an amount of 1 to 30 % w/w of total weight of composition
In an embodiment, the present invention relates to pharmaceutical composition comprising a combination of therapeutically effective amount of tegoprazan and domperidone in a single dosage form, wherein the tegoprazan is present in an amount of
2 to 20 % w/w of total weight of composition and domperidone is present in an amount
of 5 to 20 % w/w of total weight of composition.
For the purpose of present invention, the term 'pharmaceutically acceptable excipients' as used herein may include but not limited to, diluent, binder, disintegrant, glidant,

lubricant, diluent, flavouring agent, coating material, release modifying agents, sweetener, preservative, solvent, co-solvant, stabilizer, colourant, film forming polymer, plasticizer, anti-caking agent, vehicle, surfactants, stabilizers, antioxidants, tonicity agents, suspending agents, filers or their combination.
For the purpose of present invention, the term "diluent" refers to an agent used as filler in order to achieve the desired composition volume or weight. The diluent may be used in pharmaceutical composition as single compound or mixture of compounds. Examples of the diluents used in the present invention include are but not limited to, anhydrous or hydrated lactose, starch such as potato or corn or maize starch, and pre-gelatinized starch, sucrose, mannitol, sorbitol, lactitol, cellulose, powdered or microcrystalline cellulose, calcium phosphates, dibasic calcium phosphate and the like. The diluent may be used in an amount of 0.05 to 65% by weight.
For the purpose of present invention, the term "binder(s)" used herein include, but are not limited to, cellulose and its derivatives including, ethyl cellulose, hydroxypropyl cellulose, hydroxypropyl methylcellulose (hypromellose), hydroxyethyl cellulose, carboxymethyl cellulose, copovidone, gelatin, glucose, corn or maize starch, pre-gelatinized starch, hydrocolloids, sugars, polyvinyl pyrrolidone, sodium alginate, acacia, alginic acid, tragacanth, xanthan and the like or mixture thereof. The binders may be used in an amount of 1 to 25% by weight.
For the purpose of present invention, the term "disintegrant" used herein may include, but are not limited to, povidone, crospovidone, sodium starch glycolate, hydroxypropyl starch, microcrystalline cellulose, carboxymethylcellulose sodium or calcium, croscarmellose sodium, pregelatinized starch, polacrilin potassium, low-substituted hydroxypropylcellulose, sodium or calcium alginate, agar, guar gum, chitosan, alginic acid and the like or mixture thereof. The disintegrants may be used in an amount of 0.1 to 50% weight.
For the purpose of present invention, the term "glidant(s)" used herein may include, but are not limited to, fumed silica (colloidal silicon dioxide), colloidal silica, powdered cellulose, talc, tribasic calcium phosphate, magnesium stearate, magnesium carbonate,

and the like or mixtures thereof. The glidants may be used in an amount of 0.1 to 15% weight.
For the purpose of present invention, the term "lubricant" used herein may include, but are not limited to sodium oleate, sodium stearate, sodium benzoate, sodium chloride, stearic acid, sodium stearyl fumarate, calcium stearate, magnesium stearate, stearic acid, glyceryl distearate, magnesium lauryl sulfate, sodium stearyl fumarate, sucrose esters or fatty acid, zinc, polyethylene glycol, talc, mixtures thereof and the like; or mixture thereof. The lubricants may be used in an amount of 0.1 to 15% weight.
For the purpose of present invention, the term "sweetener" used herein may include, but are not limited to any natural or artificial sweetener, such as sucrose, xylitol, sodium saccharin, cyclamate, aspartame, acsulfame, fructose, glucose, maltitol, sorbitol, alitame, Neotame, sucralose or mixture thereof. The sweeteners may be used in an amount of 0.05 to 10% by weight.
For the purpose of present invention, the term "preservative" used herein may include, but are not limited to benzalkonium chloride, benzethonium chloride, benzoic acid, sodium benzoate, benzyl alcohol, bronopol, cetrimide, cetylpyridinium chloride, chlorhexidine, chlorbutanol, chlorocresol, chloroxylenol, cresol, ethyl alcohol, glycerin, hexetidine, imidurea, phenol, phenoxyethanol, phenylethyl alcohol, phenylmercuric nitrate, propylene glycol, sodium propionate, thimerosal, methyl paraben, ethyl paraben, propyl paraben, butyl paraben, isobutyl paraben, benzyl paraben, sorbic acid and potassium sorbate and the like or mixture thereof. The preservative may be present in an amount of 0.05 to 10% by weight.
For the purpose of present invention, the term "solvent" and "co-solvent" used herein may include, but are not limited to, water, ketones, esters, chlorinated solvents, alcohols, which are preferably aliphatic, alkanes or mixtures thereof and the like. Specific solvent examples, may include, but are not limited to Ci - C6 compound solvents, such as acetone, methyl ethyl ketone, methanol, ethanol, isopropanol, cyclohexane and methylene chloride and the like or mixture thereof.
For the purpose of present invention, the term "stabilizer and/or surface-active agent(s)" used herein may include, but are not limited to polysorbates, polyvinyl alcohol,

hydroxypropyl methylcellulose, propylene glycol, sodium oleate and/or polyoxyethylenated sorbitan laurate, Tweens, poloxamers, blockcopolymers, SLS and the like or mixture thereof. The stabilizers may be present in an amount of 0.1 to 30% by weight.
For the purpose of present invention, the term "coating" used herein may include, but are not limited to sugar, ethyl cellulose, hydroxyl propyl methyl cellulose, acrylate polymers, polyamides (nylons), polymethacrylates, polyalkenes (polyethylene, polypropylene), bio-degradable polymers (including homo- or hetero-polymers of polyhydroxy butyric or valeric acids and homo or hetero-polymers of polylactic, polyglycolic, polybutyric, polyvaleric, and polycaprolactic acids), waxes, natural oils, other hydrophobic insoluble materials such as polydimethylsiloxane, hydrophilic materials such as cross-linked sodium carboxymethyl cellulose and cross-linked sodium or uncross-linked carboxymethyl starch and the like or mixture thereof.
For the purpose of present invention, the term "plasticizer" for use in the present invention may include, but are not limited to castor oil, and/or diethyl phthalate, and/or triethyl citrate and/or salicylic acid, glyceryl triacetate and the like or mixture thereof. The plasticizers may be present in an amount of 0.05 to 20% by weight.
For the purpose of present invention, the term "release modifying agent" refers to any agent which modifies the release of the active ingredient. It can be polymeric or non-polymeric. Polymeric release modifying agents may include, but are not limited to cellulose acetate phthalate, cellulose acetate trimaletate, hydroxy propyl methylcellulose phthalate, polyvinyl acetate phthalate, polyvinyl alcohol phthalate, shellac; hydrogels and gel-forming materials, such as carboxyvinyl polymers, sodium alginate, sodium carmellose, calcium carmellose, sodium carboxymethyl starch, poly vinyl alcohol, hydroxyethyl cellulose, methyl cellulose, ethyl cellulose, gelatin, starch, and cellulose based cross-linked polymers in which the degree of crosslinking is low so as to facilitate adsorption of water and expansion of the polymer matrix, hydroxypropyl cellulose, hydroxypropyl methylcellulose, polyvinylpyrrolidone, crosslinked starch, macrocrystalline cellulose, chitin, pullulan, collagen, casein, agar, gum arabic, sodium carboxymethyl cellulose, (swellable hydrophilic polymers) poly(hydroxyalkyI methacrylate) (molecular weight 5 k to 5000 k), polyvinylpyrrolidone (molecular

weight 10 k to 360 k), anionic and cationic hydrogels, zein, polyamides, polyvinyl alcohol having a low acetate residual, a swellable mixture of agar and carboxymethyl cellulose, copolymers of maleic anhydride and styrene, ethylene, propylene or isobutylene, pectin (molecular weight 30 k to 300 k), polysaccharides such as agar, acacia, karaya, tragacanth, algins and guar, polyacrylamides, POLYOX® polyethylene oxides (molecular weight 100 k to 5000 k), AQUAKEEP® acrylate polymers, diesters of polyglucan, crosslinked polyvinyl alcohol and poly N-vinyl-2-pyrrolidone, hydrophilic polymers such as polysaccharides, methyl cellulose, sodium or calcium carboxymethyl cellulose, hydroxypropyl methyl cellulose, hydroxypropyl cellulose, hydroxyethyl cellulose, nitro cellulose, carboxymethyl cellulose, cellulose ethers, methyl ethyl cellulose, ethylhydroxy ethylcellulose, cellulose acetate, cellulose butyrate, cellulose propionate, gelatin, starch, maltodextrin, pullulan, polyvinyl pyrrolidone, polyvinyl alcohol, polyvinyl acetate, glycerol fatty acid esters, polyacrylamide, polyacrylic acid, natural gums, lecithins, pectin, alginates, ammonia alginate, sodium, calcium, potassium alginates, propylene glycol alginate, agar, and gums such as arabic, karaya, locust bean, tragacanth, carrageens, guar, xanthan, scleroglucan and mixtures and blends thereof. The polymers may be present in an amount of 0.1 to 50% by weight.
For the purpose of present invention, the term "flavouring agent" or "flavours used herein may include, natural or artificial flavours but are not limited to American Ice cream flavour, Vanillin, menthol, apple, fruity, mint, chocolate, anise oil, peppermint oil, lemongrass oil and the like or mixture thereof. The flavours may be present in an amount of 0.01 to 10% by weight.
For the purpose of present invention, the term "Suspending agents and/or thickeners" used herein may include but are not limited to microcrystalline cellulose, carboxymethyl cellulose sodium, hydroxypropyl cellulose, hydroxyethyl cellulose, hydroxypropylmethyl cellulose, methylcellulose, carboxymethyl cellulose and its salts/derivatives, and microcrystalline cellulose; carbomers; gums such as locust bean gum, xanthan gum, tragacanth gum, arabinogalactan gum, agar gum, gellan gum, guar gum, apricot gum, karaya gum, sterculia gum, acacia gum, gum arabic, and carrageenan; pectin; dextran; gelatin; polyethylene glycols; polyvinyl compounds such as polyvinyl acetate, polyvinyl alcohol, and polyvinyl pyrrolidone; sugar alcohols such

as xylitol and mannitol; colloidal silica;- and mixtures thereof. The suspending agent may be present in an amount of 0.1 to 20% by weight.
For the purpose of present invention, the term "buffering agent(s)" used herein may include but are not limited to citric acid, sodium citrate, sodium phosphate, potassium citrate, acetate buffer, and mixtures thereof. The buffering agents may be present in an amount of 0.001 to 5% by weight.
For the purpose of present invention, the term "Chelating agent(s)" used herein are selected from EDTA, dimercaprol. The chelating agents may be present in an amount of 0.01 to 5%.
For the purpose of present invention, the term "pH adjusting agent(s)" used herein may include organic acid, inorganic acids, base but are not limited sodium hydroxide, hydrochloric acid, acetic acid, tartaric acid, sodium hhydrogen phosphate, sodium carbonate and mixtures thereof. The pH adjusting agents are added in the composition to maintain the required pH.
For the purpose of present invention, the 'coating materials' used in the pharmaceutical formulation are selected from, but not limited to, sugars, hydroxypropyl methylcellulose (hypromellose), hydroxypropyl cellulose, methylcellulose, ethylcellulose, polyvinyl alcohol, sodium carboxylmethylcellulose, polymethacrylate-based copolymers based coatings such as Eudragit®, partly pre-formulated coating products such as available as OP ADR Y™ will be used; and the like, or mixtures thereof.
For the purpose of present invention, the terms, "formulation" or "composition" or "pharmaceutical composition" or "dosage form" as used herein include the composition is suitable for oral administration in the form of Tablets, capsules, tablet-in-capsule, granules, powders, pellets, spheres, mini-tablets, layered tablets, beads and particles, multiunit particulate systems (MUPS), solution, colloids, suspension, liquid, powder for reconstitution, powder for suspension, emulsions, syrups, elixirs, kit, liquid-filled capsules, co-packaged drug kit and/or unit dose packets and the like.
In one embodiment, the present invention relates to a pharmaceutical composition comprising a combination of therapeutically effective amount of (i) a potassium-

competitive acid blocker (P-CAB) agent or its pharmaceutically acceptable salt, and (ii) a prokinetic agent; wherein the present invention may be formulated into various dosage forms and may exhibit different drug release profile, including but not limited to immediate-release (IR) dosage form or Modified-release (MR) dosage form including extended-release (ER) dosage, sustained-release (SR) dosage, Controlled-release (CR) dosage, Delayed Release (DR) dosage, Long-Acting Release (LAR) dosage, Prolonged Release (PR) dosage, Pulsatile release dosage and Timed Release (TR) dosage.
For the purpose of present invention, the terms, "formulation" or "composition" or "pharmaceutical composition" or "dosage form" as used herein include the composition is suitable for oral administration, wherein composition may be administered once-daily (QD), twice-daily (BID), thrice-daily (TID), or four-times daily.
In one embodiment, the present invention relates to a pharmaceutical composition comprising a combination of therapeutically effective amount of (i) a potassium-competitive acid blocker (P-CAB) agent or its pharmaceutically acceptable salt and (ii) a prokinetic agent in a single dosage form, together with one or more pharmaceutically acceptable excipients, wherein the potassium-competitive acid blocker (P-CAB) is present in an amount from about 1 mg to about 200 mg. and a prokinetic agent is present in an amount from about 1 mg to about 100 mg.
In one embodiment, the present invention relates to a pharmaceutical composition comprising a combination of therapeutically effective amount of (i) a potassium-competitive acid blocker (P-CAB) agent or its pharmaceutically acceptable salt and (ii) a prokinetic agent in a single dosage form, together with one or more pharmaceutically acceptable excipients, wherein the potassium-competitive acid blocker (P-CAB) is present in an amount from about 1 mg to about 100 mg. and a prokinetic agent is present in an amount from about 1 mg to about 100 mg.
In one embodiment, the potassium-competitive acid blocker (P-CAB) is present in an amount from about 1 mg to about 50 mg.

In one embodiment, the potassium-competitive acid blocker (P-CAB) is present in an amount from about 5 mg to about 30 mg.
In one embodiment, the prokinetic agent is present in an amount from about 1 mg to about 50 mg.
In one embodiment, the prokinetic agent is present in an amount from about 5 mg to about 30 mg.
In one embodiment, the present invention relates to a pharmaceutical composition comprising a combination of therapeutically effective amount of (i) a potassium-competitive acid blocker (P-CAB) agent or its pharmaceutical^ acceptable salt and (ii) a prokinetic agent in a single dosage form, together with one or more pharmaceutical^ acceptable excipients, wherein the potassium-competitive acid blocker (P-CAB) is present in an amount from about 5 mg to about 50 mg. and a prokinetic agent is present in an amount from about 5 mg to about 30 mg.
In one embodiment, vonoprazan fumarate is present in an amount from about 5 mg to about 50 mg. More preferably, vonoprazan fumarate is present in an amount from about 5 mg to about 30 mg. More preferably, vonoprazan fumarate is present in an amount from about 10 mg to about 20 mg
In one embodiment, domperidone is present in an amount from about 5 mg to about 50 mg. More preferably, vonoprazan fumarate is present in an amount from about 5 mg to about 30 mg. More preferably, vonoprazan fumarate is present in an amount from about 10 mg to about 30 mg
In one embodiment, the present invention relates to a pharmaceutical composition comprising a combination of therapeutically effective amount of (i) vonoprazan fumarate and (ii) domperidone in a single dosage form, together with one of more pharmaceutically acceptable excipients, wherein vonoprazan fumarate is present in an amount from about 5 mg to about 50 mg. and domperidone is present in an amount from about 5 mg to about 30 mg.

In one embodiment, tegoprazan is present in an amount from about 1 mg to about 100 mg. More preferably, tegoprazan is present in an amount from about 5 mg to about 50 mg. More preferably, tegoprazan is present in an amount from about 5 mg to about 30 mg
In one embodiment, the present invention relates to a pharmaceutical composition comprising a combination of therapeutically effective amount of (i) tegoprazan and (ii) domperidone in a single dosage form, together with one or more pharmaceutically acceptable excipients, wherein tegoprazan is present in an amount from about 1 mg to about 100 mg. and domperidone is present in an amount from about 1 mg to about 100 mg.
In one embodiment, the present invention relates to a pharmaceutical composition comprising a combination of therapeutically effective amount of (i) tegoprazan and (ii) domperidone in a single dosage form, together with one or more pharmaceutically acceptable excipients, wherein tegoprazan is present in an amount from about 5 mg to about 50 mg. and domperidone is present in an amount from about 5 mg to about 50 mg.
In one embodiment, the present invention relates to a pharmaceutical composition comprising a combination of therapeutically effective amount of (i) tegoprazan and (ii) domperidone in a single dosage form, together with one or more pharmaceutically acceptable excipients, wherein tegoprazan is present in an amount from about 5 mg to about 30 mg. and domperidone is present in an amount from about 5 mg to about 30 mg.
In an embodiment, the pharmaceutical composition of the present invention comprising a combination of therapeutically effective amount of a potassium-competitive acid blocker (P-CAB) agent or its pharmaceutically acceptable salt and a prokinetic agent in a single dosage form, together with one or more pharmaceutically acceptable excipients, wherein the potassium-competitive acid blocker (P-CAB) is present in an amount from about 1 mg to about 100 mg. and a prokinetic agent is present in an amount from about 1 mg to about 100 mg.

In an embodiment, the pharmaceutical composition of the present invention comprising a combination of therapeutically effective amount of a potassium-competitive acid blocker (P-CAB) agent or its pharmaceutically acceptable salt and a prokinetic agent in a single dosage form, together with one or more pharmaceutically acceptable excipients, wherein the potassium-competitive acid blocker (P-CAB) is present in an amount from about 1 mg to about 50 mg. and a prokinetic agent is present in an amount from about 1 mg to about 50 mg.
It should be understood that, a person of ordinary skill in the art may select one or more of these excipients described above having regard to the particular desired properties of the dosage form. The corresponding amount of each type of excipient as employed, for example, diluent, binder, disintegrant, glidant and/or lubricant may vary within ranges conventional in the art.
In another aspect, the present invention relates to a pharmaceutical formulation comprising a combination of an therapeutically effective amount of a potassium-competitive acid blocker (P-CAB) agent or its pharmaceutically acceptable salt and a prokinetic agent, together with one or more pharmaceutically acceptable excipients.
In an embodiment, the present invention relates to a pharmaceutical formulation
comprising a combination of an therapeutically effective amount of;
(i) a potassium-competitive acid blocker (P-CAB) agent or its pharmaceutically
acceptable salt,
(ii) a prokinetic agent, and
(iii) one or more pharmaceutically acceptable excipients.
For the purpose of present invention, the suitable pharmaceutical formulation include oral dosage forms such as, but are not limited to, tablets, capsules, tablet-in-capsule, granules, powders, liquid, solution, suspension, emulsions, syrups, elixirs, liquid-filled capsules, kit, co-packaged drug kit and/or unit dose packets.
In an embodiment, the pharmaceutical formulation is Tablet.

In an embodiment, the pharmaceutical formulation is Capsule.
In an embodiment, the pharmaceutical formulation is Tablet-in-capsule.
In an embodiment, the pharmaceutical formulation is Capsule, wherein the Capsule is filled with Tablet(s).
In an embodiment, the pharmaceutical formulation is Capsule, wherein the Capsule is filled with one or more Tablet in a coated or non-coated form.
For the purpose of present invention, the pharmaceutical composition is a Capsule is filled with Tablets of potassium-competitive acid blocker (P-CAB) agent or its pharmaceutically acceptable salt and prokinetic agent; wherein the Tablet comprising of active ingredients in an amount of % w/w of total weight of composition and one or more of the excipients in an amount of % w/w of total weight of Capsule composition as depicted in below Table-2:
Table-2
Ingredient amount % w/w of total weight
of composition
potassium-competitive acid blocker (P- 1 to 80 % w/w
CAB) agent or its pharmaceutically
acceptable salt (Tablet)
prokinetic agent (Tablet) 1 to 80 % w/w
Excipient(s) 1 to 20 % w/w
Net Fill weight of Capsule (Tablet-in- 100% w/w
capsule)
In an embodiment, the pharmaceutical formulation comprises a potassium-competitive acid blocker (P-CAB) agent or its pharmaceutically acceptable salt in a. immediate release Tablet dosage form.
In an embodiment, the pharmaceutical formulation comprises a prokinetic agent in an immediate release (IR) or Sustained release (SR) Tablet dosage form.

In an embodiment, the pharmaceutical formulation comprises a potassium-competitive acid blocker (P-CAB) agent selected from a group consisting of, but not limited to Tegoprazan, Vonoprazan, Linaprazan, Soraprazan, Revaprazan, Fexuprazan, Zastaprazan and Keverprazan; or its pharmaceutically acceptable salt.
In an embodiment, the potassium-competitive acid blocker (P-CAB) agent used in the pharmaceutical combination of the present invention is Vonoprazan or its pharmaceutically acceptable salt.
In an embodiment, the potassium-competitive acid blocker (P-CAB) agent used in the pharmaceutical combination of the present invention is Vonoprazan Fumarate or vonoprazan base equivalent.
In an embodiment, the potassium-competitive acid blocker (P-CAB) agent used in the pharmaceutical combination of the present invention is Tegoprazan.
In an embodiment, the pharmaceutical formulation comprises a prokinetic agent selected from the group consisting of but not limited to Domperidone, Itopride Benzamide, Cisapride, Mosapride, Metoclopramide, Prucalopride, Renzapride, Tegaserod, Mitemcinal, Levosulpiride, Cinitapride, Linaclotide, and the like.
In an embodiment, the pharmaceutical formulation comprising a combination of a potassium-competitive acid blocker (P-CAB) agent or its pharmaceutically acceptable salt, and domperidone; is used in the treatment, prevention and/or reduction of symptoms of gastro-intestinal disease, gastro-esophageal disease, gastro-esophageal reflux disease (GERD), peptic ulcer, gastric ulcer, duodenal ulcer, NSAID-induced ulcers, gastritis, infection of Helicobacter pylori, dyspepsia, functional dyspepsia, Zollinger-Ellison syndrome, non-erosive reflux disease (NERD), visceral pain, heartburn, nausea, esophagitis, dysphagia, erosive esophagitis (EE), Barrett esophagus (BE) and erosive reflux disease.
In an embodiment, the pharmaceutical formulation comprising a combination of a potassium-competitive acid blocker (P-CAB) agent or its pharmaceutically acceptable

salt, and a prokinetic agent; wherein the potassium-competitive acid blocker (P-CAB) agent or its pharmaceutical^ acceptable salt and the prokinetic agent are present as a single dosage form.
In an embodiment, the pharmaceutically acceptable excipient(s) is selected from the group consisting of diluent, binder, disintegrant, lubricant, optionally glidant, optionally coating material or a combination thereof.
In an embodiment, the diluent is selected from the group consisting of lactose such as a-lactose monohydrate, spray dried lactose and anhydrous lactose, starch such as potato or corn or maize starch and pre-gelatinized starch, sucrose, mannitol, sorbitol, cellulose such as powdered cellulose and microcrystalline cellulose, calcium phosphates and the like, or mixture thereof.
In an embodiment, the binder is selected from the group consisting of cellulose and its derivatives including, ethyl cellulose, hydroxypropyl cellulose, hydroxypropyl methylcellulose (hypromellose), hydroxyethyl cellulose, carboxymethyl cellulose, Copovidone, gelatin, glucose, corn or maize starch, pre-gelatinized starch, hydrocolloids, sugars, polyvinyl pyrrolidone, sodium alginate, acacia, alginic acid, tragacanth, xanthan, used alone or combinations thereof.
In another embodiment, the disintegrant is selected from the group consisting of povidone, crospovidone, sodium starch glycolate, hydroxypropyl starch, microcrystalline cellulose, carboxymethylcellulose sodium or calcium, croscarmellose sodium, pregelatinized starch, polacrilin potassium, low-substituted hydroxypropylcellulose, sodium or calcium alginate, agar, guar gum, chitosan, alginic acid and mixtures thereof.
In another embodiment, the glidant is selected from the group consisting of fumed silica (colloidal silicon dioxide), colloidal silica, powdered cellulose, talc, tribasic calcium phosphate, magnesium stearate, magnesium carbonate, and the like or mixtures thereof.
In another embodiment, the lubricant is selected from the group consisting of sodium oleate, sodium stearate, sodium benzoate, sodium chloride, stearic acid, sodium stearyl fumarate, calcium stearate, magnesium stearate, magnesium lauryl sulfate, sodium

stearyl fumarate, sucrose esters or fatty acid, zinc, polyethylene glycol, talc, mixtures thereof and the like; or mixture thereof.
For the purpose of present invention, the terms as used herein, "formulation" or "composition" or "pharmaceutical composition" or "dosage form" as used herein synonymously include solid dosage forms such as granules, multiunit particulate systems (MUPS), pellets, spheres, tablets, capsules, mini-tablets, tablet-in-capsule, layered tablets, beads and particles, and the like; and liquid dosage forms such as solutions, suspensions, emulsions, colloids, kit, co-packaged drug kit and the like.
It should be understood that, a person of ordinary skill in the art may select one or more additional excipients such as surfactants, co-surfactants, emulsifiers, stabilizers, solubilizers, dispersing agents, suspending agents, thickening agents, preservatives, co-solvents, vehicles, pH-adjusting agents, flavourants or sweetners; depending on the type of the dosage form or with regards to the particular desired properties of the dosage form.
In an embodiment, the pharmaceutical combination for the effective treatment, prevention and/or reduction of symptoms of gastro-intestinal disease, gastro-esophageal disease, gastro-esophageal reflux disease (GERD), peptic ulcer, gastric ulcer, duodenal ulcer, NSAID-induced ulcers, gastritis, infection of Helicobacter pylori, dyspepsia, functional dyspepsia, Zollinger-Ellison syndrome, non-erosive reflux disease (NERD), visceral pain, heartburn, nausea, esophagitis, dysphagia, erosive esophagitis (EE), Barrett esophagus (BE) and erosive reflux disease comprising therapeutically effective amount of a potassium-competitive acid blocker (P-CAB) agent or its pharmaceutically acceptable salt, and a prokinetic agent; wherein the composition shown better synergy and stability^ along with reduced side effect.
In one embodiment, the present invention relates to a Stable Capsule, tablet or Tablet-in-capsule dosage form comprising a combination of therapeutically effective amount of a potassium-competitive acid blocker (P-CAB) agent or its pharmaceutically acceptable salt and a prokinetic agent in a single dosage form, together with one or more pharmaceutically acceptable excipients, wherein the potassium-competitive acid blocker

(P-CAB) is present in an amount from about 1 mg to about 100 mg. and a prokinetic agent is present in an amount from about 1 mg to about 100 mg.
In one embodiment, the present invention relates to a Stable Capsule, tablet or Tablet-in-capsule dosage form comprising a combination of therapeutically effective amount of a potassium-competitive acid blocker (P-CAB) agent or its pharmaceutically acceptable salt and a prokinetic agent in a single dosage form, together with one or more pharmaceutically acceptable excipients, wherein the potassium-competitive acid blocker (P-CAB) is present in an amount from about 1 mg to about 100 mg. and a prokinetic agent is present in an amount from about 1 mg to about 100 mg. and wherein the formulation is stable at 25°C ± 2°C and RH 60% ± 5% storage condition.
It is evident from the stability data study of the Formulation prepared as per example 1 and example 2 of the present invention, that the product is stable for at least 3 month at 25°C ± 2°C and RH 60% ± 5% storage condition. For the purpose of present invention, the Capsule of finalized formulation were packed in Alu-Alu Strip pack respectively. It is evident from the stability data study of the formulation prepared as per example 1 and example 2 of the present invention, that the product is stable for at least 3 month at 25 °C ± 2°C and RH 60% ± 5% storage condition, wherein the Assay [%] was observed 97.1 to 100.1% with respect to the specification limit of Not less than 90.0 and not more than 110.0
For the purpose of present invention, there is provided dissolution profile of the formulation obtained according to Example-1 of the instantly presented patent specification. Accordingly, Figure-1 depicts graphic representation of dissolution profile (% drug cumulative release) of the formulation obtained according to Example-1. It is evident from the dissolution study of the formulation obtained from Example 1, that the % drug cumulative release is about 33% in 0.5 hours, about 50% in 8 hours and more than 90% in 24 hours. More precisely, the % drug release is more than 90% in 24 hours.

For the purpose of present invention, two types of capsule are commonly used and are classified according to the nature and flexibility of the capsule shell: soft and hard capsules. The Soft capsules are single unit solid dosage forms comprising a liquid or semi-solid fill. It is formed, filled and sealed in one operation using a rotary die process. Similarly, the hard capsules have been conventionally used for delivery of solids in the form of powders, granulates and pellets. The Hard capsules are single unit dosage forms, consisting of a cap and a body, which are manufactured separately and which are supplied empty for filling.
The invention also provides a method of preparing an oral liquid pharmaceutical composition comprising: preparing suspending system, suspending at least one substantially insoluble pharmaceutical active in the suspending system and matching the true density of the substantially insoluble pharmaceutical active with the specific gravity of the aqueous medium.
The invention is further illustrated by the following examples which are provided to be exemplary of the invention, and do not limit the scope of the invention. While the present invention has been described in terms of its specific embodiments, certain modifications and equivalents will be apparent to those skilled in the art and are intended to be included within the scope of the present invention. These examples, which set forth the best mode presently contemplated for carrying out the invention, are intended to illustrate and not to limit the invention. Also, modifications that do not substantially affect the activity of the various embodiments of this invention are included within scope of the invention disclosed herein. Accordingly, the following examples are intended to illustrate but not to limit the scope of the present invention.
Examples;
Example 1:
Preparation of Vonoprazan and Domperidone Capsule (10 mg + 30 mg)
According to the present invention there is provided a capsule which is filled with Part
A, Part B and Part C comprising of;
Part A : Tablet of Vonoprazan Fumarate (equivalent to Vonoprazan base 10 mg)

[Vonoprazan Fumarate (13.36 mg) equivalent to Vonoprazan base (10 mg)] Part B : Tablet (Immediate release - IR) of Domperidone (10 mg) Part C : Tablet (Sustained release - SR) of Domperidone (20 mg)
Composition of Part A : Tablet of Vonoprazan Fumarate equivalent to Vonoprazan base (10 mg) as follows :

Part A
Tablet of Vonoprazan Fumarate equivalent to Vonoprazan base (10 mg)
Ingredients Quantity in mg / Tablet
Dry Mix
Vonoprazan Fumarate
equivalent to Vonoprazan base (10 mg) 13.360
Mannitol 33.090
Fumaric Acid 2.750
Hydroxy Propyl Cellulose 2.250
Microcrystalline Cellulose 14.000
Croscarmellose Sodium 3.500
Lubrication
Magnesium Stearate 1.050
Total weight of uncoated Tablet 70.000
Film - coating
Hydroxy Propyl Methylcellulose 1.650
Polyethylene Glyolol 6000 0.195
Titanium Dioxide' 0.300
Purified Talc 0.433
Ferric Oxide Red 0.022

Purified Water 23.400
Weight build up 2.000
Total weight of film coated Tablet 72.000
Comi position of Part B : Tablet (Immediate release - IR) of Domperidone (10 m s) as
follows : 5
PartB Tablet (Immediate release - IR) of Domperidone (10 mg)
Ingredients Quantity in mg /
Tablet
10
Dry Mix
Domperidone 10
Lactose Monohydrate 41.4
Microcrystalline Cellulose 10
Sodium Starch Glycolate 2 15
Binder
Hydroxypropyl Cellulose 2.1
Isopropyl alcohol 13
Pre-Lubrication
Croscarmellose Sodium 2.000
Colloidal Silicon Dioxide 0.500
Purified Talc 1.000
Lubrication
Magnesium Stearate i.ooo 25
Total weight of uncoated Tablet 70.000

Composition < Df Part C : Tablet (Sustained release - SR) of Domperidone f20 mg) as
follows :
Part C Tablet (Sustained release - SR) of Domperidone (20 mg)
Ingredients Quantity in mg / Tablet
Dry Mix
Domperidone 20
Fumaric Acid 64
Hydroxypropyl Methylcellulose 6
Hypromellose 5
Binder
Povidone 2
Isopropyl Alcohol 28
Prelubrication
Lactose Anhydrous 12
Lubrication
Magnesium Stearate 1
Total weight of uncoated Tablet 110
Coating
Methacrylic Acid & Ethyl Acrylate Copolymer 3.185
Triethyl Citrate 0.520
Purified Talc 1.134
Titanium Dioxide 0.166
Quinoline Yellow Lake 0.065
Isopropyl Alcohol 65.000
Weight build up 3.900
Total weight of coated Tablet 113.900
Purified Talc IP 0.100
Final weight of coated Tablet 114.000
5 Man ufacturing formula for CAPSULE of Example 1 :
Filling content Quantity / Capsule


Part A Vonoprazan Tablets 10 mg [Vonoprazan Fumarate (13.36 mg) equivalent to Vonoprazan base (10 mg)] 1 Tablet
PartB Domperidone Tablets 10 mg 'Immediate release - IR) 1 Tablet
PartC Domperidone Tablets 20 mg 'Sustained release - SR) 1 Tablet
Manufacturing process for the formulation of example 1:
Process steps
Part A : Tablet of Vonoprazan Fumarate equivalent to Vonoprazan base (10 mg)
Sifting / Co-sifting Co-sift Vonoprazan Fumarate with Microcrystalline cellulose (Avicel PH 200) through s.s sieve #30 ASTM on a vibro sifter, Mannitol (Pearlitol 200 GT) through s.s.sieve # 30 ASTM on a vibro sifter; Fumaric Acid, Hydroxy Propyl Cellulose (Klucel LXF) and Croscarmellose Sodium through #40 ASTM on a vibro sifter.
Blending Load the sifted material in blender and mix as per following parameters as Speed of 10 RPM for 30 min,
Lubrication Co-Sift Magnesium stearate through s.s sieve # 60 ASTM on vibro sifter with the blend above material.
Compression Compress the above lubricated blend on rotary compression machine and check physical parameters of compressed tablets as per In-process specification.
Store the compressed tablets in s.s container / HDPE container lined with double polythene bags. Keep the s.s container /HDPE container well closed.
Film - coating Dissolve Hydroxypropyl methyl cellulose, Polyethylene Glycol 6000 in purified water under stirring. Sift Colour Ferric oxide red, Titanium Dioxide and Purified Talc through s.s.sieve # 40 ASTM using vibro sifter. Load the uncoated tablets into auto coater. Spray the film-coating suspension on cascading tablets.
Part B : Tablet (Immediate release - IR) of Domperidone (10 mg)
Sifting Sift Domperidone through s.s.sieve # 40 ASTM on a vibro sifter; Lactose Monohydrate (Pharmatose 200 M) through s.s.sieve # 40 ASTM on a vibro sifter; Sift Microcrystalline Cellulose (Avicel PH 101) through s.s.sieve # 40 ASTM on a vibro sifter; Sodium Starch Glycolate (Type A, Glycols) through s.s.sieve # 40 ASTM on a vibro sifter.


Dry Mixing Load the above sifted material in planetary mixer / rapid mixer granulator and mix it for 20/7 minutes at slow speed.
Binder preparation Dissolve Hydroxypropyl Cellulose (HPC-L) in Isopropyl Alcohol under stirring till clear solution is obtained.
Granulation Add above binder solution to the dry mix blend present in planetary mixer / rapid mixer granulator, continue mixing till granules of required consistency is achieved.
Drying and Sizing Transfer the above wet mass in to the fluid bed dryer. Air dry the wet mass in fluid bed dryer inlet air on for 10 min at room temperature. Reshuffle the granules and again dry the granules.
Pre -Lubrication Co-sift Croscarmellose Sodium (AC-DI-SOL SD -711) and Colloidal Silicon Dioxide (Aerosil 200) through s.s.sieve # 40 ASTM on a vibro sifter, Sift Purified Talc through s.s.sieve # 40 ASTM on a vibro sifter. Load into the above sized granules.
Lubrication Sift Magnesium Stearate (Liga MF-2-V- MB) through s.s.sieve # 60 ASTM on a vibro sifter and add to the blender and lubricate.
Compression Compress the above lubricated granules on the rotary compression machine and check physical parameters of compressed tablets as per In-process specification.
Part C : Tablet (Sn istained release - SR) of Domperidone (20 mg)
Sifting Sift Fumaric Acid through s.s.sieve # 40 ASTM on a vibro sifter; Co-sift Domperidone, Hypromellose (K100M), Hypromellose (Methocel K15M Premium) with sifted Fumaric Acid of step 6.16.1 through s.s.sieve # 30 ASTM on a vibro Sifter.
Dry Mixing Load the above sifted material in planetary mixer / rapid mixer granulator and mix it for 20/7 minutes at slow speed.
Binder preparation Dissolve Povidone K30 in Isopropyl Alcohol under stirring till clear solution is observed.
Granulation Add above binder solution to the dry mix blend present in planetary mixer / rapid mixer granulator continuously at slow / fast impeller and chopper speed till to get the required consistency of granules.
Drying and Sizing Transfer the above wet mass in to the fluid bed dryer. Air dry the wet mass in fluid bed dryer inlet air on for 10 min at room temperature. Reshuffle the granules and again dry the granules.
Pre -Lubrication Sift Lactose anhydrous through s.s.sieve # 40 ASTM on a vibro sifter; and load into the above granules
Lubrication Sift Magnesium Stearate through s.s.sieve # 60 ASTM on a vibro sifter; and add into the above pre-lubricated material
Compression Compress the above lubricated granules on the rotary compression machine and check physical parameters of compressed tablets as per In-process specification.
Coating add Methacrylic acid- ethyl Acrylate copolymer (Eudragit L 100-55) and Triethyl citrate in Isopropyl alcohol. Disperse Purified Talc, Titanium Dioxide and Quinoline Yellow Lake in Isopropyl alcohol and pass through colloid mill. Transfer the slurry to the polymer solution. Load the uncoated tablets into the coating pan.

Spray the coating solution on pre-heated tablets using suitable coating apparatus.
CAPSULE FILLING PROCESS (PART A + PART B + PART C)
Capsule Filling
Load 01 (one) no. of Vonoprazan Tablet 10 mg (of Part A) from separate filling station.
Load 01 (one) no. of Domperidone Tablets 10 mg (of Part B) from separate filling
station.
Load 01 (one) no. of Domperidone Sustained Release Tablets 20 mg (of Part C) from
separate filling station.
Collect the capsules in a s. s. container lined with double polythene bags and keep the
container well closed.
Finished Product Analysis and Packing as per specification.
Example 2:
Preparation of Vonoprazan and Domperidone Capsule (20 mg + 30 mg)
5 According to the present invention there is provided a capsule which is filled with Part
A, Part B and Part C comprising of;
Part A : Tablet of Vonoprazan Fumarate (equivalent to Vonoprazan base 20 mg)
[Vonoprazan Fumarate (26.72 mg) equivalent to Vonoprazan base (20 mg)]
Part B : Tablet (Immediate release - IR) of Domperidone (10 mg)
10 Part C : Tablet (Sustained release - SR) of Domperidone (20 mg)
The composition of Part A, Part B and Part C of Example-2 is manufactured using the
similar procedure and formula of Example-1.
15 Manufacturing formula for CAPSULE of Example 2 :
Filling content Quantity / Capsule
Part A Vonoprazan Tablets 20 mg [Vonoprazan Fumarate (26.72 mg) equivalent to Vonoprazan base (20 mg)] 1 Tablet
PartB Domperidone Tablets 10 mg (Immediate release - IR) 1 Tablet
PartC Domperidone Tablets 20 mg (Sustained release - SR) 1 Tablet
Ca Dsule filling process (Part A + Part B + Part C) of Example-2 is performed usinj I the
sin lilar procedi ore and formula of Example-1.

Example 3: Tablet formulation of Tegoprazan and Domperidone (25 mg + 10 mg)
According to the present invention there is provided a composition consisting of
Tegoprazan and Domperidone, along with required ingredients. 5
Ingredients Quantity in mg / Tablet
Tegoprazan 25
Domperidone 10
Mannitol 33.090
Fumaric Acid 2.750
Hydroxy Propyl Cellulose 2.250
Microcrystalline Cellulose 14.000
Croscarmellose Sodium 3.500
Magnesium Stearate 1.050
Hydroxy Propyl Methylcellulose 1.650
Polyethylene Glyolol 6000 0.195
Titanium Dioxide 0.300
Purified Talc 0.433
Ferric Oxide Red 0.022
Purified Water 23.400
The Tat )let composition of Example-3 is manufactured using the similar procedure and
formula of Example-1.
10 Example 4: Tablet formulation of Tegoprazan and Domperidone (50 mg + 20 mg)
The Tablet composition of Example-4 is manufactured using the similar procedure and
formula of Example-3.
Example 5: Tablet formulation of Vonoprazan and Domperidone (10 mg + 30 mg)
15 According to the present invention there is provided a composition consisting of
Vonoprazan and Domperidone, along with required ingredients.
Ingredients Quantity in mg / Tablet
Vonoprazan 10

Domperidone 30
Mannitol 33.090
Fumaric Acid 2.750
Hydroxy Propyl Cellulose 2.250
Microcrystalline Cellulose 14.000
Croscarmellose Sodium 3.500
Magnesium Stearate 1.050
Hydroxy Propyl Methylcellulose 1.650
Polyethylene Glyolol 6000 0,195
Titanium Dioxide 0.300
Purified Talc 0.433
Ferric Oxide Red 0.022
Purified Water 23.400
The Tablet composition of Example-5 is manufactured using the similar proced ure and
formula of Example-1.
5 Example 6: Tablet formulation of Vonoprazan and Domperidone (20 mg + 30 mg)
The Tablet composition of Example-6 is manufactured using the similar procedure and
formula of Example-5.
Stability data:
10 Stability data of Capsule formulation prepared as per Example 1 or Example 2:
The hard gelatin capsule of finalized formulation contains :
Vonoprazan Fumarate equivalent to Vonoprazan 20 mg (As immediate release tablet) Domperidone 10 mg (As immediate release tablet) Domperidone 20 mg (As sustained release tablet) 15 Pack: Alu-Alu Strip
Storage Condition: 25°C ± 2°C and RH 60% ± 5%
The obtained stability results are summarized as follows:
Testing parameters Specifications Initial 1M 3M

Testing parameters Specifications Initial IM 3M
Description Size "0" hard gelatine capsule having light green cap and light yellow body filled with one tablet
of Vonoprazan Tablets 20 mg, one tablet of Domperidone Tablets 10 mg and one tablet of Domperidone SR Tablets 20 mg Complies Complies Complies
Average net filled 324.0 mg ± 7.5 % 328.5 326.3 331.5
content (mg)
Assay [%] Not less than 90.0 and not more
a. Vonoprazan
b. Domperidone
(As immediate
release tablet) than 110.0
Not less than 90.0 and not more than 110.0 99.8 98.0 100.1 99.3 99.4 100.1
c. Domperidone Not less than 90.0 and not more 97.1 98.1 99.2
(As sustained than 110.0
release tablet)
The hard gelatin capsule of finalized formulation contains :
Vonoprazan Fumarate equivalent to Vonoprazan 10 mg (As immediate release tablet)
5 Domperidone 10 mg (As immediate release tablet)
Domperidone 20 mg (As sustained release tablet)
Pack: Alu-Alu Strip
Storage Condition: 25°C ± 2°C and RH 60% ± 5%
10 The obtained stability results are summarized as follows:
Testing Specifications Initial IM 3M
parameters
Description Size "0" hard gelatin capsule having red cap and white body filled with one tablet of Vonoprazan Tablets 10 mg (pink
coloured), one tablet of Domperidone Tablets 10 mg (white to off white) and one tablet of Domperidone SR Tablets 20 mg (yellow Complies Complies Complies
coloured).

_^ . *>
We claim "*
5 LA pharmaceutical composition comprising a combination of therapeutically effective
amount of,
(i) a potassium-competitive acid blocker (P-CAB) agent or its pharmaceutical^
acceptable salt, and
(ii) a prokinetic agent; 10 Wherein, the potassium-competitive acid blocker (P-CAB) agent or its pharmaceutical^
acceptable salt, and the prokinetic agent in the pharmaceutical composition are present
in a weight ratio within the range of 1:9 to 9:1, for the effective treatment, prevention
and/or reduction of symptoms of gastro-intestinal disease, gastro-esophageal disease
and gastro-esophageal reflux disease (GERD). 15
2. The pharmaceutical composition of claim 1, wherein the potassium-competitive acid
blocker (P-CAB) agent selected from Vonoprazan, Tegoprazan, Linaprazan,
Soraprazan, Revaprazan, Fexuprazan, Zastaprazan and Keverprazan; or its
pharmaceutically acceptable salt.
20
3. The pharmaceutical composition of claim 1, wherein the prokinetic agent is selected
from Domperidone, Itopride Benzamide, Cisapride, Mosapride, Metoclopramide,

Prucalopride, Renzapride, Tegaserod, Mitemcinal, Levosulpiride, Cinitapride and Linaclotide, or mixture thereof.
4. The pharmaceutical composition of claim 1, wherein the potassium-competitive acid blocker (P-CAB) agent and the prokinetic agent each individually present in an amount of 1 to 80 % w/w of total weight of composition.
5. The pharmaceutical composition of claim 1, wherein the potassium-competitive acid blocker (P-CAB) and the prokinetic agent each individually present in an amount from about 1 mg to about 100 mg.
6. The pharmaceutical composition of claim 1, wherein the potassium-competitive acid blocker (P-CAB) or its pharmaceutically acceptable salt, and the prokinetic agent are present as a single dosage form.
7. The pharmaceutical composition of claim 1 to claim 6, wherein the composition is suitable for oral administration in the form of Tablets, capsules, granules, powders, pellets, spheres, mini-tablets, tablet-in-capsule, layered tablets, beads and particles, multiunit particulate systems (MUPS), solution, colloids, suspension, liquid, powder for reconstitution, powder for suspension, emulsions, syrups, elixirs, kit, liquid-filled capsules, co-packaged drug kit and/or unit dose packets.
8. The pharmaceutical composition of claim 1 to claim 7, wherein composition may be in the form of immediate-release (IR) dosage form or Modified-release (MR) dosage form including extended-release (ER) dosage, sustained-release (SR) dosage, Controlled-release (CR) dosage, Delayed Release (DR) dosage, Long-Acting Release (LAR) dosage, Prolonged Release (PR) dosage, Pulsatile release dosage and Timed Release (TR) dosage.
9. The pharmaceutical composition of claim 1 to claim 8, wherein composition may be administered once-daily (QD), twice-daily (BID), thrice-daily (TID), or four-times daily.

10. The pharmaceutical composition of claim 1 to claim 9, wherein the pharmaceutical composition comprising a combination of therapeutically effective amount of a potassium-competitive acid blocker (P-CAB) agent or its pharmaceutically acceptable salt and a prokinetic agent in a single dosage form, together with one or more pharmaceutically acceptable excipients, wherein the potassium-competitive acid blocker (P-CAB) is present in an amount from about 1 mg to about 100 mg. and a prokinetic agent is present in an amount from about 1 mg to about 100 mg.
11. A pharmaceutical composition comprising vonoprazan fumarate or vonoprazan base equivalent in an amount of 1 to 100 mg and Domperidone in an amount of 1 to 100 mg in a single dosage form;, together with one or more pharmaceutically acceptable excipients; for the effective treatment, prevention and/or reduction of symptoms of gastro-intestinal disease, gastro-esophageal disease and gastro-esophageal reflux disease (GERD).
12. The pharmaceutical composition of claim 11, wherein the composition is a Tablet, Capsule or tablet-in-capsule dosage form comprising vonoprazan or its salts in an amount of 1 to 80% w/w, Domperidone in an amount of 1 to 80% w/w in a single dosage form; along with one or more excipients selected from a diluent, binder, disintegrant, glidant, lubricant, diluent, flavouring agent, coating material, release modifying agents, sweetener, preservative, solvent, co-solvant, stabilizer, colourant, film forming polymer, plasticizer, anti-caking agent, vehicle, surfactants, stabilizers, antioxidants, tonicity agents, suspending agents, filers or their combination.
13. The pharmaceutical composition of claim 11, wherein the composition is a Tablet, Capsule or tablet-in-capsule dosage form comprising vonoprazan fumarate or vonoprazan base equivalent in an amount of 1 to 30 mg, Domperidone in an amount of 1 to 30 mg in a single dosage form; along with one or more excipients selected from a diluent, binder, disintegrant, glidant, lubricant, diluent, flavouring agent, coating material, release modifying agents, sweetener, preservative, solvent, co-solvant, stabilizer, colourant, film forming polymer, plasticizer, anti-caking agent, vehicle,

*
surfactants, stabilizers, antioxidants, tonicity agents, suspending agents, filers or their combination.
14. The pharmaceutical composition of claim 1 to claim 13, wherein the combination is used in the treatment, prevention and/or reduction of symptoms of gastro-intestinal disease, gastro-esophageal disease, gastro-esophageal reflux disease (GERD), peptic ulcer, gastric ulcer, duodenal ulcer, NSAID-induced ulcers, gastritis, infection of Helicobacter pylori, dyspepsia, functional dyspepsia, Zollinger-Ellison syndrome, non-erosive reflux disease (NERD), visceral pain, heartburn, nausea, esophagitis, dysphagia, erosive esophagitis (EE), Barrett esophagus (BE) and erosive reflux disease.