FIELD OF THE INVENTION The present invention relates to oral pharmaceutical compositions and process for preparing compositions comprising at least one gastric acid suppressing agent, at least one prokinetic agent and at least one alginic acid optionally with pharmaceutically acceptable excipients; such that the gastric acid suppressing agent is present in a delayed release form, prokinetic agent is present in a bimodal release form such as an immediate release form, and a delayed release form to provide a dose with a lag time form and alginic acid is present in an immediate release form. The said compositions are useful in the treatment of gastric acid related disorders such as gastro esophageal reflux disease, reflux esophagitis, peptic ulcer, gastric ulcer, heartburn, sour stomach, acid ingestion, upset stomach and/or pain associated with heartburn, sour stomach and acid ingestion, bloating, fullness, dyspepsia, nocturnal heartburn, disorders not manifested by the presence of ulcerations in the gastric mucosa, including chronic active or atrophic gastritis, and Zollinger-Ellison syndrome.

BACKGROUND OF THE INVENTION Gastro esophageal reflux disease (GERD), reflux esophagitis, peptic ulcer, gastric ulcer and other gastric acid related disorders are disorders having a pathogenesis related to reduced gastric motility and release of excessive gastric acid. Apart from lifestyle modifications, GERD and gastric ulcer have been successfully treated with a range of gastric acid inhibitors, such as ranitidine and omeprazole, which are acid-suppressing agents. Stimulation of gastric motility has been proposed to accelerate the healing of gastric ulcer. Prokinetic agents, such as domperidone, are known to enhance gastrointestinal motility and prevent duodenogastric reflux, and are widely used to treat GERD. Proton pump inhibitors, H2 receptor antagonists and prokinetic agents have been used in combination to treat gastric ulcer and other related disorders.

Proton pump inhibitors (PPIs) are a class of acid-labile pharmaceutical compounds that

I block gastric acid secretion pathways. Exemplary proton pump inhibitors include, omeprazole (Prilosec.RTM.), lansoprazole (Prevacid.RTM.), esomeprazole (Nexium.RTM.), rabeprazole (Aciphex.RTM.), paπtoprazole (Protonix.RTM.), pariprazole, tenatoprazole, and leminoprazole. The drugs of this class suppress gastrointestinal acid secretion by the specific inhibition of the H.sup.+/K.sup.+-ATPase enzyme system (proton pump) at the secretory surface of the gastrointestinal parietal cell. Most proton pump inhibitors are susceptible to acid degradation and, as such, are rapidly destroyed in an acidic pH environment in the stomach. Therefore, proton pump inhibitors are often administered as enteric-coated dosage forms in order to permit release of the drug in the duodenum after having passed through the stomach. Prilosec.RTM. (omeprazole) is formulated as enteric-coated granules in gelatin capsules. Prevacid.RTM. (lansoprazole) is available as enteric-coated granules in gelatin capsules, and as enteric-coated microspheres for use as a liquid suspension. Nexium.RTM. (esomeprazole magnesium) is enteric-coated granules in gelatin capsules.

Proton pump inhibitors are typically prescribed for short-term treatment of active duodenal ulcers, gastrointestinal ulcers, gastroesophageal reflux disease (GERD), severe erosive esophagitis, poorly responsive symptomatic GERD, and pathological hypersecretory conditions such as Zollinger Ellison syndrome. These above-listed conditions commonly arise in healthy or critically ill patients of all ages, and may be accompanied by significant upper gastrointestinal bleeding. H2 -receptor antagonists are frequently employed to treat disorders linked to the hypersecretion of gastric acid, for example the treatment of gastric ulcers, as they inhibit the secretion of gastric acid. Histamine H2-receptor antagonists may be chosen from a series of well-known products such as cimetidine, ranitidine, famotidine, etc.

Prokinetic agents may be prescribed in the treatment of various gastrointestinal diseases, such as gastroesophageal reflux disease (GERD), inflammatory bowel disease, or to treat primary gastrointestinal motility disorders, such as diffuse esophageal spasm or irritable bowel syndrome. Motility disorders of the gastrointestinal tract may be caused by neural, muscular or receptor damage dysfunction. Prokinetic agents would be useful in concomitant therapy with proton pump inhibitors to treat patients with GERD, erosive esophagitis or functional dyspepsia. PPI and prokinetic agent combinations increase the tone of the lower esophageal sphincter, decrease the number of transient lower esophageal relaxations, and increase gastric emptying while the proton pump inhibitor administered decreases the volume of gastric juice available for reflux into the esophagus and increases the pH so Jhat refluxed gastric contents are much less injurious to the esophageal mucosa.

Alginic acid and its salts with sodium and potassium bicarbonate have shown that, after entering the stomach environment they form a viscous suspension or a gel exerting protecting activity over gastric mucosa. The scientific and patent literature on its activity is wide. Alginates may be used alone in the treatment of heartburn. They have a short duration of action but are seen as inexpensive and safe. Alginates further give some mechanical protection against reflux or gastric acid into the esophagus. Sodium alginate forms a 'raft' which floats to the top of the stomach, forming a barrier between the acid and the oesophagus, thus preventing acid refiuxing into the oesophagus and protecting the mucosa from further irritation. The main advantage of alginates is that they provide fast relief of symptoms.

Esomeprazole magnesium is bis (5-methoxy-2-[(S)-[(4-methoxy-3,5-dimethyl-2- pyridinyl) methyl]sulfϊnyl]-lH-benzimidazole-l-yl) magnesium trihydrate, a compound that inhibits gastric acid secretion. Esomeprazole is the S-isomer of omeprazole, which is a mixture of the S- and R- isomers. Its molecular formula is (C ₁ 7H ₁₈ NsO ₃ S) ₂ Mg.3 H ₂ O with molecular weight of 767.2 as a trihydrate and 713.1 on an anhydrous basis. Metoclopramide is 4-amino-5-chloro-N-(2-(diethylamino) ethyl)-2-methoxybenzamide and a potent dopamine receptor antagonist used for its antiemetic and prokinetic properties. Thus it is primarily used to treat nausea and vomiting, and to facilitate gastric emptying in patients with gastroparesis. It is available under various trade names including Maxolon (Shire/Valeant), Reglan (Wyeth), Degan (Lek), Maxeran (Sanofi Aventis), Primperan (Sanofi Aventis), and Pylomid (Bosnalijek). Alginic acid is a polysaccharide and exists as homopolymers or mixed sequence polymers of two types of uronic acid-mannuronic acid (if a homopolymer, also known as an M block) and guluronic acid (if a homopolymer, also known as a G block). The mixed sequence polymers are typically known as MG blocks. Alginic acid is a natural acidic polysaccharide extracted from so-called brown algae (Phaecophyceae) with a high molecular weight varying between about 30,000 and 200,000 or higher, and containing chains formed by D-mannuronic acid and L-guluronic acid. The degree of polymerization varies according to the type of alga used for extraction, the season in which the algae were gathered and the place of origin of the algae, as well as the age of the plant itself. The main species of brown algae used to obtain alginic acid are, for example, Macrocystis pyrifera, Laminaria cloustoni, Laminaria hyperborea, Laminaria flexicaulis, Laminaria digitata, Ascophyllum nodosum, and Fucus serratus.

Dexrabeprazole is a R (+) isomer of 2-[[[4-(3-methoxypropoxy)-3-methyl-2-pyridinyI] methyl]sulfinyl-[lH]-benzimidazole(I). R(+)Rabeprazole inhibits the H.sup.+, K.sup.+ -ATPase associated with the gastric proton pump and ^' the resulting secretion of gastric acid by parietal cells providing therapy in diseases associated with gastric hyperacidity. Optically pure (+) rabeprazole provides this treatment while substantially reducing adverse effects, including, but not limited to, hepatocellular neoplasia, gastrin hypersecretion, gastric neoplasms or carcinoids, headache, diarrhea and skin alterations which are associated with the administration of the racemic mixture of rabeprazole.

I

Domperidone is a dopamine antagonist with anti-emetic properties. Its anti-emetic effect may be due to a combination of peripheral (gastrokinetic) effects and antagonism of dopamine receptors in the chemoreceptor trigger zone, which lies outside the blood- brain barrier in the area postrema. Animal studies, together with the low concentrations found in the brain, indicate a predominantly peripheral effect of domperidone on dopamine receptors. Studies in man have shown oral domperidone to increase lower oesophaegeal pressure, improve antroduodenal motility and accelerate gastric emptying.

US patent no. 6,132,771 discloses a combination therapy of proton pump inhibitor and a prokinetic agent wherein, the prokinetic agent may be in the form of instant release, sustained release or extended release formulations. WO publication no. 2005117870 describes a pharmaceutical composition comprising: a therapeutically effective amount of at least one acid labile proton pump inhibitor;(b) at least one buffering agent in an amount sufficient to increase gastric fluid pH to a pH that prevents acid degradation of at least some of the proton pump inhibitor in the gastric fluid; and a therapeutically effective amount of at least one prokinetic agent. US publication no. 20070281015 describes an anti-acid pharmaceutical composition for the rapid and prolonged neutralization of gastric acidity with mucosa-protecting activity in powder form to prepare, by dispersion in water, a pharmaceutical solution or suspension for oral use characterized in that the composition includes sodium alginate; an anti-acid soluble agent or a combination of anti-acids; an inhibitor of proton pump; diluent and sweetening agents. Us publication no. 20070166370 describes an oral pharmaceutical composition comprising multiple populations of at least one of beads, pellets, tablets 5 and granules provided in a capsule, the composition comprising a first population of a pharmaceutical active comprising a pharmaceutical active substance releasable at a first rate; a population of a basic substance; and a second population of a pharmaceutical active comprising a pharmaceutical active substance releasable at a second rate. US patent no. 6183776 describes an oral pharmaceutical dosage form comprising an acid

10 susceptible proton pump inhibitor and one or more antacid agents or an alginate in a fixed formulation, wherein the proton pump inhibitor is protected by an enteric coating layer and an optional separating layer in between the proton pump inhibitor and the enteric coating. EP patent application no. EPl 842544 describes a pharmaceutical composition for forming a protective coating on gastrointestinal mucosal tissue, the

15 composition comprising an alginate or alginic acid having a mannuronic acid residue to guluronic acid residue ratio (M/G) of at least 1 for forming a protective coating on gastrointestinal mucosal tissue when brought into contact with same, and a pharmaceutically acceptable carrier. WO publication no. WO9823272 describes methods , and compositions for treating one or more gastrointestinal disorders

2.0 comprising a therapeutically effective amount of a proton pump inhibitor and a therapeutically effective amount of an antacid rafting agent. The term antacid rafting agent refers to the combination of one or more antacid agents and at least one alginate compound wherein, after ingested, the antacid floats on the stomach contents. WO publication no. WO9501780 describes pharmaceutical compositions for use in the

25 treatment and relief of indigestion, sour stomach, heartburn and other gastrointestinal disorders in mammals, including humans, by administering compositions comprising: (i) an amount effective in the relief of gastrointestinal or esophagus disorders of an H2 antagonist selected from a compound of formula (I) and its pharmaceutically acceptable salts, hydrates, stereoisomers or polymorphs and (ii) an amount effective in relief of

30 gastrointestinal or esophagus disorders of at least one of the alginates and optionally (iii) an anti-flatulent amount of simethicone. WO publication no. 2004071374A2 describes pharmaceutical compositions for once a day oral administration, comprising at least one delayed release component, wherein said delayed release component comprises a proton pump inhibitor, said composition further including at least one immediate release and/or a sustained release prokinetic agent. The said application discloses use of polymers to formulate sustained release compositions of the prokinetic agent. However, such compositions suffer from a major disadvantage in terms of absorption of the prokinetic agent which is primarily absorbed from the intestine and hence a delayed release composition is highly desirable.

In spite of so many attempts, there exists no single satisfactory therapy available which can be used for the complete, and overall management of GERD and related disorders and all their associated symptoms. Hence, there still exists a need to develop a pharmaceutical composition preferably comprising a combination therapy of useful agents, which can be used in alleviating the associated symptoms and in the treatment of GERD and related disorders.

SUMMARY OF THE INVENTION

An aspect of the present invention relates to an oral pharmaceutical composition comprising at least one gastric acid. suppressing agent, at least one prokinetic agent and at least one alginic acid, optionally with pharmaceutically acceptable excipients; such that the gastric acid suppressing agent is present in a delayed release form, prokinetic agent is present in a bimodal release form such as an immediate release form, and a delayed release form to provide a dose with a lag time form and alginic acid is present in an ^' immediate release form.

One aspect of the present invention is also to provide a process for preparing the composition of the invention, comprising the following steps:

• i) processing the acid suppressing agent(s) with pharmaceutically acceptable excipients, ii) processing the prokinetic agent(s) with pharmaceutically acceptable excipients, iii). processing the alginic acid with pharmaceutically acceptable excipients, iv) formulating the material of step i), ii) and iii) into a suitable dosage form.

In another aspect, the present invention also relates to a method of treatment of gastro esophageal reflux disease, reflux esophagitis, peptic ulcer, gastric ulcer, heartburn, sour stomach, acid ingestion, upset stomach and/or pain associated with heartburn, sour stomach and acid ingestion, bloating, fullness, dyspepsia, nocturnal heartburn, disorders not manifested by the presence of ulcerations in the gastric mucosa, including chronic active or atrophic gastritis, Zollinger-Ellison syndrome and other gastric acid related disorders by administering to a patient in need thereof a pharmaceutical composition of the present invention.

DETAILED DESCRIPTION OF THE INVENTION

The phrase "combination therapy" means the administration of a composition of the present invention in conjunction with another pharmaceutical agent. The therapeutic compounds which make up the combination therapy may be a combined dosage form or in separate dosage forms intended for substantially simultaneous administration. The therapeutic compounds that make up the combination therapy may also be administered sequentially, with either therapeutic compound being administered by a regimen calling for two step administration. Substantially simultaneous administration can be accomplished, for example, by administering to the subject a single tablet or capsule having a fixed ratio of each therapeutic agent or in multiple, single capsules, or tablets for each of the therapeutic agents. Sequential or substantially simultaneous administration of each therapeutic agent can be effected by any appropriate route. Thus, a regimen may call for sequential administration of the therapeutic compounds with spaced-apart administration of the separate, active agents. The time period between the multiple administration steps may range from, for example, a few minutes to several hours to days, depending upon the properties of each therapeutic compound such as potency, solubility, bioavailability, plasma half-life and kinetic profile of the therapeutic compound, as well as depending upon the effect of food ingestion and the age and condition of the subject.

A combination therapy comprising a gastric acid suppressing agent and a prokinetic agent is attractive, rational and effective. A combination of gastric acid suppressing agent and prokinetic agent could be an alternative to individual monotherapies in case of failure. However, because of the large number of therapeutical tablets/pills that must be taken each day in such a therapy, the compliance of such a treatment may be a problem. It is well known that patient compliance is a major factor in receiving good results in medical treatments. Administration of two, three or even more different tablets to the patient is not convenient or satisfactory to achieve the most optimal results. The present invention now provides a new oral dosage form comprising two or more different active substances combined in one fixed unit dosage form.

Combination therapy includes, for example, administration of a composition of the present invention in conjunction with another pharmaceutical agent as part of a specific treatment regimen intended to provide a beneficial effect from the co-action of these therapeutic agents. The beneficial effect of the combination includes, but is not limited to, pharmacokinetic or pharmacodynamic co-action resulting from the combination of therapeutic agents.

The present invention relates to an oral pharmaceutical composition comprising at least one gastric acid suppressing agent, at least one prokinetic agent and at least one alginic acid, optionally with pharmaceutically acceptable excipients; such that the gastric acid suppressing agent is present in a delayed release form, prokinetic agent is present in a bimodal release form such as an immediate release form, and a delayed release form to provide a dose with a lag time form and alginic acid is present in an immediate release form.

It might be appreciated that the phrase "gastric acid suppressing agent" and "prokinetic agent" wherever appears in the patent specification also covers their pharmaceutically acceptable salts, esters, polymorphs, isomers, prodrugs, solvates, hydrates, or derivatives and the phrase "alginic acid" wherever appears in the patent specification also encompasses its salts, esters or derivatives unless otherwise mentioned.

In an embodiment, the present invention provides an oral pharmaceutical composition in the form of a trilayered tablet-in-tablet dosage form wherein the first layer containing the gastric acid suppressing agent(s) is in the form of a compressed tablet surrounded by an enteric material surrounded by a second layer containing prokinetic agent(s) in an immediate release form alongwith alginic acid in an immediate release form compressed on to the first layer, and a third layer compressed on to the second layer containing prokinetic agent(s) in a delayed release form, optionally further comprising a coating such as film coating or sugar coating over the third layer wherein the coat may or may not comprise an active agent.

In another embodiment, the present invention provides an oral pharmaceutical composition comprising at least one gastric acid suppressing agent(s), one or more prokirietic agent(s) and at least one alginic acid(s), optionally with other pharmaceutically acceptable excipients, such that the gastric acid suppressing agent is present in a delayed release form and the prokinetic agent is present in a bimodal release form such as an immediate release form, and a delayed release form to provide a dose with a lag time, and wherein the prokinetic agent in immediate release form is coated with alginic acid in immediate release form.

In an embodiment, the present invention provides an oral pharmaceutical composition in the form of granules, beads, compacts, pellets, minitablets or minicapsules filled in a capsule which is of animal or vegetable .origin comprising at least one gastric acid suppressing agent(s), one or more prokinetic agent(s) and alginic acid optionally with other pharmaceutically acceptable excipients, such that the gastric acid suppressing agent is present in a delayed release form and the prokinetic agent is present in a bimodal release form such as an immediate release form and a delayed release form, and wherein the alginic acid in an immediate release form is present as an admixture alongwith prokinetic agent.

In an embodiment, the present invention provides an oral pharmaceutical composition in the form of granules, beads, compacts, pellets filled in a capsule which is of animal or vegetable origin wherein the capsule is optionally coated with a coating agent comprising at least one gastric acid suppressing agent(s), one or more prokinetic agent(s) and alginic acid optionally with other pharmaceutically acceptable excipients, such that the gastric acid suppressing agent is present in a delayed release form and the prokinetic agent is present in a bimodal release form such as an immediate release form and a delayed release form, and wherein the alginic acid in an immediate release form is present as an admixture alongwith prokinetic agent.

In an embodiment, the present invention provides an oral pharmaceutical composition in the form of granules, beads, compacts, pellets , minitablets or minicapsules filled in a capsule which is of animal or vegetable origin comprising at least one gastric acid suppressing agent(s), one or more prokinetic agent(s),and alginic acid optionally with other pharmaceutically acceptable excipients, such that the gastric acid suppressing agent is present in a delayed release form and the prokinetic agent is present in a bimodal release form such as an immediate release form and a delayed release form, wherein the alginic acid in an immediate release fcAn is coated over the prokinetic agent. In an embodiment of the present invention, the capsules used in the present invention may be selected from animal and vegetable sources. The capsules from vegetable sources used in the present invention are termed as "non-gelatin based capsules" selected from but not limited to cellulose capsules, starch capsules, kappa carrageenan and the like. The capsules from animal sources used in the present invention are termed as "gelatin based capsules" such as hard and soft gelatin capsules. In an embodiment, the individual minicapsules of size 4 comprising the proton pump inhibitor, the prokinetic agent and the alginic acid are administered in a gelatin capsule of size 0. As can be appreciated by one skilled in the art, one can administer different types of capsules depending upon the dosage of the active agent(s) as required and the desired therapeutic effect.

In an embodiment, the present invention provides an oral pharmaceutical composition in the form of minitablets or minicapsules filled in a capsule which is of animal or vegetable origin comprising at least one gastric acid suppressing agent(s) and one or more prokinetic agent(s) optionally with other pharmaceutically acceptable excipients, such that the gastric acid suppressing agent is present in a delayed release form and the prokinetic agent is present in a bimodal release form such as an immediate release form and a delayed release form and wherein the alginic acid in an immediate release form is uniformly distributed throughout the capsule fill in the form of powder, beads, granules, and the like. In an embodiment, the gastric acid suppressing agent(s) is a proton pump inhibitor or a H ₂ receptor antagonist.

The proton pump inhibitor of the present invention is selected from but not limited to a group comprising pantoprazole, lansoprazole, omeprazole, rabeprazole, and the like, their pharmaceutically acceptable salts, esters, polymorphs, isomers, prodrugs, solvates, hydrates, or derivatives used either alone or in combination thereof. Suitable proton pump inhibitors are for example disclosed in EP-A 1-0005129, EP-A-1 174726, EP- Al 166287, GB2163747, WO90/06925, W091/19711, W091/19712, W095/01977, W094/27988, WO2004/071374 and US patent numbers 4,544,750, 4,620,008, 4,75.8,579, 5,045,552, 5,374,730, 5,386,032, 5,502,195, the disclosures of which are each incorporated herein by express reference thereto. The prokinetic agent of the present invention is selected from but not limited to a group comprising domperidone, itopride, mosapride, cisapride, renzapride, dazopride, mosapride zacopride, octreotide, naloxone, erythromycin and bethanechol, exepanol, lintopride, motilin, idremcinal, mitemcinalum, neurotrophin-3, KC-11458, MKC-733, Braintree-851 , zacopride, ecabapide, prucalopride, fedotozine, cinitapride, itopride, polycarbophil, tegaserod, INKP-100, diacol, motilides such as motilin, and the like, their pharmaceutically acceptable salts, esters, polymorphs, isomers, prodrugs, solvates, hydrates, or derivatives used either alone or in combination thereof. Such suitable prokinetic agents are described in EP243959 and EP76530, the disclosures of which are each incorporated herein by express reference thereto. Preferably the prokinetic agent is domperidone or metoclopramide, esters, polymorphs, isomers, prodrugs, solvates, hydrates or derivatives thereof. The alginic acid of the present invention is selected from but not limited to a group comprising the alkaline and alkaline earth metal salts such as calcium, sodium, acetyl alginate and 1, 2-propanediol ester of alginic acid and the like used either alone or in combination thereof. The R ₂ receptor antagonist of the present invention is selected from but not limited to a group comprising ranitidine, famotidine, cimetidine, nizatidine, and the like or esters, polymorphs, isomers, prodrugs, solvates, hydrates or derivatives used either alone or in combination thereof.

In an embodiment, the gastric acid suppressing agent is optionally mixed with alkaline substances and further mixed with suitable constituents can be formulated into a core material. Said core material may be produced by extrusion/spheronization, balling or compression utilizing conventional process equipment. In an embodiment, the proton pump inhibitor may also be mixed with an alkaline, pharmaceutically acceptable substance(s) selected from but not limited to sodium, potassium, calcium, magnesium and aluminium salts of phosphoric acid, carbonic acid, citric acid or other suitable weak inorganic or organic acids; aluminium hydroxide/sodium bicarbonatecoprecipitate, substances normally used in antacid preparations such as aluminium, calcium and magnesium hydroxides; magnesium oxide or composite substances, such as disodium hydrogen orthophosphate and similar compounds; organic pH-buffering substances such astrihydroxymethylaminomethane, basic amino acids and their salts or other similar, pharmaceutically acceptable pH-buffering substances used alone or in combination thereof.

In another embodiment of the present invention, the gastric acid suppressing agent layer optionally comprises a separating layer(s) which separates the core from the enteric coating layer. The separating layer(s) can be applied to the core material by coating or layering procedures in suitable equipments such as coating pan, coating granulator or in fluidized bed apparatus using water and/or organic solvents for the coating process. As an alternative the separating layer(s) can be applied to the core material by using powder coating technique. The materials for the separating layers are selected from a group comprising but not limited to pharmaceutically acceptable compounds such as sugar, polyethylene glycol, polyvinylpyrrolidone, polyvinyl alcohol, polyvinyl acetate, hydroxypropyl cellulose, methylcellulose, ethylcellulose, hydroxypropyl methylcellulose, carboxymethylcellulose sodium and others, used either alone or in combination thereof. Additives such as plasticizers, colorants, pigments, fillers anti-tacking and anti-static agents, such as for instance magnesium stearate, titanium dioxide, talc and other additives may also be included into the separating layer(s).

In an embodiment of the present invention, the alginic acid can be coated on the granules, beads, pellets, and minitablets by coating or layering procedures in suitable equipments such as coating pan; coating granulator or in a fluidized bed apparatus using water and/or organic solvents for the coating or layering process. The materials for coating are selected from but not limited to pharmaceutically acceptable compounds such as, for instance sugar, polyethylene glycol, polyvinylpyrrolidone, polyvinyl alcohol, polyvinyl acetate, hydroxypropyl cellulose, methylcellulose, ethylcellulose, hydroxypropyl methylcellulose, carboxymethylcellulose sodium and others, used either alone or in combination thereof. Additives such as plasticizers, colorants, pigments, fillers, anti-tacking and anti-static agents, such for instance magnesium stearate, titanium dioxide, talc and other additives may also be included into the coating layer(s).

In an embodiment, the composition of the present invention comprises one or more pharmaceutically acceptable excipient(s) selected from but not limited to a group comprising diluents; disintegrants; binders; fillers; bulking agent; organic acid(s); colorants; stabilizers; preservatives; lubricants; glidants; chelating agents; vehicles; bulking agents; stabilizers; preservatives; hydrophilic polymers; solubility enhancing agents such as glycerine, various grades of polyethylene oxides, transcutol and glycofurol; tonicity adjusting agents; local anesthetics; pH adjusting agents; antioxidants; osmotic agents; chelating agents; viscosifying agents; acids; sugar alcohol; reducing sugars; non-reducing sugars and the like used either alone or in combination thereof. Certain excipients used in the present composition can serve more than one purpose. Suitable binders include for example starch, polyvinylpyrrolidone, hydroxypropyl methylcellulose, pregelatinized starch, hydroxypropylcellulose, or mixtures thereof. The disintegrants useful in the present invention include but not limited to a group comprising croscarmellose sodium (e.g. Primellose®), sodium starch glycollate, cross-linked sodium carboxymethyl cellulose (e.g. Ac-di-sol®), Solutab®, Vivasol®, starches, pregelatinized starch, celluloses, cross-linked carboxymethylcellulose, crospovidone, corn starch, potato starch, maize starch and modified starches, croscarmellose sodium, low substituted hydroxypropyl cellulose, clays, alginates, gums and the like used either alone or in combination thereof. The diluents or fillers useful in the present invention are selected from but not limited to a group comprising lactose such as lactose monohydrate, lactose anhydrous and Pharmatose® DCL 21, starch, mannitol, sorbitol, dextrose, microcrystalline cellulose such as Avicel® PH 101, Avicel® PH 102, Avicel® PH 1 12, Avicel® PH 200,

Avicel® PH 301 and Avicel® PH 302, dibasic calcium phosphate, sucrose-based diluents, confectioner's sugar, monobasic calcium sulfate monohydrate, calcium sulfate, calcium lactate, dextrose, dextran, dextrates, inositol, hydrolyzed cereal solids, amylose, powdered cellulose, calcium carbonate, cellulose powder, starches, pregelatinized starch, sucrose, xylitol, lactitol, mannitol, sorbitol, sodium chloride, polyethylene glycol, glycine, or bentonites, saccharides such as mannitol, Pearlitol® SD 200, starch, sorbitol, sucrose, and glucose, alkaline agents such as magnesium oxide, sodium bicarbonate and the like, or mixtures thereof. The lubricants useful in the present invention are selected from but not limited to a group comprising talc, magnesium stearate, calcium stearate, zinc stearate, stearic acid, hydrogenated vegetable oil, sodium stearyl fumarate, glyceryl behenate, waxes and the like used either alone or in combination thereof. The anti-adherents or glidants are selected from but not limited to a group comprising talc, corn starch, DL-leucine, sodium lauryl sulfate, magnesium stearate, calcium stearate, sodium stearate, colloidal silicon dioxide, and the like, or mixtures thereof. In an embodiment of the present invention, the composition may additionally comprise a conventionally known antioxidant such as ascorbyl palmirate, butyl hydroxy anisole, butyl hydroxy toluene, propyl gallate, α- tocopherol, and the like or mixtures thereof. In another' embodiment, the dosage form of the present invention additionally comprises at least one surfactant selected from a group comprising anionic surfactants, cationic surfactants, non-ionic surfactants, zwitterionic surfactants or mixtures thereof.

In an embodiment, the tablets can be prepared by either wet granulation, direct compression, or by dry compression (slugging). The granulation technique is either aqueous or non-aqueous. The non-aqueous solvent used is selected from a group comprising acetone, ethanol, isopropyl alcohol or methylene chloride. In an embodiment, the compositions of the present invention are in the form of compressed tablets, multilayered tablets, mini-tablets, capsules, minicapsules, compacts, pellets, beads, granules or the like. ₍

Upon ingestion, an acid-labile pharmaceutical compound must be protected from contact with acidic stomach secretions to maintain its pharmaceutical activity. Thus, compositions with enteric-coatings have been designed to dissolve at a pH to ensure that the drug is released in the proximal region of the small intestine (duodenum), not in the stomach. An "enteric-coating" is a substance that remains substantially intact in the stomach but dissolves and releases at least some of the drug once reaching the small intestine. Generally, the enteric-coating comprises a polymeric material that prevents release in the low pH environment of the stomach but that ionizes at a slightly higher pH, typically a pH of 4 or .5, and thus dissolves sufficiently in the small intestines to gradually release the active agent therein.

In an embodiment, the enteric coating applied to the minitablet of the gastric acid suppressing agent and the prokinetic agent is formed from a coating composition comprising a major proportion of a methacrylic acid-methyl methacrylate copolymer, a glycerin fatty acid ester mainly as a plasticizer, and talc mainly as an anti-adhesion agent. Any other additives including coloring agents, flavors and extenders may be added if desired. Suitable coating materials according to the present invention comprise one or more agents selected from but not limited to enteric polymer/film former such as polymethacrylate ethylacrylate copolymer (Eudragit© L30D-55), copolymers synthesized from acrylic and methacrylic acid esters such as Eudragit® L-IOO, Eudragit® L-IOO 55, Eudragit® SlOO, Eudragit® LlOO and the like or mixtures thereof; cellulose acetate phthalate, hydroxypropyl methylcellulose phthalate, hydroxypropyl methylcellulose acetate succinate, polyvinyl acetate phthalate, cellulose acetate trimellitate, carboxymethylethylcellulose, shellac, plasticizer such as triethyl citrate, propylene glycol; anti-adherants/lubricants such as colloidal silicon dioxide, talc; and solvents such as isopropyl alcohol, dichloromethane, purified water, and the like or mixtures thereof.

In an embodiment, the alginic acid used in the present invention optionally comprises alkali/alkaline earth metal carbonates/bicarbonates that after entering the stomach environment form viscous suspension or a gel foam or raft exerting protecting activity over gastric mucosa. The alkali/alkaline earth metal carbonates/bicarbonates are a source of polyvalent ions which aid in cross-linking between the guluronic acid residues in the alginic acid chains and form a raft. The said 'raft' floats to the top of the stomach, forming a barrier between the acid and the oesophagus, thus preventing acid refluxing into the oesophagus and protecting the mucosa from further irritation.

The active substance in form of alginic acid is dry mixed with inactive excipients such as fillers, binders; disintegrants, and other pharmaceutically acceptable additives. The mixture is wet massed with a granulation liquid. The wet mass is dried preferably to a loss on drying of less than 3% by weight. Thereafter the dry mass is milled to a suitable size for the granules, such as smaller than 4 mm, and preferably smaller than 1 mm. Suitable inactive excipients are for instance mannitol, corn starch, potato starch, low substituted hydroxypropylcellulose, microcrystalline cellulose and crosslinked polyvinylpyrrolidone. The dry mixture comprising antacid agent(s) is mixed with a suitable granulation liquid comprising for instance hydroxypropylcellulose or polyvinylpyrrolidone dissolved in purified water or alcohol or a mixture thereof.

During developmental studies of the present invention, it was surprisingly found that when prokinetic agents such as domperidone and metoclopramide were co-processed with an organic acid they exhibited an improved dissolution even at alkaline pH conditions encountered in the gastro-intestinal tract. According to a preferred embodiment of the invention, metoclopramide is co-processed with ^' an organic acid in the ratio of from about 1:0.25 to about 0.25:1, preferably from about 1:0.5 to about 0.5:1, most preferably about 1:1. The co-processing may be aided by dissolving the two ingredients with the help of heat followed by cooling, when the dissolved material separates out. The material separated out may be removed and dried. The co-processed material may be incorporated into dosage forms such as tablets, which may further be combined with enteric coated tablets of a gastric 'acid suppressing agent and an immediate release tablet of metoclopramide, in a hard gelatin capsule. According to another preferred embodiment, domperidone is co-processed with an organic acid in the ratio of from about 1:0.25 to about 0.25: 1, preferably from about 1 :0.5 to about 0.5:1, most- preferably about 1:1. The co-processing may be aided by dissolving the two ingredients with the help of heat followed by cooling, when the dissolved material separates out. The material separated out may be removed and dried. The co-processed material may be incorporated into dosage forms such as tablets, which may further be combined with enteric coated tablets of a gastric acid suppressing agent and an immediate release tablet of domperidone or metoclopramide, in a hard gelatin capsule. In yet another embodiment, the composition comprises the prokinetic agent as 5 to 70 % by weight of total prokinetic agent in immediate , release form and the remaining prokinetic agent in delayed release form.

In another embodiment of the present invention, the composition of the prokinetic agent present in immediate release form and delayed release form additionally comprises a permeation enhancer, preferably Vitamin E tocopheryl propylene glycol succinate.

In an embodiment the present invention provides a process for preparing a composition of the present invention, comprising the following steps: i) processing the acid suppressing agent(s) with pharmaceutically acceptable excipients, ii) processing the prokinetic agent(s) with pharmaceutically acceptable excipients, iii) processing the alginic acid with pharmaceutically acceptable excipients, iv) formulating the material of step i), ii) and iii) into a suitable dosage form.

In yet another embodiment of the present invention is provided a method of using such composition according to the present invention which comprises administering to a subject in need thereof an effective amount of the composition. The compositions of the present invention comprising a gastric acid suppressing agent, prokinetic agent and a sodium salt of alginic acid provide effective prophylactic or therapeutic concentrations of the active agent(s) for extended periods of time.

In still another embodiment of the present invention ; is provided a use of the dosage form composition comprising proton pump inhibitor, prokinetic agent and a sodium salt of alginic acid for the preparation of a medicament for treating gastro esophageal reflux disease, reflux esophagitis, peptic ulcer, gastric ulcer, heartburn, sour stomach, acid ingestion, upset stomach and/or pain associated with heartburn, sour stomach and acid ingestion, bloating, fullness, dyspepsia, nocturnal heartburn, disorders not manifested by the presence of ulcerations in the gastric mucosa, including chronic active or atrophic gastritis, Zollinger-Ellison syndrome and other gastric acid related disorders.

In a further embodiment of the present invention, is provided an use of the dosage form for the management of one or more disease(s)/disorder(s) which includes prophylaxis, amelioration and/or treatment of gastro esophageal reflux disease, reflux esophagitis, peptic ulcer, gastric ulcer, heartburn, sour stomachj acid ingestion, upset stomach and/or pain associated with heartburn, sour stomach and acid ingestion, bloating, fullness, dyspepsia, nocturnal heartburn, disorders not manifested by the presence of ulcerations in the gastric mucosa, including chronic active or atrophic gastritis, Zollinger-Ellison syndrome and other gastric acid related disorders.

The examples given below serve to illustrate embodiments of the present invention.

However they do not intend to limit the scope of present invention in any manner whatsoever.

Example-1

A) Esomeprazole delayed release tablets:

S. No. Ingredients Qty/ tab (mg)

1. Esomeprazole 40

2. Sodium carbonate 12

3. Mannitol 5

4. Micrόcrystalline cellulose 11

5. Crospovidone _' . 13

6. Calcium stearate 0.5

7. Talc 0.5 8. Crospovidone 2

9. Calcium stearate ^■ • 0.5

10. Talc 0.5

Seal coat

11. Opadry yellow 2.5

12. Water q.s. (Lost in processing)

Enteric coating

13. ■ Polymethacrylate ethylacrylate copolymer 8.8

14. Talc 4.2

15. Triethyl citrate 1

16. Water q.s. (Lost in processing)

Procedure: i) Sodium carbonate was crushed and sifted with sieve of mesh size 60. ii) The material of step (i), microcrystalline cellulose, mannitol and crospovidone were dried separately at 60 ⁰ C for 2 hours in a tray drier. iii) Esomeprazole, microcrystalline cellulose, crospovidone, calcium stearate and talc were, sifted separately through of mesh size 40. iv) The bulk of step (iii) and the material of step (ii) were mixed together, v) The mixed mass of step (iv) was slug/deslugged to obtain granules of sieve of mesh size 20/60. vi) Crospovidone, calcium stearate and talc were sifted through sieve of mesh size

60. vii) The sifted mass of step (vi) was added to the bulk of step (v) and further blended for 10 mins. viii) The blend of step (vii) was compressed into tablets. ix) The tablets of step (viii) were coated by seal coat followed by coating with enteric polymer.

B) Metoclopramide immediate release tablets with coating of alginic acid: S. No. Ingredients Qty/ tab (mg)

1. Metoclopramide 10

2. Mannitol 31

3. Microcrystalline cellulose . 31.25 4. Magnesium stearate ^;; 0.75

5. Croscarmellose sodium 2

6. Sodium bicarbonate 50.0 Film coating 7. Alginic acid 200

8. Hydroxypropyl methylcellulose 20

9. Polyethylene glycol 6000 30

10. Iron oxide red 3

11. Isopropyl alcohol q.s. (Lost in processing) 12. Dichloromethane q.s. (Lost in processing)

Procedure: i) Metoclopramide, microcrystalline cellulose, sodium bicarbonate, mannitol and croscarmellose sodium were sifted through sieve of mesh size 40. ii) Magnesium stearate was sifted through sieve of mesh size 40. iii) The bulk of step (i) and (ii) were mixed together and compressed into tablets, iv) The tablets of step (iii) were finally film coated.

C) Metoclopramide delayed release tablets:

S. No. Ingredients Qty/ tab (mg) 1. Metoclopramide 20

2. Mannitol 31

3. Microcrystalline cellulose 21.25

4. Magnesium stearate 0.25

5. Croscarmellose sodium 2 Enteric coating

6. Polymethacrylate ethylacrylate copolymer 16.13

7. Talc 3.63

8. Triethyl citrate 0.48

9. Simethicone 0.046 10. Water q.s. (Lost in processing)

Procedure: i) Metoclopramide, microcrystalline cellulose, mannitol and croscarmellose sodium were sifted through sieve of mesh size 40. ii) Magnesium stearate was sifted through sieve of mesh size 40. iii) The bulk of step (i) and (ii) were mixed together and compressed into tablets, iv) The tablets of step (iii) were finally enteric coated.

The tablets of A step (ix), B step (iv) and C step (iv) were filled into a hard gelatin capsule.

ExampIe-2

A) Esomeprazole delayed release tablets:

S. No. Ingredients Qty/ tab (mg) 1. Esomeprazole 40

2. Sodium carbonate 12

3. Mannitol 5

4. Microcrystalline cellulose 11

5. Crospovidone . 13 6. Calcium stearate 0.5

7. Talc 0.5

8. Crospovidone 2

9. Calcium stearate 0.5

10. Talc 0.5 Seal coat

11. Opadry yellow 2.5

12. Water q.s. (Lost in processing) Enteric coating

13. Polymethacrylate ethylacry late copolymer 8.8 14. ^■ Talc 4.2

15. Triethyl citrate 1

16. Water q.s. (Lost in processing) Procedure: i) Sodium carbonate was crushed and sifted with sieve of mesh size 60. ii) The material of step (i), microcrystalline cellulose, mannitol and crospovidone were dried separately at 6O ⁰ C for 2 hours in a tray drier, iii) Esomeprazole, microcrystalline cellulose, crospovidone, calcium stearate and talc were sifted separately through of mesh size 40. iv) The bulk of step (iii) and the material of step (ii)were mixed together. v) The mixed mass of step (iv) was slug/deslugged to obtain granules of sieve of mesh size 20/60. vi) Crospovidone, calciuin stearate and talc were sifted through sieve of mesh size 60. vii) The sifted mass of step (vi) was added to the bulk of step (v) and further blended for 10 mins. viii) ^" The blend of step (vii) was compressed into tablets.

^' ix) The tablets of step (viii) were coated by seal coat followed by coating with enteric polymer.

B) Metoclopraraide immediate release tablets with coating of alginic acid: S. No. Ingredients Qty/ tab (mg)

1. Metoclopramide 10 2. Mannitol- 31

3. Microcrystalline cellulose 31.25

4. Magnesium stearate 0.75

5. Croscarmellose sodium 2

6. Sodium bicarbonate 50.0 Film coating

7. Alginic acid 200

8. Aqueous ethylcellulose dispersion 20

9. Polyethylene glycol 6000 30

10. Iron oxide red 3 11. Isopropyl alcohol q.s. (Lost in processing)

12. Dichloromethane q.s. (Lost in processing)

Procedure: i) Metoclopramide, microcrystalline cellulose, sodium bicarbonate, mannitol and croscarmellose sodium were sifted through sieve of mesh size 40. ii) Magnesium stearate was sifted through sieve of mesh size 40. iii) The bulk of step (i) and (ii) were mixed together and compressed into tablets. iv) The tablets of step (iii) were finally film coated.

C) Metoclopramide delayed release tablets: S. No. Ingredients Qty/ tab (mg)

1. Metoclopramide 20

2. Mannitol 31

3. Macrocrystalline cellulose 21.25

4. Magnesium stearate 0.25

5. Croscarmellose sodium 2

Enteric coating

6. Polymethacrylate ethylacrylate copolymer 16.13

7. Talc 3.63

8. Triethyl citrate 0.48

9. Simethicone 0.046

10. Water q.s. (Lost in processing) Procedure: i) Metoclopramide, microcrystalline cellulose, ^" mannitol and croscarmellose sodium were sifted through sieve of mesh size 40. ii) Magnesium stearate was sifted through sieve of mesh size 40. iii) The bulk of step (i) and (ii) were mixed together and compressed into tablets. iv) ^' The tablets of step (iii) were finally enteric coated.

The tablets of A . step (ix),. B step (iv) and C step (iv) were filled into a hard gelatin capsule.

Example-3

A) Esomeprazole delayed release granules:

S. No. Ingredients Qty (mg)

1. Esomeprazole 40

2. Sodium carbonate 12

3. Mannitol 5

4. Microcrystalline cellulose 1 1

5. Crospovidone 13

6. Calcium stearate 0.5

7. Talc 0.5

8. Crospovidone 2

9. Calcium stearate 0.5 10. Talc 0.5 Seal coat

11. Opadry yellow 2.5

12. Water q.s. (Lost in processing) • Enteric coating

13. Copolymers of acrylic and methacrylic acid 8.8 esters

14. Talc ^' 4.2

15. Triethyl citrate 1 16. Isopropyl alcohol q.s. (Lost in processing)

Procedure: i) Sodium carbonate was crushed and sifted with sieve of mesh size 60. ii) The material of step (i), macrocrystalline cellulose, mannitol and crospovidone were dried separately at 6O ⁰ C for 2 hours in a tray drier. iii) Esomeprazole, microcrystalline cellulose, crospovidone, calcium stearate and talc were sifted separately through of mesh size 40. iv) The bulk of step (iii) and the material of step (ii) were mixed together, v) The mixed mass of step (iv) was slug/deslugged to obtain granules of sieve of mesh size 20/60. vi) Crospovidone, calcium stearate and talc were sifted through sieve of mesh size

60. vii) The sifted mass of step (vi) was added to the bulk of step (v) and further blended for 10 mins to finally obtain the granules. viii) The granules of step (viii) were coated by seal coat followed by coating with enteric polymer.

B) Metoclopramide immediate release granules alongwith sodium alginate:

S. No. Ingredients Qty (mg)

1. Metoclopramide 10 2. Sodium alginate • 200

3. Sodium bicarbonate 70

4. Microcrystalline cellulose 35

5. Mannitol . 22 6. Croscarmellose sodium 10

7. Isopropyl alcohol 0.75

8. Croscarmellose sodium q.s. (Lost in processing)

9. Magnesium stearate ^■ • 3 Procedure: i) Metoclopramide, sodium alginate, microcrystalline cellulose, sodium bicarbonate, and mannitol and croscarmellose sodium were sifted through sieve of mesh size 40. ii) The bulk of step (i) was mixed together and granulated with isopropyl alcohol. iii) The granules of step (ii) were dried and then sifted the dried granules to sieve of mesh size 20. iv) Magnesium stearate was sifted through sieve of mesh size 40. v) The bulk of step (iii) and (iv) were mixed together to obtain final granules.

C) Metoclopramide delayed release granules:

S. No. Ingredients Qty (mg)

1. Metoclopramide 20

2. Mannitol 21.25

3. Microcrystalline cellulose 31.5

4. Croscarmellose sodium 0.75

5. Isopropyl alcohol q.s. (Lost in. processing)

6. Magnesium stearate 2

Enteric coating

7. Polymethacrylate ethylacrylate copolymer 16.13

8. Talc 3.63

9. Triethyl citrate 0.48

10. Simethicone 0.046

11. Water q.s. (Lost in processing)

Procedure: i) Metoclopramide, microcry stall ine cellulose, mannitol and croscarmellose sodium were sifted through sieve of mesh size 40. ii) The bulk of step (i) was mixed and the granulated with isopropyl alcohol, iii) - The granules of step (ii) were dried and passed through sieve of mesh size 20. iv) Magnesium stearate was sifted through sieve of mesh size 40. v) The bulk of step (iii) and (iv) were mixed together to obtain granules. vi) The granules of step (v) were finally enteric coated.

The granules of A step (viii), B step (v) and C step (vi) were filled into a hard gelatin capsule.

Example-4

A) Esomeprazole delayed release tablets:

S. No. Ingredients Qty/ tab (mg)

1. Esomeprazole 40

2. Sodium carbonate 12

3. Mannitol 5

4. Microcrystalline cellulose 11

5. Crospovidone 13

6. Calcium stearate 0.5

7. Talc 0.5

8. Crospovidone 2

9. Calcium stearate 0.5

10. Talc 0.5

Seal coat

11. Opadry yellow 2.5

12. Water q.s. (Lost in processing)

Enteric coating 13. Polymethacrylate ethylacry late copolymer 8.8

14. Talc 4.2

15. Triethyl citrate 1

16. Water q.s. (Lost in processing) Procedure: i) Sodium carbonate was crushed and sifted with sieve of mesh size 60. ii) The material of step (i), microcrystalline cellulose, mannitol and crospovidone were dried separately at 6O ⁰ C for 2 hours in a tray drier, iii) Esomeprazole, microcrystalline cellulose, crospovidone, calcium stearate and talc were sifted separately through of mesh size 40. iv) The bulk of step (iii) and the material of step (ii) were mixed together. v) The mixed mass of step (iv) was slug/deslugged to obtain granules of sieve of mesh size 20/60. vi) Crospovidone, calcium stearate and talc were sifted through sieve of mesh size .60. vii) The sifted mass of step (vi) was added to the bulk of step (v) and further blended for lO mins. viii) The blend of step (vii) was compressed into tablets. ix) The tablets of step (viii) were coated by seaj coat followed by coating with enteric polymer.

B) Domperidone immediate release tablets with coating of alginic acid: S. No. Ingredients Qty/ tab (mg)

1. Domepridone 10 2. Mannitol 31

3. Macrocrystalline cellulose 31.25

4. Magnesium stearate 0.75

5. Croscarmellose sodium 2

6. Sodium bicarbonate 50.0 Film coating

7. Alginic acid 200

8. Hydroxypropyl methylcellulose 20

9. Polyethylene glycol 6000 30

10. Iron oxide red 3 11. Isopropyl alcohol q.s. (Lost in processing)

12. Dichloromethane q.s. (Lost in processing)

Procedure: i) Domepridone, microcrystalline cellulose, sodium bicarbonate, mannitol and croscarmellose sodium were sifted through sieve of mesh size 40. ii) Magnesium stearate was sifted through sieve of mesh size 40. iii) The bulk of step (i) and (ii) were mixed together and compressed into tablets, iv) The tablets of step (iii) were finally film coated.

C) Domperidone delayed release tablets: S. No. Ingredients Qty/ tab (mg)

1. Domepridone . 20

2. . Mannitol ^; 31

3. Microcrystalline cellulose 21.25 4. Magnesium stearate 0.25

5. . Croscarmellose sodium 2 Enteric coating

6. Polymethacrylate ethylacrylate copolymer 16.13

7. Talc ^' 3.63 8. Triethyl citrate 0.48

9. Simethicone 0.046

10. Water q.s. (Lost in processing) Procedure: i) Domepridone, microcrystalline cellulose, mannitol and croscarmellose sodium were sifted through sieve of mesh size 40. ii) Magnesium stearate was sifted through sieve of mesh size 40. iii) The bulk of step (i) and (ii) were mixed together and compressed into tablets. iv) The tablets of step (iii) were finally enteric coated.

The tablets of A step (ix), B step (iv) and C step (iv) were filled into a hard gelatin capsule.

Example-5

A) Dexrabeprazole delayed release tablets:

S. No. Ingredients Qty (mg)

1. Dexrabeprazole sodium 10

2. Mannitol 20

3. . Microcrystalline cellulose 23.95

4. Magnesium oxide 20

5. Hydroxy propylcellulose 4.25

6. Crospovidone 4.25

7. Sodium stearyl fumarate 1.7

8. Talc 0.85

Base coat 9. Opadry II Brown 2.125

10. Purified water q.s . (Lost in processing)

Enteric coating

11. Polymethacrylate ethylacrylate copolymer 20.1

12. Talc 3

13. Triethyl citrate 1.25

14. Purified water q.s. (Lost in processing)

Procedure: i) ^' Dexrabeprazole sodium, mannitol, macrocrystalline cellulose, magnesium oxide, hydroxy propylcellulose, crospovidone, sodium stearyl fumarate and talc were mixed together. ii) The material of step (i) was compressed into tablets iii) The tablets of step (iii) A were coated by opadry brown with enteric polymer.

B) Domperidone immediate release tablets:

S. Nt >. Ingredients Qty (mg)

1. Domperidone maleate 10

2. . Lactose DCL21 11.75

3. Microcrystalline cellulose ! 25

4. Citric acid 10

5. Maize starch 7.5

6.. Pregelatinized starch 3

7. Crospovidone 1.125

8. Povidone K30 0.75

9. Purified water q.s. (Lost in processing)

10. Sodium lauryl sulphate 0.375

11. Magnesium stearate 1

12. Crospovidone 1.5

13. Pregelatinized starch ^' 3

Base coating

14. Opadry II white 2.5

15. Purified water q.s. (Lost in processing) Procedure: i) Domperidone maleate, lactose, macrocrystalline cellulose, maize starch, pregelatinized starch, crospovidone and citric acid were mixed together. ii) The material of step (i) was mixed with the binder solution (povidone in purified water) to obtain the granules. iii) The granules of step (ii) were dried followed .by blending with sodium lauryl sulfate, magnesium stearate, crospovidone and pregelatinized starch. iv) The bulk of step (iii) was compressed to obtain tablets. v) The tablets of step (iv) were coated with opadry II white.

C) Domperidone delayed release tablets:

S. N( }. Ingredients Qty (mg)

1. Domperidone maleate 20

2. Lactose DCL 21 11.75

3. Microcrystalline cellulose ! 15

4. Citric acid 10

5. Maize starch 7.5

6. Pregelatinized starch 3

7. Crospovidone 1.125

8. Povidone K30 0.75

9. Purified water q.s. (Lost in processing)

10. Sodium lauryl sulphate 0.375

11. Magnesium stearate 1

12. Crospovidone 1.5

13. Pregelatinized starch 3

Base coating

14. Opadry pink 1.875

15. Purified water q.s. (Lost in processing)

Enteric coating

16. Polymethacrylate ethylacrylate copolymer 18.3

17. Glyceryl monostearate 2.6

18. Triethyl citrate 1.1

19. Water q.s. (Lost in processing) Procedure: i) Domperidone maleate, lactose, microcrystalline cellulose, maize starch, pregelatinized starch, crospovidone and citric acid were mixed together, ii) The material of step (i) was mixed with the binder solution (povidone in purified water) to obtain the granules. iii) The granules of step (ii) were dried followed by blending with sodium lauryl sulfate, magnesium stearate, crospovidone and pregelatinized starch, iv) The bulk of step (iii) was compressed to obtain tablets. v) The tablets of step (iv) were coated with opadry pink followed by coating with enteric polymer.

D) Sodium alginate 200 mg granules:

S. No. Ingredients Qty (mg)

1. Sodium alginate 200 2. Sodium bicarbonate 100

3. Calcium carbonate 50

4. Sodium bicarbonate 100

5. Purified water q.s. (Lost in processing) Procedure: i). . Sodium alginate, sodium bicarbonate and calcium carbonate were mixed together. ii). The material of step (i) was mixed with purified water to obtain the granules, iii). The granules of step (ii) were mixed with sodium bicarbonate.

The tablets of A step (iii), B step (v) and C step (v) and granules of D step (iii) were filled into a hard gelatin capsule.

Example-6

A) Panto prazole delayed release tablets: S. No. Ingredients Qty (mg)

1. Pantoprazole sodium sesquihydrate 423

2. Sodium carbonate (anhydrous) 12

3. Mannitol 5

4. Microcrystalline cellulose 8.7 5. Crospovidone 13

6. Calcium stearate 0.5

7. Talc 0.5

8. Crospovidone 2

9. Calcium stearate 0.5

10. Talc 0.5

Seal coat

11. Opadry II Brown 2.125

12. Purified water q.s. (Lost in processing)

Enteric coating

13. Polymethacrylate ethylacrylate copolymer 20.1

14. Talc 3

15. Triethyl citrate 1.25

16. Purified water q.s. (Lost in processing) Procedure: i) Pantoprazole sodium, sodium carbonate (anhydrous), mannitol, microcrystalline cellulose, crospovidone, calcium stearate and talc were mixed together. H) The material of step (i) was slug and deslug. iii) The material of step (ii) was mixed with calcium stearate, crospovidone and talc. iv) The material of step (iii) was compressed into tablets. v) The tablets of step (iv) were coated by opadry II brown followed by coating with enteric polymer.

B) Domperidone immediate release tablets:

S. No. Ingredients Qty (mg)

1. Domperidone maleate 10

2. Lactose DCL21 1 1.75

3. Microcrystalline cellulose 25 44.. CCiittriricc aacciidd 10

5. Maize starch 7.5

6. Pregelatinized starch 3

7. Crospovidone 1.125 8. Povidone K30 0.75

9. Purified water q.s. (Lost in processing)

10. Sodium lauryl sulphate 0.375

11. Magnesium stearate 1 12. Crospovidone 1.5

13. Pregelatinized starch 3 Base coating

14. Opadry II white 2.5

15. Purified water q.s. (Lost in processing) Procedure: i) Domperidone maleate, lactose, microcrystalline cellulose, maize starch, pregelatinized starch, crospovidone and citric acid were mixed together. ii) The material of step (i) was mixed with the binder solution (povidone in purified water) to obtain the granules. iii) The granules of step (ii) were dried followed by blending with sodium lauryl sulfate, magnesium stearate, crospovidone and pregelatinized starch. iv) The bulk of step (iii) was compressed to obtain tablets. v) The tablets of step (iv) were coated with opadry II white.

C) Domperidone delayed release tablets: S. No. Ingredients Qty (mg)

1. Domperidone maleate 20

2. Lactose DCL 21 11.75

3. Microcrystalline cellulose 15

4. Citric acid 10 5. Maize starch ' 7.5

6. Pregelatinized starch 3

7. Crospovidone 1.125

8. Povidone K30 . 0.75

9. Purified water q.s. (Lost in processing) 10. Sodium lauryl sulphate . 0.375

11. Magnesium stearate 1

12. Crospovidone 1.5

13. Pregelatinized starch 3 Base coating

14. Opadry pink 1.875

15. Purified water q.s. (Lost in processing)

Enteric coating

16. Polymethacrylate ethylacrylate copolymer 18.3

17. Glyceryl monostearate 2.6

18. Triethyl citrate • 1.1

19. Water q.s. (Lost in processing)

Procedure: i) Domperidone maleate, lactose, microcrystalline cellulose, maize starch, pregelatinized starch, crospovidone and citric acid were mixed together, ii) The material of step (i) was mixed with the binder solution (povidone in purified water) to obtain the granules. iii) The granules of step (ii) were dried followed by blending with sodium lauryl sulfate, magnesium stearate, crospovidone and pregelatinized starch, iv) The bulk of step (iii) was compressed to obtain tablets, v) The tablets of step (iv) were coated with opadry pink followed by coating with enteric polymer.

D) Sodium alginate 200 mg granules: S. No. Ingredients Qty (rag)

1. _. Sodium alginate 200

2. - Sodium bicarbonate 100

3. Calcium carbonate 50

4. Sodium bicarbonate 100 5. Purified water q.s. (Lost in processing)

Procedure: i) Sodium alginate, sodium bicarbonate and calcium carbonate were mixed together. ii) The material of step (i) was mixed with purified water to obtain the granules. iii) The granules of step (ii) were mixed with sodium bicarbonate.

The tablets of A step (v), B step (v) and C step (v) and granules of D step (iii) were filled into a hard gelatin capsule.