DESC:MULTI LAYERED FORMULATION AND PROCESS OF PREPARATION THEREOF”
FIELD OF THE INVENTION:
The present invention relates to a multi-layered dosage form comprising combination of potassium-competitive acid blockers (PCAB) inhibitors or proton-pump inhibitor and prokinetic agents more particularly to a multi-layer formulation comprising Vonoprazan and Domperidone pellets or granules, tablets in a capsule or bilayer tablet composition and process of preparation thereof.
BACKGROUND OF THE INVENTION:
Vonoprazan fumarate is chemically known as 1-[5-(2-Fluorophenyl)-1-(pyridin-3-ylsulfonyl)-1H-pyrrol-3-yl]-N-methylmethanamine mono fumarate was approved by USFDA under the brand name VOQUEZNA of innovator Phathom pharmaceuticals INC.
Domperidone is chemically known as 1-[3-(Piperidin-1-yl) propyl]-1,3-dihydro-2H benzimidazol-2-one.

Potassium-competitive acid blockers (P-CABs) are a new class of medications used to treat and prevent conditions caused by excess stomach acid such as Gastroesophageal reflux disease (GERD), Peptic ulcers, Erosive esophagitis. P-CABs work differently than proton pump inhibitors (PPIs) which are the most commonly used type of acid-reducing medication. PPIs work by blocking the production of acid in the stomach, while P-CABs work by blocking the action of potassium, which is necessary for acid production. P-CABs have several potential advantages over PPIs including Faster onset of action, more effective for some conditions, fewer side effects.

Proton pump inhibitors are the most common over-the counter and prescribed medication which are generally used for treatment of various Gastrointestinal Diseases such as Gastroesophageal reflux disease, peptic ulcers, heartburn, acidity and Zollinger-Ellison syndrome. Gastroesophageal reflux disease (GERD) is a gastrointestinal condition in which stomach acid repeatedly flows back to the esophagus and causes heart burn and acid regurgitation. Proton pump inhibitors used to relive GERD. Peptic ulcers are a condition where stomach acid damages the lining of digestive tracts and form sores on the lining of oesophagus, stomach and small intestines. Zollinger-Ellison syndrome is a rare gastrointestinal disorder which occurs when one or more tumors are formed in pancreas or duodenum which release the hormone gastrin causing the stomach to release too much acid. PPIs are generally available in combination with histamine type 2-receptor antagonists (H2 blocker), Prokinetics agents and Antacids. Proton pump inhibitors alone (PPIs) were found to be less effective than combination therapy. The most preferable combination with PPIs are Prokinetics agents.

Prokinetic agents are a class of medications that help regulate the movement of food and fluids through your digestive system. They work by increasing the strength or frequency of muscle contractions in the digestive tract, promoting smoother and more efficient digestion.
Potassium-competitive acid blockers for example Vonoprazan, Revaprazan, Tegoprazan, Fexuprazan, Keverprazan.

Prokinetic agents, or prokinetic for example Cisapride, Domperidone, Metoclopramide helps in controlling the acid reflux by strengthening the contractions of lower esophageal sphincter (LES) muscles and fasten Gastric emptying.

On the other hand, since proton pump inhibitors of benzimidazole compound such as lansoprazole, omeprazole and the like (hereinafter sometimes to be abbreviated as “PPI”) have a gastric acid secretion-inhibitory action, a gastric mucosa-protective action and the like, and therefore, have been widely used as therapeutic agents for peptic ulcer and the like. In recent years, potassium-competitive acid blockers have been attracting attention as medicaments that effectively suppress secretion of gastric acid, and improve instability under acidic conditions, variations in effects based on metabolic enzyme polymorphisms and interaction between drugs, which are the problems of known proton pump inhibitors. Particularly, as for vonoprazan preparations, in Japan, the efficacy of “inhibition of recurrence of gastric ulcer or duodenal ulcer by administration of low dose acetylsalicylic acid” and “suppression of recurrence of gastric ulcer or duodenal ulcer by administration of non-steroidal anti-inflammatory drug” was approved and clinical effects have been demonstrated for suppression of the onset of gastric ulcer or duodenal ulcer caused by administration of acetylsalicylic acid.

Thus, combining PPIs and prokinetic agents is a rational approach for effective treatment of gastrointestinal disorders such as acidity, heartburn, peptic ulcers, Gastroesophageal reflux disease (GERD) and Zollinger-Ellison syndrome.

US10835541B2, WO2017018473A1 disclosed the tablet containing an inner core and an outer layer, wherein the inner core is an enteric-coated tablet containing acetylsalicylic acid, and the outer layer contains a potassium-competitive acid blocker free of enteric coating.
US7977488B2, IN264318, WO2007026916 disclosed the 1-heterocyclylsulfonyl, 2-aminomethyl, 5-(hetero-) aryl substituted 1-H-pyrrole derivatives as acid secretion inhibitors.

US11696893B2, WO2019013310 disclosed the formulation preparation comprising Vonoprazan, preparation containing fine granules or granules containing core granule containing an organic acid salt of Vonoprazan, an intermediate layer containing the same organic acid as the organic acid forming the salt of Vonoprazan or a salt thereof, and a coating layer containing a water-insoluble polymer.

WO2018133009A1 disclosed the Vonoprazan fumarate composition and preparation method thereof, the composition comprises Vonoprazan fumarate, a solubilizer, a buffer, a pH control agent, and a solvent.

CN116687873A disclosed the Vonoprazan fumarate tablet comprises the components in parts by mass: 12-15 parts of a bulk drug Vonoprazan fumarate, 36-65 parts of a filler, 6-10 parts of a disintegrating agent, 8-12 parts of an adhesive, 1-3 parts of a stabilizer, 3-5 parts of a lubricant, 10-15 parts of a film-forming material, 20-30 parts of a plasticizer and 0.2-0.5 part of titanium oxide.

CN115944743A disclosed the Vonoprazan fumarate composition and a preparation method thereof, belongs to the technical field of medicines, and particularly provides a Vonoprazan fumarate composition which comprises the following components: Vonoprazan fumarate, vitamin C, an oil phase and sodium bicarbonate or calcium carbonate, the invention also provides a preparation method of the Vonoprazan fumarate composition.

IN202211076599 disclosed the bilayer drug composition and method for preparation thereof to prepare a bilayer drug composition by combining drugs Domperidone and itopride for treatment of gastro esophageal reflux disease (GERD).

IN380409 disclosed the pharmaceutical excipient and more specifically to a universal demodulator employing probabilistic neural network.

At present, the marketed dosage form of Vonoprazan fumarate is a tablet, and no other dosage forms have been disclosed. Since the tablets preparations, the compliance is poor for patients with dysphagia, children, and the elderly; and for patients with acute gastritis and gastric ulcers that require rapid onset of action. Therefore, the development of a new pharmaceutical formulation of Vonoprazan fumarate, such as capsule, Pellet in Capsule, Tablet in capsule is of great significance for providing more therapeutic options for patients.

Furthermore, Vonoprazan fumarate and Domperidone have already been commercially available each as a single agent but combination of Vonoprazan fumarate and Domperidone is not available.

Hence, there is an unmet need in the art to develop a simple, manufacturing process of Vonoprazan and Domperidone, the present inventors have developed a robust, reproducible and cost-effective pharmaceutical composition of Vonoprazan and Domperidone or its pharmaceutical acceptable salt thereof, which provides stable product, as well as improved dissolution and bioavailability.

OBJECTIVE OF THE INVENTION:

The primary objective of the present invention relates to the pharmaceutical composition comprising potassium-competitive acid blockers (PCAB) inhibitor is Vonoprazan or its pharmaceutically acceptable salts combination with prokinetic agents is Domperidone or its pharmaceutically acceptable salts and one or more pharmaceutically acceptable excipients.

The secondary objective of the present invention relates to the pharmaceutical composition comprising potassium-competitive acid blockers (PCAB) inhibitor is Vonoprazan or its salts combination with prokinetic agents Domperidone or its salts, wherein the composition is a multi-layer composition comprising capsule or bilayer tablet dosage form.

The another objective of the present invention relates to the pharmaceutical composition comprising combination of Vonoprazan and Domperidone or its salts and one or more pharmaceutically acceptable excipients, where in the Vonoprazan is present in one layer (Enteric coating layer), Domperidone is present in the another layer (Sustained release layer).

The another objective of the present invention relates to the pharmaceutical composition comprising combination of Vonoprazan and Domperidone or its salts and one or more pharmaceutically acceptable excipients, where in the Vonoprazan is present in one layer (Immediate release layer), Domperidone is present in the another layer (Sustained release layer).

The another objective of the present invention relates to the pharmaceutical composition comprising combination of Vonoprazan and Domperidone or its salts and one or more pharmaceutically acceptable excipients, where in the said formulation has no or minimum drug-drug interaction, maximum stability along with optimal bioavailability.

The another objective of the present invention relates to the pharmaceutical composition comprising combination of Vonoprazan and Domperidone or its salts and one or more pharmaceutically acceptable excipients like diluent, binder, glidant, lubricant, solubilizer, disintegrant anti-adherent, anti-tacking agent, plasticizer, solubility enhancer and colorant.

The another objective of the present invention provides multi-layer formulation wherein Vonoprazan and Domperidone are present in the separate layer.

The another objective of the present invention relates to the pharmaceutical composition comprising combination of Vonoprazan and Domperidone or its salts and one or more pharmaceutically acceptable excipients, where in the formulation is prepared by wet granulation fluidized bed process (bottom spray).

The another objective of the present invention provides a multi-layer pellet composition comprising a gastro-resistant Vonoprazan layer which is soluble at specific pH and a sustained release Domperidone layer and wherein the multilayer pellets or granules are encapsulated in a capsule shell.

The another objective of the present invention Enteric coating material is Eudragit L 30 D 55 is present in the invention 20-55% from the total weight of the composition.

SUMMARY OF THE INVENTION:
The present invention relates to the pharmaceutical composition comprising potassium-competitive acid blockers (PCAB) inhibitor is Vonoprazan or its pharmaceutically acceptable salts combination with prokinetic agents Domperidone or its pharmaceutically acceptable salts and one or more pharmaceutically acceptable excipients.

The present invention relates to the pharmaceutical composition comprising potassium-competitive acid blockers (PCAB) inhibitor is Vonoprazan or its pharmaceutically acceptable salts combination with prokinetic agents Domperidone or its pharmaceutically acceptable salts, wherein the composition is a multi-layer composition comprising capsule dosage form or bilayer tablet dosage form.

The present invention relates to the pharmaceutical composition comprising potassium-competitive acid blockers (PCAB) inhibitor is Vonoprazan or its salts combination with prokinetic agents Domperidone or its salts, wherein the composition is a multi-layer capsule composition comprising Enteric coated layer comprising Vonoprazan fumarate, sustained release layer comprising Domperidone.

The present invention relates to the pharmaceutical composition comprising potassium-competitive acid blockers (PCAB) inhibitor is Vonoprazan or its salts combination with prokinetic agents Domperidone or its salts, wherein the composition is a multi-layer capsules composition comprising immediate release layer comprising Vonoprazan fumarate, Sustained release layer comprising Domperidone.

The present invention relates to the pharmaceutical composition comprising potassium-competitive acid blockers (PCAB) inhibitor is Vonoprazan or its salts combination with prokinetic agents Domperidone or its salts, wherein the composition is a multi-layer composition comprising enteric coated pellets or granules or tablets of Vonoprazan, sustained release pellets or granules or tablets of Domperidone.

The present invention relates to the pharmaceutical composition comprising potassium-competitive acid blockers (PCAB) inhibitor is Vonoprazan or its salts combination with prokinetic agents Domperidone or its salts, wherein the composition is a multi-layer composition comprising immediate release pellets or granules or tablets of Vonoprazan, sustained release pellets or granules or tablets of Domperidone.

The present invention relates to the pharmaceutical composition comprising combination of Vonoprazan and Domperidone or its salts and one or more pharmaceutically acceptable excipients, where in the formulation is prepared by wet granulation fluidized bed process (Bottom Spray).

The present invention relates to the pharmaceutical composition comprising combination of Vonoprazan and Domperidone or its salts and one or more pharmaceutically acceptable excipients, process for the preparation of such composition.

The present invention relates to the pharmaceutical composition comprising combination of Vonoprazan and Domperidone or its salts and one or more pharmaceutically acceptable excipients used for the treatment of Gastroesophageal Reflux Disease (GERD), heart burn or acidity, peptic ulcers or Zollinger-Ellison syndrome.

The process for the preparation of pharmaceutical composition comprising drug load dispersion preparation contain the hydroxy propyl methyl cellulose, talc, colloidal silicon di oxide with Vonoprazan, load the sugar sphere in to fluidized bed processor, seal coat the dispersion preparation contain the inactive ingredient, prepare the dispersion under continuous stirring, load the drug loaded pellets into fluidized bed process dry the pellets after coating, completion of seal coating pass the pellets of step sieve and discard the retentions, prepare enteric coating dispersion preparation by add Methacrylic acid –ethyl acrylate dispersion under stirring add Polysorbate, polyethylene glycol and purified talc, Enteric coating procedure load seal coated pellets of into fluidized bed processor bowl and pre-warm, perform the lubrication, prepare the Domperidone sustained release pellets with the same above procedure and fill the Vonoprazan enteric coated pellets and Domperidone sustained pellets in capsule.

DETAILED DESCRIPTION OF THE INVENTION:

The term "composition" or "formulation" or "dosage form" has been employed interchangeably for the purpose of the present invention and mean that it is a pharmaceutical composition which is suitable for administration to a patient or subject.
Unless defined otherwise, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this disclosure belongs. Although any methods and materials similar or equivalent to those described herein can be used in the practice or testing of the disclosure, the preferred methods, and materials are now described. All publications mentioned herein are incorporated herein by reference.
The present disclosure is not to be limited in scope by the specific embodiments described herein, which are intended for the purposes of exemplification only. Functionally equivalent products and processes are clearly within the scope of the disclosure, as described herein.
The term “inert core” as used herein refers to spheres/pellets which doesn’t comprises any active agents; wherein the core is coated with multi-layer coating system.
The term “delayed release” as used herein refers to drug delivery system which release the active agents in delayed on prolonged period of time and prevents the release of active agent in acidic environment. For the purpose of this invention enteric-coated articles are delayed release dosage forms.
The subject can be an animal, preferably a mammal, more preferably a human. For the purpose of the present invention terms "controlled release" or "sustained release" or "extended release" or "prolonged release" have been used interchangeably and mean broadly that Upadacitinib is released at a predetermined rate that is slower than the immediate release formulation. AUC, as used herein, refers to the area under the curve that represents changes in blood concentrations of Upadacitinib over time. Cmax, as used herein, refers to the maximum value of blood concentration shown on the curve that represents changes in blood concentrations of Upadacitinib over time. Tmax, as used herein, refers to the time that it takes for Upadacitinib blood concentration to reach the maximum value. T 1/2, as used in this disclosure, refers to the time that it takes for Upadacitinib blood concentration to decline to one-half of the maximum level. Collectively AUC, Cmax, Tmax, and T1/2 are the principle pharmacokinetic parameters that characterize the pharmacokinetic responses of a particular drug product such as Upadacitinib in an animal or human subject.

The term Vonoprazan as employed herein refers is used in broad sense to include not only “Vonoprazan its pharmaceutically acceptable salts, pharmaceutically acceptable solvates, pharmaceutically acceptable hydrates, pharmaceutically acceptable esters, pharmaceutically acceptable enantiomers, pharmaceutically acceptable derivatives, pharmaceutically acceptable polymorphs, pharmaceutically acceptable prodrugs, pharmaceutically acceptable complexes etc.
The term Domperidone as employed herein refers is used in broad sense to include not only “Domperidone its pharmaceutically acceptable salts, pharmaceutically acceptable solvates, pharmaceutically acceptable hydrates, pharmaceutically acceptable esters, pharmaceutically acceptable enantiomers, pharmaceutically acceptable derivatives, pharmaceutically acceptable polymorphs, pharmaceutically acceptable prodrugs, pharmaceutically acceptable complexes etc.
The term "salt" as used herein, refers to salts derived from inorganic or organic acids. Examples of suitable salts include, but are not limited to, acetate, adipate, alginate, citrate, aspartate, benzoate, benzenesulfonate, bisulfate, butyrate, camphorate, camphorsulfonate, digluconate, cyclopentanepropionate, dodecyl sulfate, ethanesulfonate, glucoheptanoate, glycerophosphate, hemi sulfate, heptanoate, hexanoate, fumarate, hydrochloride, carbonates, bicarbonates, hydrobromide, hydroiodide, 2-hydroxy-ethanesulfonate, lactate, maleate, mandelate, methanesulfonate, nicotinate, 2-naphthalenesulfonate, oxalate, palmoate, pectinate, persulfate, 2-phenylpropionate, picrate, pivalate, propionate, salicylate, succinate, sulfate, nitrates, tartrate, sulfonates, thiocyanate, tosylate, mesylate, and undecanoate.
As used herein and in the appended claims, the singular forms “a,” “and,” and “the” include plural referents unless the context clearly dictates otherwise. Thus, for example, reference to “an agent” includes a plurality of such agents, and reference to “the composition” includes reference to one or more compositions (or to a plurality of compositions) and equivalents thereof known to those skilled in the art, and so forth. When ranges are used herein for physical properties, such as molecular weight, or chemical properties, such as chemical formulae, all combinations and sub-combinations of ranges and specific embodiments therein are intended to be included. The term “about” when referring to a number or a numerical range means that the number or numerical range referred to is an approximation within experimental variability (or within statistical experimental error), and thus in some embodiments, The term “comprising” (and related terms such as “comprise” or “comprises” or “having” or “including”) is not intended to exclude that in other certain embodiments, for example, an embodiment of any composition of matter, composition, method, or process, or the like, described herein, may “consist of’ or “consist essentially of’ the described features.
“Pharmaceutically acceptable salt” as used herein includes both acid and base addition salts. In some embodiments, the pharmaceutically acceptable salt of any one of the compounds described herein is the form approved for use by the US Food and Drug Administration. Preferred pharmaceutically acceptable salts of the compounds described herein are pharmaceutically acceptable acid addition salts and pharmaceutically acceptable base addition salts.
As used herein, “treatment” or “treating” or “palliating” or “ameliorating” are used interchangeably herein. These terms refer to an approach for obtaining beneficial or desired results including but not limited to anti-diabetic effect, therapeutic benefit and/or a prophylactic benefit. By “therapeutic benefit” or “anti-diabetic effect” is meant eradication or amelioration of the underlying disorder being treated. A therapeutic benefit is achieved with the eradication or amelioration of one or more of the physiological symptoms associated with the underlying disorder (e.g., an improvement in: hyperglycemia, polyuria, polydipsia, polyphagia, diabetic dermadromes etc.) such that an improvement is observed in the patient, notwithstanding that the patient may still be afflicted with the underlying disorder. Also, a therapeutic benefit is achieved with the eradication or amelioration of one or more of the complications associated with the underlying disorder (e.g., cardiovascular disease). For prophylactic benefit, the compositions may be administered to a patient at risk of developing a particular disease, or to a patient reporting one or more of the physiological symptoms of a disease, even though a diagnosis of this disease may not have been made.
The enteric coated compositions of the present invention comprise along with Vonoprazan comprises of at least one enteric coating material. The term " Enteric coating material" as used herein means any excipient that can delayed the release of active ingredient in stomach and includes, but is not limited to, Eudragit, polymeric release agent, non-polymeric release agent or combinations thereof.

The sustained release compositions of the present invention comprise along with Domperidone comprises of at least one sustained release material. The term " sustained release material" as used herein means any excipient that can, retard the release of active agent and includes, but is not limited to, polymeric release controlling agent, non-polymeric release controlling agent or combinations thereof.

Suitable polymeric release controlling agent may be employed in the compositions of the present invention. In an embodiment, the polymeric release controlling agent employed in the compositions of the present invention may be swelling or non-swelling. The release controlling agent can be incorporated as polymer matrix or as a rate controlling polymer coating. In a further embodiment, polymeric release controlling agents that may be employed in the compositions of the present invention include, but are not limited to, cellulose derivatives, saccharides or polysaccharides, poly(oxyethylene)-poly(oxypropylene) block copolymers (poloxamers), vinyl derivatives or polymers or copolymers thereof, polyalkylene oxides and derivatives thereof, maleic copolymers, acrylic acid derivatives or the like or any combinations thereof. Cellulose derivatives include, but are not limited to, ethyl cellulose, methylcellulose, hydroxypropylmethylcellulose (HPMC), hydroxypropyl cellulose (HPC), hydroxy ethyl cellulose, hydroxymethyl cellulose, hydroxypropyl ethylcellulose, carb oxy methyl ethyl cellulose, carboxy ethylcellulose, carboxymethyl hydroxyethylcellulose, hydroxyethylmethyl carboxymethyl cellulose, hydroxyethyl methyl cellulose, carboxymethyl cellulose, methylhydroxyethyl cellulose, methylhydroxypropyl cellulose, carboxymethyl sulfoethyl cellulose, sodium carboxymethyl cellulose, cellulose acetate, cellulose acetate phthalate, cellulose acetate butyrate, hydroxypropylmethylcellulose acetate succinate, hydroxypropylmethylcellulose phthalate, hydroxymethyl ethylcellulose phthalate, cellulose acetate phthalate, cellulose acetate succinate, cellulose acetate maleate, cellulose acetate trimelliate, cellulose benzoate phthalate, cellulose propionate phthalate, methylcellulose phthalate, ethylhydroxy ethylcellulose phthalate, or combinations thereof.

Saccharides or polysaccharides include, but are not limited to, guar gum, xanthan gum, gum arabic, tragacanth or combinations thereof. Vinyl derivatives, polymers and copolymers thereof include, but are not limited to, polyvinylacetate aqueous dispersion (Kollicoat® SR 30D, copolymers of vinyl pyrrolidone, copolymers of polyvinyl alcohol, mixture of polyvinyl acetate and polyvinylpyrrolidone (e.g. Kollidon® SR), polyvinyl alcohol phthalate, polyvinylacetal phthalate, polyvinyl butylate phthalate, polyvinylacetoacetal phthalate, polyvinylpyrrolidone (PVP), or combinations thereof. Polyalkylene oxides and derivatives thereof include, but are not limited to, polyethylene oxide and the like or any combinations thereof. The term "polyethylene oxide polymer" or "PEO" as used herein includes all forms and MWs of PEO polymers. Sources of PEO polymers include, e.g., Polyox WSR-303™. Acrylic acid derivatives include, but are not limited to, methacrylic acids, poiymethacrylic acids, polyacrylates, especially polymethacrylates like a) copolymer formed from monomers selected from methacrylic acid, methacrylic acid esters, acrylic acid and acrylic acid esters b) copolymer formed from monomers selected from butylmethacrylate, (2-dimethylaminoethyl) methacrylate and methyl methacrylate c) copolymer formed from monomers selected from ethyl acrylate, methyl methacrylate and trimethylammonioethyl methacrylate chloride or d) copolymers of acrylate and methacrylates with/without quarternary ammonium group in combination with sodium carboxymethylcellulose, e.g. those available from Rohm GmbH under the trademark Eudragit ® like Eudragit EPO (dimethylaminoethyl methacrylate copolymer; basic butylated methacrylate copolymer), Eudragit RL and RS (trimethylammonioethyl methacrylate copolymer), Eudragit NE30D and Eudragit NE40D (ethyl acrylate methymethacrylate copolymer), Eudragit® L 100 and Eudragit® S (methacrylic acid'methyl methacrylate copolymer), Eudragit® L 100-55 (methacrylic acid'ethyl acrylate copolymer), Eudragit RD 100 (ammoniomethacrylate copolymer with sodium carboxymethylcellulose); or the like or any combinations thereof. Maleic copolymer based polymeric release controlling agent includes, but is not limited to, vinylacetate maleic acid anhydride copolymer, styrene maleic acid anhydride copolymer, styrene maleic acid monoester copolymer, vinylmethylether maleic acid anhydride copolymer, ethylene maleic acid anhydride copolymer, vinylbutylether maleic acid anhydride copolymer, acrylonitrile methyl acrylate maleic acid anhydride copolymer, butyl acrylate styrene maleic acid anhydride copolymer and the like, or combinations thereof. In one embodiment, polymers with low viscosity are employed in the compositions of the present invention as release controlling agent such as, but not limited to, Methocel K4M, and the like or combinations.

Binders includes, but are not limited to, binder is hydroxypropyl methylcellulose (HPMC E5), hydroxypropyl methylcellulose E3 LV, hydroxypropyl cellulose LM, hydroxypropyl cellulose E5, hydroxypropyl methylcellulose, hydroxyethyl cellulose, Povidone, hydroxypropyl cellulose, carbomers, carboxymethylcellulose sodium, dextrin, shellac, zein, gelatin, polymethacrylates, polyvinyl pyrrolidone, or combinations thereof.
Disintegrant includes, but are not limited to, croscarmellose sodium, sodium starch glycolate, pregelatinized starch, sodium carboxymethyl cellulose, microcrystalline cellulose, cross-linked polyvinylpyrrolidone, sodium alginate and mixtures thereof.
Diluents are inert ingredients sometimes used as bulking agents in order to decrease the concentration of the active ingredient in the final formulation. Suitable diluents used in the present invention are selected from, not limited to, sucrose, glucose, sorbitol, acacia, alginic acid, sodium alginate, gelatin, starch, pregelatinized starch, mannitol (Mannitab F1), microcrystalline cellulose 101 (Hicel 50 M), magnesium aluminum silicate, carboxymethylcellulose sodium (CMC sodium), methylcellulose, ethyl cellulose.

Suitable glidants/lubricants included in the present formulation can be selected from the group consisting of silica, fumed silica, silicified cellulose, sodium stearate, magnesium stearate, magnesium aluminum silicate, pyrogenic silica, hydrated sodium silio-aluminate, cellulose, calcium phosphate, sodium lauryl sulfate, pregelatinized starch, talc, Colloidal silicon dioxide and physical or co-processed combinations thereof. The glidant can be silica, and can be a hydrophilic fumed silica (colloidal silicon dioxide).

Examples of suitable lubricants include, but are not limited to, polyethylene glycol (e.g., having a molecular weight of from 1000 to 6000), magnesium stearate, calcium stearate, sodium stearyl fumarate, talc, and the like. In one embodiment, the lubricant is magnesium stearate.

Suitable disintegrants be employed in the formulations of the present invention include croscarmellose sodium, crospovidone, sodium starch glycolate, starch or combinations thereof.

As discussed herein, sustained peak plasma concentrations can theoretically be achieved by means of sustained release matrix systems. However, when such systems are made of hydrophilic polymers, such as HPMC, they seldom provide pH independent drug release of pH-dependent soluble drugs, and they are normally incapable of attaining zero-order release except for practically insoluble drugs. Unexpectedly, is has now been discovered that when a pH modifier, such as tartaric acid, fumaric acid, citric acid, succinic acid, malic acid, or combinations thereof, is used in a hydrophilic sustained release matrix system, it allows Compound 1 or a pharmaceutically acceptable salt or solid state form thereof to be released at a steady rate regardless of the pH of the environment. In an unexpected finding, it was discovered that as a tablet containing the hydrophilic polymer matrix system erodes.

The multilayer composition of the present invention is present in the form of pellets, granules, beads, mini-tablets or tablets, capsule. In a preferred embodiment the multilayer composition of the present invention is present in the form of pellets, granules, beads, mini-tablets or tablets, which are encapsulated in a capsule shell. In a most preferred embodiment the multilayer composition of the present invention is present in the form of pellets encapsulated in a capsule shell.

The Gastro resistant layer comprises Gastro-resistant polymer, plasticizer, surfactant, anti-tacking agent, colorant, basifier, wherein Gastro-resistant polymer is selected from group consisting of hydroxypropyl methylcellulose phtalate (HMPCP), polyvinyl acetate phtalate (PVAP), hydroxypropylmethylcellulose acetate succinate (HPMCAS), alginate, carbomer, carboxymethylcellulose, methacrylic acid copolymer (Eudragit L, Eudragit S, 10 Acrycoat), shellac, cellulose acetate phthalate (CAP), starch glycolate, polacrylin, methyl cellulose acetate phtalate, hydroxypropyulcellulose acetate phthalate, cellulose acetate terephtahalate, cellulose acetate isophthalate and cellulose acetate trimellitate.

In one of the embodiments of the present invention relates to the pharmaceutical composition comprising potassium-competitive acid blockers (PCAB) inhibitor is Vonoprazan or its pharmaceutically acceptable salts combination with prokinetic agents is Domperidone or its pharmaceutically acceptable salts and one or more excipients.

In one of the embodiments of the present invention relates to the pharmaceutical composition comprising potassium-competitive acid blockers (PCAB) inhibitor is Vonoprazan or its pharmaceutically acceptable salts combination with prokinetic agents is Domperidone or its pharmaceutically acceptable salts and one or more pharmaceutically acceptable excipients.

In one of the embodiments of the present invention relates to the pharmaceutical composition comprising potassium-competitive acid blockers (PCAB) inhibitor is Vonoprazan or its salts combination with prokinetic agents Domperidone or its salts, wherein the composition is a multi-layer composition comprising capsule or bilayer tablet dosage form.

In one of the embodiments of the present invention relates to the pharmaceutical composition comprising combination of Vonoprazan and Domperidone or its salts and one or more pharmaceutically acceptable excipients, where in the Vonoprazan is present in one layer (Enteric coating layer), Domperidone is present in the another layer (Sustained release layer).

In one of the embodiments of the present invention relates to the pharmaceutical composition comprising combination of Vonoprazan and Domperidone or its salts and one or more pharmaceutically acceptable excipients, where in the Vonoprazan is present in one layer (Immediate release layer), Domperidone is present in the another layer (Sustained release layer).
In one of the embodiments of the present invention relates to the pharmaceutical composition comprising combination of Vonoprazan and Domperidone or its salts and one or more pharmaceutically acceptable excipients, where in the said formulation has no or minimum drug-drug interaction, maximum stability along with optimal bioavailability.

In one of the embodiments of the present invention relates to the pharmaceutical composition comprising combination of Vonoprazan and Domperidone or its salts and one or more pharmaceutically acceptable excipients like diluent, binder, glidant, lubricant, solubilizer, disintegrant anti-adherent, anti-tacking agent, plasticizer, solubility enhancer and colorant.

In one of the embodiments of the present invention provides multi-layer formulation wherein Vonoprazan and Domperidone are present in the separate layer.

In one of the embodiments of the present invention relates to the pharmaceutical composition comprising combination of Vonoprazan and Domperidone or its salts and one or more pharmaceutically acceptable excipients, where in the formulation is prepared by wet granulation fluidized bed process (bottom spray).
In one of the embodiments of the present invention provides a multi-layer pellet composition comprising a gastro-resistant Vonoprazan layer which is soluble at specific pH and a sustained release Domperidone layer and wherein the multilayer pellets or granules are encapsulated in a capsule shell.
In one of the embodiments of the present invention Enteric coating material is Eudragit L 30 D 55 is present in the invention 20-55% from the total weight of the composition.
The process details of the invention are provided in the examples given below, which are provided by way of illustration only and therefore should not be construed to limit the scope of the invention.

Examples:
Example 1:
Manufacturing Formula for Vonoprazan Enteric Coated Pellets:
Drug Loading
(114.07% w/w
weight gain) Ingredients For 10 mg
mg/unit For 20 mg
mg/unit % w/w
Sugar Spheres (# 25-30#) 15.00 30.00 --
Vonoprazan Fumarate 13.36 26.72 41.61
Hydroxy Propyl Methyl Cellulose (HPMC E5) 3.25 6.50 10.12
Talc 0.25 0.50 0.78
Colloidal silicon di oxide 0.25 0.50 0.78
Purified Water Q.S. Q.S. --
Total Weight of
Drug loaded pellets 32.11 64.22 --
Seal Coating
(14.72 % w/w
weight gain)
HPMC E5 LV Premium 3.50 7.00 9.50
Talc 1.225 2.45 3.33
Purified Water Q.S. Q.S. --
Total Weight of
Seal coated pellets 36.84 73.67 --
Enteric Coating
(68.84 % w/w
weight gain)
Eudragit L 30 D 55 16.00 32.00 25.73
PEG 6000 1.60 3.20 2.57
Polysorbate 80 0.26 0.52 0.42
Talc 7.50 15.00 12.06
Purified Water Q.S. Q.S. --
Total Weight of
Enteric Coated pellets 62.195 124.39 --
Blending and Lubrication Talc 0.305 0.61 0.49
Final Lubricated
weight of Pellets 62.50 125.00 --

Brief Manufacturing Procedure
Drug loading Stage:
Drug Loading Dispersion Preparation:
i. Add Hydroxypropyl methyl cellulose (HPMC E5) to purified water under stirring and continue stirring till a clear solution is formed.
ii. Add Vonoprazan Fumarate to step-i under stirring and continue stirring for 15 minutes.
iii. Add Talc to step-ii under stirring and continue stirring for 20 minutes.
iv. Keep the dispersion under continuous stirring throughout the drug loading process.
Drug Loading
v. Load the sugar spheres (#25-30#) into fluidized bed processor bowl and pre warm at inlet temperature of 55 ± 5ºC at low fluidization for 5 minutes.
vi. Spray step-iv drug loading dispersion on to the sugar spheres of step-v to get weight gain up to 114.07 % w/w with following parameters.
Note:
1. If drug loaded pellets assay does not meet the specification, calculate the amount of drug loading materials to be sprayed. Dispense the required quantity of materials and spray the drug loading solution on to the step-viii drug loaded pellets.
2. If any lumps or twins observed during drug loading stage sift the pellets through ASTM # 18 or # 20 and discard retains.
vii. After completion of drug loading, dry the pellets for 10 minutes at an inlet temperature of 50 ± 5°C.
viii. Pass the pellets through ASTM #16 sieve and discard the retentions.
ix. Sift the step-xii passing’s through ASTM #24 sieve and discard the passing’s.
x. Submit the step-viii retentions for assay analysis.
Seal Coating Stage
Seal Coating Dispersion Preparation
xi. Add Hydroxypropyl methyl cellulose (HPMC E5) under stirring and continue stirring until to get the clear solution.
xii. Add Talc to above step No - xi and Keep the dispersion under continuous stirring throughout the coating process.
Seal Coating
xiii. Load the step-xi drug loaded pellets into fluidized bed processor and pre warm at inlet temperature of 55 ± 5ºC at low fluidization for 5 minutes.
xiv. Spay the Step-xiv seal coating dispersion on to the drug loaded pellets of step-xv to get weight gain up to 14.72 % w/w with following parameters.
xv. Dry the pellets of step-xiv for 5 minutes after coating at inlet temperature of 50°C to 55°C.
xvi. After completion of seal coating pass the pellets of step-xviii through ASTM #16 sieve and discard the retentions.
xvii. Sift the step-xvi passing’s through ASTM #24 sieve and discard the passing’s.
Enteric Coating Stage
Enteric Coating Dispersion Preparation:
xviii. Take 45% w/w of purified water and add Methacrylic acid – ethyl acrylate dispersion (Eudragit L30 D55) under stirring and continue stirring for 15 minutes at slow RPM.
xix. Take 55 % w/w of purified water and kept under stirring, add Polysorbate 80, polyethylene glycol 8000 and purified talc and continue stirring for 15 minutes.
xx. Add step-xix solution to step-xxii solution under stirring and continue stirring for 15 min.
Enteric Coating Procedure
xxi. Load seal coated pellets of step-xx into fluidized bed processor bowl and pre-warm at inlet temperature of 40 ± 5ºC at low fluidization for 5 minutes.
xxii. Spray step-xxi enteric coating-I dispersion on to the seal coated pellets of step-xxiv to get weight gain up to 68.84 % w/w with the following parameters.
xxiii. Dry the pellets of step- xxvi for 2 hours after coating at inlet temperature of 40 ± 5°C.
xxiv. After completion of enteric coating pass the pellets through ASTM #14 sieve and discard the retentions.
xxv. Sift the step-xxiv passing’s through ASTM #20 sieve and discard the passing’s.
Lubrication
xxvi. Sift the Talc (Luzenac pharma) through ASTM # 60.
xxvii. Load the pellets form step-xxvi into blender and add talc from step-xxx and blend for 10 minutes at 10 rpm.
Manufacturing Formula for Domperidone Sustained Release Pellets:
Drug Loading
(60.30% w/w
weight gain) Ingredients For 30 mg
mg/unit % w/w
Sugar Spheres
(# 25-30#) 58.98 --
Domperidone 30.00 31.73
Hydroxy Propyl Methyl Cellulose (HPMC E5) 0.57 0.60
Colloidal silicon di oxide 0.48 0.51
Talc 4.51 4.77
Isopropyl Alcohol Q.S. --
Purified water Q.S. --
Total Weight of
Drug loaded pellets 94.54 --
Seal Coating
(3.90 % w/w
weight gain)
HPMC E5 LV Premium 2.34 2.38
Talc 0.71 60.17
Yellow iron oxide 0.12 23.35
Red iron oxide 0.04 46.51
Titanium di oxide 0.47 0.48
Purified Water Q.S. --
Total Weight of
Seal coated pellets 98.22 --
Sustained release
(1.41 % w/w
weight gain)
Ethyl Cellulose 1.18 1.18
Triacetin 0.514 0.514
Talc 0.086 0.086
Acetone Q.S. --
Isopropyl Alcohol Q.S. --
Purified Water Q.S. --
Total Weight of
Enteric Coated pellets 100.00 --

Drug loading Stage:
Drug Loading Dispersion Preparation:
i. Add Hydroxypropyl methyl cellulose (HPMC E5) to Isopropyl Alcohol and Purified water (70:30 ratio) under stirring and continue stirring till a clear solution is formed.
ii. Add Talc and Colloidal silicon di oxide to step-i under stirring and continue stirring for 15 minutes.
iii. Add Domperidone to step-ii under stirring and continue stirring until to get the uniform dispersion.
iv. Keep the dispersion under continuous stirring throughout the drug loading process.
Drug Loading
v. Load the sugar spheres (#25-30#) into fluidized bed processor bowl and pre warm at inlet temperature of 55 ± 5ºC at low fluidization for 5 minutes.
vi. Spray step No-iv drug loading dispersion on to the sugar spheres of step-v to get weight gain up to 60.30 % w/w with following parameters.
Note:
1. If drug loaded pellets assay does not meet the specification, calculate the amount of drug loading materials to be sprayed. Dispense the required quantity of materials and spray the drug loading solution on to the step-vi drug loaded pellets.
2. If any lumps or twins observed during drug loading stage sift the pellets through ASTM # 18 or # 20 and discard retains.
vii. After completion of drug loading, dry the pellets for 10 minutes at an inlet temperature of 50 ± 5°C.
viii. Pass the pellets through ASTM #16 sieve and discard the retentions.
ix. Sift the step-x passing’s through ASTM #24 sieve and discard the passing’s.
x. Submit the step-ix retentions for assay analysis.
Seal Coating Stage
Seal Coating Dispersion Preparation
xi. Add Hydroxypropyl methyl cellulose (HPMC E5) under stirring and continue stirring until to get the clear solution.
xii. Add Talc, Yellow iron oxide, Red iron oxide and Titanium di oxide to above step no - xi and Keep the dispersion under continuous stirring throughout the coating process.
Seal Coating
xiii. Load the step-xi drug loaded pellets into fluidized bed processor and pre warm at inlet temperature of 55 ± 5ºC at low fluidization for 5 minutes.
xiv. Spay the Step-xiii seal coating dispersion on to the drug loaded pellets of step-xv to get weight gain up to 3.90 % w/w with following parameters.
Enteric Coating Stage
Enteric Coating Dispersion Preparation:
xv. Take Acetone, Isopropyl Alcohol and Purified water (ratio of 70:25:5) in suitable beaker and kept under stirring at slow RPM.
xvi. Add Ethyl Cellulose to step no.-xix under stirring until to get the clear solution
xvii. Add Triacetin and Talc to step no-xxii under stirring, and continue stirring for 15 minutes
Enteric Coating Procedure
xviii. Load seal coated pellets of step-xx into fluidized bed processor bowl and pre-warm at inlet temperature of 40 ± 5ºC at low fluidization for 5 minutes.
xix. Spray step-xxiii enteric Coating dispersion on to the seal coated pellets of step-xxii to get weight gain up to 1.41 % w/w with the following parameters.
xx. Dry the pellets of step- xxvi for 2 hours after coating at inlet temperature of 40 ± 5°C.
xxi. After completion of enteric coating pass the pellets through ASTM #14 sieve and discard the retentions.
xxii. Sift the step-xxviii passing’s through ASTM #20 sieve and discard the passing’s.
Capsule Filling
xxiii. Fill the Vonoprazan Enteric Coated Pellets and Domperidone Sustained Pellets in Size ‘0‘ Capsule for 10 mg/30 mg and 20 mg/30 mg in Capsule filling machine with suitabe Parameters.
Example 2:
Manufacturing Formula for Vonoprazan Enteric Coated Tablets:
S. No. Ingredients Functional category Qty per Unit (mg) % w/w
10 mg 20 mg
Intra-granular
1 Vonoprazan API 13.36 26.72 24.30
2 Mannitol (Mannitab F1) Diluent 66.09 52.73 47.93
3 Microcrystalline Cellulose 101
(Hicel 50 M) Diluent 20.00 20.00 18.18
Binder Solution
4 Hydroxy Propyl Cellulose LM Binder 3.30 3.30 3.00
5 Citric Acid Acidifying agent 0.75 0.75 0.68
6 Purified Water Solvent Q.S Q.S --
Extra granular Portion
7 Croscarmellose Sodium Disintegrant 5.50 5.50 5.00
8 Magnesium Stearate Lubricant 1.00 1.00 0.90
Core Tablet Weight (mg) 110.00 110.00 --
Enteric Coating
9 Eudragit L 100 Controlled release polymer 16.50 33.00 22.00
10 Purified Talc Glidant 1.50 3.00 2.00
11 Triethyl citrate Plasticizer 2.00 4.00 2.67
12 Isopropyl alcohol (80%) Solvent Q.S. Q.S. --
13 Dichloromethane (20%) Solvent Q.S. Q.S. --
Enteric Coated Tablet weight (mg) 130.00 150.00 --
Film Coating
14 Opadry II Yellow Coating material 3.90 -- 3.00
15 Opadry II Red Coating material -- 4.50 3.00
16 Purified water Solvent Q.S. Q.S. --
Film Coated Tablet weight 133.90 154.50 --
Brief Manufacturing Procedure
Sifting:
i. Co-sift Vonoprazan Fumarate,Mannitol andMicrocrystalline cellulose PH 101 and through 30 # mesh.
ii. Load the step i material into Rapid mixer granulator and dry mix for 10 mnutes.
Binder preparation:
iii. Add required quantiry of Citric acid Hydroxypropyl cellulose to Purified wate runder stirring and continue stirring upto clear solution was formed.
Granulation:
iv. Granulate the step ii with step iii Binder solution to attain desired granules
Drying:
v. Dry the wet granules to attain desired % LOD and mill with 1.50 mm screen until all the dried granules passes through 20# mesh.
Extragranular agents:

vi. Sift Croscarmellose Sodium through 30# mesh
vii. Sift Magnesium stearate through 60# mesh
Pre-Lubrication:
viii. Blend the step v materials with step vi for 10 mins.
Lubrication
ix. Blend the step viii materials with step vii for 5 mins.
Compression:
x. Compress the above blend by using suitable punches.
Enteric Coating:
xi. Add Ethyl cellulose to Isopropyl alcohol and Dichloromethane mixture (70:30 ratio) under stirring and continue stirring until to get the clear solution.
xii. Add Talc and Triethyl citrate to abovestep xi under stirring and keep the solution under stirring in entire process.
xiii. Coat the solution onto the core tablets of step No. x with suitable parameters.
Film Coating:
xiv. Add Opadry Yellow (for 10 mg) and Opadr Red (for 20 mg) to purifed water under stirring and continue stirring throughout the process.
xv. Coat the above coating dispersion onto the core tablets of step No. x with suitable parameters
Manufacturing Formula for Domperidone Sustained Release Tablets:
S. No. Ingredients Functional category Qty per Unit (mg)
30 mg % w/w
Intra-granular
1 Domperidone API 30.00 25.00
2 Microcrystalline cellulose (Hicel 50M) Diluent 16.00 13.33
3 Hydroxy Propyl methyl Cellulose (HPMC E3) Diluent 2.00 1.67
Binder Solution
4 Purified Water Solvent Q.S --
Extra granular Portion
5 HPMC K 100 LV Controlled release polymer 70.00 58.34
6 Talc Glidant 1.00 0.83
7 Magnesium Stearate Lubricant 1.00 0.83
Core Tablet Weight (mg) 120.00 --
Film Coating
8 Opadry II Pink Film coating material 3.60 3.00
9 Purified water Solvent Q.S. --
Film coated tablet weight 123.60 --
Sifting:
i. Co-sift Domperidone, Microcrystalline cellulose and HPMC E3 and through 30 # mesh.
ii. Load the step i material into Rapid mixer granulator and dry mix for 10 mnutes.
Binder preparation:
iii. Dispense required quantiry of Purified water
Granulation:
iv. Granulate the step ii with step iii Binder solution to attain desired granules
Drying:
v. Dry the wet granules to attain desired % LOD and mill with 1.50 mm screen until all the dried granules passes through 20# mesh.
Extragranular agents:
vi. Sift Talc, HPMC K100 LV through 30# mesh
vii. Sift Magnesium stearate through 60# mesh
Pre-Lubrication:
viii. Blend the step v materials with step vi for 10 mins.
Lubrication
ix. Blend the step viii materials with step vii for 5 mins.
Compression:
x. Compress the above blend by using suitable punches.
Film Coating:
xi. Add Opadry Pink to purifed water under stirring and continue stirring throughout the process.
xii. Coat the above coating dispersion onto the core tablets of step No. x with suitable parameters.
Capsule Filling
xiii. Fill the Vonoprazan Enteric Coated Tablets and Domperidone Sustained Tablets in Size ‘0‘ Capsule for 10 mg/30 mg and 20 mg/30 mg in Capsule filling machine with suitabe Parameters.
Example-3:
Manufacturing Formula for Vonoprazan IR portion (Layer- I):
S. No. Ingredients Functional category Qty per Unit (mg) % w/w
10 mg 20 mg
Intra-granular
1 Vonoprazan API 13.36 26.72 24.30
2 Mannitol (Mannitab F1) Diluent 66.09 52.73 47.93
3 Microcrystalline Cellulose 101
(Hicel 50 M) Diluent 20.00 20.00 18.18
Binder Solution
4 Hydroxy Propyl Cellulose LM Binder 3.30 3.30 3.00
5 Citric Acid Acidifying agent 0.75 0.75 0.68
6 Purified Water Solvent Q.S Q.S --
Extra granular Portion
7 Croscarmellose Sodium Disintegrant 5.50 5.50 5.00
8 Magnesium Stearate Lubricant 1.00 1.00 0.90
Core Tablet Weight (mg) 110.00 110.00 --
Brief Manufacturing Procedure
Sifting:
i. Co-sift Vonoprazan Fumarate,Mannitol and Microcrystalline cellulose PH 101 and through 30 # mesh.
ii. Load the step i material into Rapid mixer granulator and dry mix for 10 mnutes.
Binder preparation:
iii. Add required quantiry of Citric acid Hydroxypropyl cellulose to Purified wate runder stirring and continue stirring upto clear solution was formed.
Granulation:
iv. Granulate the step ii with step iii Binder solution to attain desired granules
Drying:
v. Dry the wet granules to attain desired % LOD and mill with 1.50 mm screen until all the dried granules passes through 20# mesh.
Extragranular agents:
vi. Sift Croscarmellose Sodium through 30# mesh
vii. Sift Magnesium stearate through 60# mesh
Pre-Lubrication:
viii. Blend the step v materials with step vi for 10 mins.
Lubrication
ix. Blend the step viii materials with step vii for 5 mins.
Manufacturing Formula for Domperidone SR portion (Layer- II):
S. No. Ingredients Functional category Unit mg/Tab % w/w

Intra-granular
1 Domperidone API 30.00 25.00
2 Microcrystalline Cellulose 101 (Hicel 50 M) Diluent 31.00 25.83
3 Hydroxy Propyl Methyl Cellulose E5 Dry Binder 2.00 1.67
Binder Solution
4 Purified Water Solvent q.s q.s
Extra granular Portion
5 HPMC K 100 LV Controlled Release Polymer 55.00 45.83
6 Talc Glidant 1.00 0.83
7 Magnesium Stearate Lubricant 1.00 0.83
Core Tablet Weight (mg) 120.00 100.00
Sifting:
i. Co-sift Domperidone, Microcrystalline cellulose and HPMC E5 and through 30 # mesh.
ii. Load the step i material into Rapid mixer granulator and dry mix for 15 minutes.
Binder preparation:
iii. Dispense required quantiry of Purified water
Granulation:
iv. Granulate the step ii with step iii Binder solution to attain desired granules
Drying:
v. Dry the wet granules to attain desired % LOD and mill with 1.50 mm screen until all the dried granules passes through 20# mesh.
Extragranular agents:
vi. Sift Talc, HPMC K100 LV and Talc through 30# mesh
vii. Sift Magnesium stearate through 60# mesh
Pre-Lubrication:
viii. Blend the step v materials with step vi for 10 mins.
Lubrication
ix. Blend the step viii materials with step vii for 5 mins.
Compression of Bi-layer Tablets (Vonoprazan IR Portion and Domperidone SR Portion – granules:
x. Compress the above blend of step – ix of Layer –I and step-ix of layer - II by using suitable punches.
Film Coating:
xi. Add Opadry II Yellow for 10 mg/30 mg and Opadry II pink for 20 mg/30 mg to purifed water under stirring and continue stirring throughout the process.
xii. Coat the above coating dispersion onto the core tablets of step No. x with suitable parameters.
,CLAIMS:We claim,
1. A pharmaceutical composition comprising potassium-competitive acid blockers (PCAB) inhibitor is Vonoprazan or its pharmaceutically acceptable salts combination with prokinetic agents Domperidone or its pharmaceutically acceptable salts and one or more pharmaceutically acceptable excipients.

2. The pharmaceutical composition as claimed in claim 1, wherein the composition is a multi-layer capsule composition comprising Enteric coated layer, sustained release layer comprising.

3. The pharmaceutical composition as claimed in claim 2, wherein the Enteric coated layer comprising Vonoprazan fumarate, sustained release layer comprising Domperidone.

4. The pharmaceutical composition as claimed in claim 1, wherein the composition is enteric coated pellets or granules or tablets of Vonoprazan, sustained release pellets or granules or tablets of Domperidone.

5. The pharmaceutical composition as claimed in claim 1, wherein the composition is a multi-layer capsules composition comprising immediate release layer comprising Vonoprazan fumarate, sustained release layer comprising Domperidone.

6. The pharmaceutical composition as claimed in claim 1, wherein the composition is Immediate release pellets or granules of Vonoprazan, sustained release pellets or granules of Domperidone.

7. The pharmaceutical composition as claimed in claim 1, wherein the excipients comprising diluent, binder, disintegrant, lubricant and glidant.

8. The pharmaceutical composition as claimed in claim 1, wherein the composition is pellets or granules in a capsule or bilayer tablet.

9. The pharmaceutical composition as claimed in claim 1, wherein the composition comprising combination of Vonoprazan and Domperidone or its salts and one or more pharmaceutically acceptable excipients, process for the preparation of such composition.

10. The pharmaceutical composition as claimed in claim 1, wherein the composition is used for the treatment of Gastroesophageal Reflux Disease (GERD), heart burn or acidity, peptic ulcers or Zollinger-Ellison syndrome.