A powder composition for oral suspension of proton pump inhibitors and the method of preparing the same

Abstract

The present invention relates to a powder composition for oral suspension of Proton Pump Inhibitor or pharmaceutically acceptable salts thereof for oral administration. The powder composition for oral suspension comprises a two phase powder mixture, where the first phase is in powder form comprising a Proton Pump Inhibitor or pharmaceutically acceptable salts thereof, at least one diluent, a first buffering agent, a binding agent, and the second phase is in powder form comprising a second buffering agent, a viscosity enhancer, at least one diluent; at least one preservative, a sweetener, and a flavour. The powder composition for oral suspension of Proton Pump Inhibitors provides the convenience of administration for the paediatric and geriatric patients, provide improved palatability of bitter drugs, and improve the solubility of Proton Pump Inhibitors of BCS class-II of biopharmaceutical classification system.

Description

[0001] A Powder composition for oral suspension of Proton Pump Inhibitors and the method of preparing the same

[0002] Field of the Invention

[0003] The present invention relates to a powder composition for oral suspension comprising a proton pump inhibitor for oral administration. The present invention more particularly relates to methods for preparing the same.

[0004] Background of the Invention

[0005] The Proton Pump Inhibitor pharmacophore is 2-pyridylmethyl sulfinyl benzimidazole, corresponding in structure to Formula (I) below. The proton pump inhibitor drugs disclosed in the present invention are omeprazole, esomeprazole, and lansoprazole, all contain this basic structural framework and differ only in the nature of substituents placed on the pyridine and benzimidazole rings. benzimidazole

[0006] Proton Pump Inhibitors are a class of drugs that reduce gastric acid development significantly and for a long time. Proton pump inhibitors act by irreversibly inhibiting the gastric parietal cells’ hydrogen / potassium adenosine tri-phosphatase enzyme mechanism (the H+ / K+ ATPase, or more colloquially, the gastric proton pump). As the proton pump is directly responsible for secreting H+ ions into the gastric lumen at the end of acid secretion, it is an ideal target for acid secretion inhibition.

[0007] The Proton pump inhibitors are used to treat a variety of disorders, including the healing of erosive esophagitis, maintenance of healed erosive esophagitis, treatment of gastroesophageal reflux disease, for gastric ulcers associated with nonsteroidal anti-inflammatory drugs, in reduction of the risk of duodenal ulcer recurrence by eradication of helicobacter pylori, in pathological hypersecretory conditions including Zollinger-Ellison (ZE) syndrome, and in short-term treatment and maintenance of duodenal ulcers. The present invention discloses the proton pump inhibitors drugs with a plasma half-life of about 1-1.5 hours. Proton Pump Inhibitors disclosed herein are Omeprazole, Esomeprazole, and Lansoprazole. Currently marketed solid dosage forms of Proton Pump inhibitors disclosed in the present invention for oral administration include delayed-release tablets, delayed-release capsules, gastro-resistant tablets, delayed-release oral suspension, enteric-coated capsules, enteric-coated tablets, multiple-unit pellet system and suspensions with micro particulates. Delayed-release capsules of Omeprazole are available in three strengths as follows: lOmg, 20mg and 40mg and delayed-release capsules of Esomeprazole is available in two strengths as follows: 20 mg and 40 mg. The delayed-release granule of Esomeprazole and Omeprazole is available in 5 Strengths as follows: 2.5mg, 5mg, lOmg, 20mg, and 40mg in the form of unit dose packets. The delayed-release capsule and delayed-release disintegrating tablets of Lansoprazole is available in 2 strengths as follows: 15mg and 30mg. Delayed-release oral suspension of omeprazole is available in two strengths: 2.5mg and lOmg and delayed-release suspension of Esomeprazole is available in five strengths: 2.5mg, 5mg, lOmg, 20mg, and 40mg. Additionally, the injectable form of Esomeprazole is available in two strengths: 20mg / ml and 40mg / ml.

[0008] US11207307B2 discloses a suspension of Proton Pump Inhibitors, the proton pump inhibitor described is Omeprazole and other inactive ingredients like Benzyl alcohol, a copolymer of ethylene oxide and propylene oxide, simethicone emulsion, sodium bicarbonate, sodium citrate, a sweetener that comprises ammonium glycyrrhizate and sucralose, a thickening agent that is xanthan gum or hydroxyethyl cellulose and water. The pH of the suspension is at least pH 8.0. The batch was transferred to containers using a bottle and cap.

[0009] EP3999066A1 discloses kits for preparing a reconstituted suspension of a proton pump inhibitor and other inactive ingredients are poloxamer, sodium carboxymethylcellulose, sodium bicarbonate, simethicone emulsion, a preservative, a sweetener, water, and optionally a flavoring agent and a coloring agent. These kits containing the omeprazole are stable under refrigerated conditions at 2-8°C.

[0010] US20050031700A1 discloses a powder suspension comprising a proton pump inhibitor in micronized form, an antacid, and suspending agent wherein upon admixture of the powder with water, a substantially uniform suspension is obtained. EP3200768B1 discloses a suspension containing micro granules of Omeprazole and other inactive ingredients which are potassium sorbate, saccharin, silicon dioxide, peppermint oil, titanium dioxide, and fractionated coconut oil. The manufacturing process involves mixing of saccharin into heated myglyol. The mixture is then allowed to cool. Then potassium sorbate, titanium dioxide, and mint are added and mixed. To this solution, silicon dioxide is then added and mixed. The final mixture was formed by mixing of Omeprazole beads.

[0011] The Proton Pump Inhibitors disclosed in the present invention belong to Class II of the Biopharmaceutical Classification System due to their poor solubility in water and high permeability through cell membranes. Suspensions are prepared for drugs that are poorly soluble in water, to mask the bitter taste of unpleasant drugs, for paediatric patients who are unable to swallow solid oral dosage forms and also need a dose adjustment, older patients with dysphagia, ICU patients, and for patients on enteral nutrition. Solid dosage forms of proton pump inhibitors require 2-3 times daily dosing which results in poor patient compliance. In order to successfully manage acid-related disorders, gastric acid production must be suppressed with the use of a Proton Pump inhibitor. Therefore, formulating a pharmaceutical composition in the form of powder composition for oral suspension of proton pump inhibitors would offer advantages over the aforementioned problems.

[0012] Summary of the Invention

[0013] In accordance with the present invention, a powder composition for oral Suspension of Proton Pump Inhibitors is prepared. The powder composition for oral suspension comprising a two phase powder mixture, where the first phase is in powder form comprising a Proton Pump Inhibitor or pharmaceutically acceptable salts thereof, at least one diluent, a first buffering agent, a binding agent, and the second phase are in powder form comprising a second buffering agent, a viscosity enhancer, at least one diluent, at least one preservative and one or more pharmaceutically acceptable salt thereof. The first phase powder mixture contains a moisture content of not more than 5.0%.

[0014] Another embodiment of the present invention is to provide a powder for reconstitution as oral suspension for oral administration comprising a Proton Pump inhibitor, which achieves to mask the bitter taste of the active ingredient and provides acceptable palatability. Another embodiment of the present invention is effectively treat a variety of disorders, including the healing of erosive esophagitis, maintenance of healed erosive esophagitis, treatment of gastroesophageal reflux disease, for gastric ulcers associated with nonsteroidal anti-inflammatory drugs, to reduce the risk of duodenal ulcer recurrence by eradication of helicobacter pylori, in pathological hyper secretory conditions including Zollinger-Ellison (ZE) syndrome, and in short-term treatment and maintenance of duodenal ulcers.

[0015] Another embodiment of the present invention is a method for assessing therapeutic equivalence and bioequivalence of Proton Pump Inhibitor comprising the steps of: a) administering a predetermined dose of the reference product (R) or test product (T) to a number of human subjects; b) collecting gastric juice samples from the human subjects by inserting the tube through the subject’s nose; c) measuring the pH of the collected gastric juice samples and storing collected gastric juice samples at -70 +15 °C for 6 months; d) collecting blood samples from the human subjects; e) determining the concentration of drug in the blood samples, preferably by High Performance-Electrospray- Liquid Chromatography-Mass Spectrometry / Mass Spectrometry (HPLC-ESI-MS / MS); and f) comparing the pharmacokinetic parameters of test product formulation with a reference formulation but not limited to Cmax (ng / mL), AUCO-t (hr*ng / mL), AUCO-inf (hr*ng / mL), Tmax (hr), Kel (1 / hr), t’A (hr), AUC ratio, residual area (%).

[0016] Objects of the Invention

[0017] The primary object of the present invention is to provide a powder composition of Proton pump inhibitor or pharmaceutically acceptable salts thereof for oral administration to be reconstituted to form a suspension.

[0018] It is an object of the present invention to provide a powder composition for oral suspension of Proton pump inhibitor, which is particularly convenient for administration for paediatric and geriatric patients. It is further another object of the present invention is to provide a process of preparation of a powder composition for oral suspension of proton pump inhibitor or its pharmaceutically acceptable salts thereof.

[0019] It is yet another object of the present invention to provide a powder composition for oral suspension of Proton Pump Inhibitors with improved palatability of bitter drugs for oral administration.

[0020] It is an object of the present invention is to provide a powder composition to be reconstituted to form suspension to improve the solubility of Proton pump inhibitor drugs or pharmaceutically acceptable salts which belongs to BCS Class-II drugs with poor solubility.

[0021] It is an object of the present invention to provide a powder composition for oral suspension of Proton pump inhibitor drugs for oral administration comprising one or more pharmaceutically acceptable excipients or additives selected from the group consisting of diluents, buffering agents, binding agents, viscosity enhancers, preservatives, sweeteners, and flavours or any combinations thereof.

[0022] Detailed description of the Invention

[0023] The present invention discloses a powder formulation for oral administration suitable for reconstitution with a pharmaceutically acceptable carrier to form a suspension oral dosage form of Proton pump inhibitors.

[0024] The term “proton-pump inhibitors” is defined as a class of anti-secretory compounds that suppress gastric acid secretion and are generally considered the most potent acid suppressants available.

[0025] The term “suspension” refers to a disperse system in which one substance (the dispersed phase) is distributed in particulate form throughout another (the continuous phase).

[0026] The term "about", as and when used in this specification, means ±10 % of the mentioned value. As used herein and in the appended claims, the singular forms "a", "an", and "the" include plural reference unless the context clearly dictates otherwise. The term "pharmaceutically acceptable salt" refers to salts prepared from pharmaceutically acceptable inorganic and organic acids.

[0027] The term “powder” as used herein refers to any composition or formulation which is dry and flowable.

[0028] The term “wet granulation” refers to a process of using a liquid binder to lightly agglomerate the powder mixture.

[0029] As per one embodiment of the present invention, a Proton pump inhibitor is selected from the group consisting of Omeprazole, Pantoprazole, Lansoprazole, Rabeprazole, Dexlansoprazole, Esomeprazole, Ilaprazole, Tenetoprazole, Azeloprazole, Anaprazole or pharmaceutically acceptable salts thereof.

[0030] As per one embodiment of the present invention, a Powder composition for oral suspension comprising a Proton Pump Inhibitor or its pharmaceutically acceptable salts thereof is Omeprazole, Esomeprazole, and Lansoprazole in a micronized or in a non-micronized form.

[0031] As per one embodiment of the present invention, the Proton Pump inhibitors or pharmaceutically acceptable salts thereof are present in the range from about 0.01% w / w to about 7.5% w / w, preferably in the range from about 0.05% w / w to about 6.5% w / w. In the present invention, a Proton Pump Inhibitor or its pharmaceutically acceptable salts thereof is Omeprazole present in the range from about 0.01% w / w to about 2.5% w / w, preferably in the range from about 0.05% w / w to about 1.5% w / w, Esomeprazole or its pharmaceutically acceptable salts thereof present in the range from about 0.05% w / w to about 5% w / w, preferably in the range from about 0.1% w / w to about 3.5% w / w, Lansoprazole or its pharmaceutically acceptable salts thereof present in the range from about 0.01% w / w to about 5% w / w, preferably in the range from about 0.05% w / w to about 3.5% w / w.

[0032] As per one embodiment of the present invention, a Proton Pump Inhibitor drug or its pharmaceutically acceptable salts thereof is Omeprazole present in the powder composition, has D50 particle size distribution from about 1.5 pm to 5.5 pm, preferably in the range from about 2.5 pm to 4.5 pm, Esomeprazole in the powder composition has D50 particle size distribution from about 0.5 pm to 4.5 pm, preferably in the range from about 1.5 pm to 3.5 pm, Lansoprazole in the powder composition has D50 particle size distribution from about 4 pm to 16 pm, preferably in the range from about 9 pm to 11 pm. The term D50 is the diameter at which 50% of a sample's mass is comprised of smaller particles. In another embodiment of the present invention, a Proton Pump Inhibitor or its pharmaceutically acceptable salts thereof is Omeprazole in the powder composition has a D90 particle size distribution from about 5 pm to 15 pm, preferably in the range from about 8 pm to 10 pm, Esomeprazole in the powder composition has D90 particle size distribution from about 1 pm to 15 pm, preferably in the range from about 4 pm to 8 pm, Lansoprazole in the powder composition has D90 particle size distribution from about 15 pm to 45 pm, preferably in the range from about 20 pm to 30 pm. The term D90 is the diameter at which 90% of a sample mass is comprised of smaller particles in that sample size.

[0033] As per one embodiment of the present invention, the diluents are selected from the group consisting of lactitol, mannitol, maltitol, xylitol, sorbitol, erythritol, isomalt, or any combinations thereof. In the present invention, the diluents are sugar alcohols selected from mannitol, maltitol, and xylitol or combination thereof present in the range from about 20% w / w to about 80% w / w, preferably in the range from about 30% w / w to about 70% w / w.

[0034] As per one embodiment of the present invention, a suitable binding agent is selected from the group consisting of povidone, starch, pre-gelatinized starch, tragacanth, dextrin, sucrose, glucose, dextrose, molasses, mannitol, sorbitol, xylitol, lactose, acacia, ghatti gum, xanthan gum, polyvinylpyrrolidone, carboxymethylcellulose, methylcellulose, microcrystalline dextrose, amylose, magnesium aluminum silicate, polysaccharide acids, bentonites, gelatin or any combinations thereof. Xanthan gum is preferred as a binding agent present in the range from about 0.0010% w / w to about 2% w / w, preferably in the range from about 0.0015% w / w to about 1.5% w / w.

[0035] As per one embodiment of the present invention, the buffering agents are selected from the group consisting of acetic acid, sodium acetate, citric acid, sodium citrate, sodium phosphate disodium phosphate, sodium hydrogen carbonate, potassium hydrogen carbonate, gluconate, tartrates, 1-methionine, potassium citrate, sodium carbonate anhydrous, potassium bicarbonate, sodium dihydrogen phosphate, disodium hydrogen phosphate, sodium hydroxide, potassium dihydrogen phosphate, fumaric acid, tartaric acid or any combinations thereof. In the present invention, the first buffering agent is sodium hydrogen carbonate present in the range from about 0.45% w / w to about 2% w / w, preferably in the range from about 0.5% w / w to about 1.5% w / w, and the second buffering agent is selected from the group consisting of sodium hydrogen carbonate, potassium hydrogen carbonate and sodium carbonate anhydrous or combinations thereof present in the range from about 15% w / w to about 65% w / w, preferably in the range from about 25% w / w to about 55% w / w. In the present invention, the pH of the reconstituted suspension is in the range from 7.0 to 11.0, preferably it is in the range from 7.5 to 10.5.

[0036] As per one embodiment of the present invention, a viscosity enhancer is selected from the group consisting of sodium alginate, carrageenan, gum acacia, gum tragacanth, sodium carboxymethyl cellulose, methylcellulose, bentonite, veegum, carbomers, colloidal silicon dioxide, glucose, fructose, acacia, bentonite, carboxymethyl cellulose sodium, gelatin, guar gum, hydroxyl ethyl cellulose, hydroxyl propyl methylcellulose, polyvinylpyrrolidone, polyvinyl alcohol, and poloxamer or any combinations thereof. Sodium alginate is preferred as a viscosity enhancer for the present invention present in the range from about 0.05% w / w to about 12.5% w / w, preferably in the range from about 0.075% w / w to about 8.5% w / w. Additionally, it contains a percentage of moisture from about 6% to about 12%, preferably in the range from about 8% to about 10%.

[0037] As per one embodiment of the present invention, the preservatives are selected from the group consisting of ethanol, propylene glycol, benzyl alcohol, quaternary amines, benzalkonium chloride, sorbic acid, benzoic acid, methyl paraben, propyl paraben, glycerin, propylene glycol, sodium propionate, cetrimide, chlorobutanol phenyl mercuric acetate, potassium sorbate, sodium benzoate, disodium edetate, butylparaben, phenyl ethyl alcohol, phenoxetol or any combinations thereof. In the present invention, the combination of sodium benzoate and sodium methyl para hydroxy benzoate is preferred as a preservative in the range from about 0.05% w / w to about 4% w / w, preferably in the range from about 0.075% w / w to about 3% w / w.

[0038] As per one embodiment of the present invention, a suitable sweetener is selected from the group consisting of sugars such as xylose, ribose, glucose, mannose, galactose, fructose, dextrose, sucrose, maltose, hydrogenated glucose syrup, sugar alcohols such as sorbitol, xylitol, mannitol and glycerin, partially hydrolyzed starch, com syrup solids, artificial sweetening agents such as sodium cyclamate, saccharin, aspartame, ammonium glycyrrhizinate or any combinations thereof. In the present invention, the sweeteners are selected from sucralose and sodium saccharine dihydrate or combinations thereof and are present in the range from about 0.05% w / w to about 8.5% w / w, preferably in the range from about 0.1% w / w to about 7% w / w.

[0039] As per one embodiment of the present invention, a flavour is selected from the group consisting of acacia, lavender oil, orange flower water, ginger, vanilla tincture, coriander oil, sarsaparilla syrup, cinnamon (oil, water), anise oil, mint spray dried flavour, lemon oil, dextrose, glucose, tolu balsam syrup, raspberry, spearmint oil, natural mint, citric acid syrup, ethyl acetate, glycerine, wild cherry syrup, ethyl vanillin, thyme oil, rosemary oil, caraway oil, nutmeg oil, fennel oil, clove oil, saccharin sodium, tolu balsam, cocoa syrup, honey cocoa, cherry syrup, vanilla, orange oil or any combinations thereof. In the present invention, Mint spray dried flavour and natural mint are preferred as flavours and are present in the range from about 0.01%w / w to about 2.5%w / w, preferably in the range from about 0.025%w / w to about 1.5%w / w.

[0040] As per preferred embodiment of the present invention, a powder composition for oral suspension comprising Proton Pump Inhibitor or pharmaceutically acceptable salts thereof, present in an amount from about 0.01% w / w to about 7.5% w / w, preferably in the range from about 0.05% w / w to about 6.5% w / w, the sugar alcohol diluent or combination thereof is present in the range from about 20% w / w to about 80% w / w, preferably in the range from about 30% w / w to about 70% w / w, binding agent is present in the range from about 0.0010% w / w to about 2% w / w, preferably in the range from about 0.0015% w / w to about 1.5% w / w, the first buffering agent is present in the range from about 0.45% w / w to about 2% w / w, preferably in the range from about 0.5% w / w to about 1.5% w / w and the second buffering agent or combination thereof is present in the range from about 15% w / w to about 65% w / w, preferably in the range from about 25% w / w to about 55% w / w and the pH of the reconstituted suspension is in range from 7.0 to 11.0, preferably it is in the range from 7.5 to 10.5, viscosity enhancer is present in the range from about 0.05% w / w to about 12.5% w / w, preferably in the range from about 0.075% w / w to about 8.5% w / w and it contains a percentage of moisture from about 6 to about 12%, preferably in the range from about 8% to about 10%, preservatives or combination thereof are present in the range from about 0.05% w / w to about 4.0% w / w, preferably in the range from about 0.075% w / w to about 3% w / w, sweeteners or combination thereof are present in the range from about 0.05% w / w to about 8.5% w / w, preferably in the range from about 0.1% w / w to about 7% w / w and flavours present in the range from about 0.01% w / w to about 2.5% w / w, preferably in the range from about 0.025% w / w to about 1.5% w / w. As per one preferred embodiment of the present invention, a powder composition for oral suspension comprising Omeprazole, Esomeprazole, and Lansoprazole or pharmaceutically acceptable salts thereof in non-micronized form is present in an amount from about 0.01% w / w to about 7.5% w / w, preferably in the range from about 0.05% w / w to about 6.5% w / w, the mannitol, maltitol, and xylitol or combination thereof is present in the range from about 20% w / w to about 80% w / w, preferably in the range from about 30% w / w to about 70% w / w, xanthan gum is present in the range from about 0.0010% w / w to about 2% w / w, preferably in the range from about 0.0015% w / w to about 1.5% w / w, sodium hydrogen carbonate is present in the range from about 0.45% w / w to about 2% w / w, preferably in the range from about 0.5% w / w to about 1.5% w / w, the sodium hydrogen carbonate, potassium hydrogen carbonate and sodium carbonate anhydrous or combinations thereof are present in the range from about 15%w / w to about 65%w / w, preferably in the range from about 25%w / w to about 55%w / w, the pH of the reconstituted suspension is in range from 7.0 to 11.0, preferably it is in the range from 7.5 to 10.5, sodium alginate is present in the range from about 0.05% w / w to about 12.5%w / w, preferably in the range from about 0.075%w / w to about 8.5%w / w and it contains a percentage of moisture from about 6% to about 12%, preferably in the range from about 8% to about 10%, the combination of sodium benzoate and sodium methyl para hydroxy benzoate is present in the range from about 0.05% w / w to about 4.0% w / w, preferably in the range from about 0.075% w / w to about 3% w / w, sucralose and sodium saccharine dihydrate or combinations thereof and are present in the range from about 0.05% w / w to about 8.5% w / w, preferably in the range from about 0.1% w / w to about 7% w / w, mint spray dried flavour and natural mint are preferred as flavours present in the range from about 0.01%w / w to about 2.5%w / w, preferably in the range from about 0.025%w / w to about 1.5%w / w.

[0041] As per one embodiment of the present invention, the ratio of a Proton Pump Inhibitor to Viscosity enhancer is in the range from about 1 : 1 to about 1 : 12 and preferably it is in the range from about 1 :2 to about 1 : 10.

[0042] As per one embodiment of the present invention, the process for the preparation of a powder composition for oral suspension comprising a Proton Pump Inhibitor drug or pharmaceutically acceptable salts thereof is by wet granulation. Wet granulation is widely used in pharmaceutical manufacturing of different dosage forms as it aids in improving the flowability, compressibility, and cohesiveness of the powder. As per one embodiment of the present invention, more than 90% of a Proton Pump Inhibitor drug from said composition is released in 60 minutes, preferably more than 90% of a Proton Pump Inhibitor drug from said composition is released within 45 minutes.

[0043] As per the preferred embodiment of the present invention, a powder composition for oral Suspension of Proton Pump Inhibitors is effective in the treatment of a variety of disorders including the healing of erosive esophagitis, maintenance of healed erosive esophagitis, treatment of gastroesophageal reflux disease, for gastric ulcer associated with nonsteroidal antiinflammatory drugs, for reduction of the risk of duodenal ulcer recurrence by eradication of Helicobacter pylori, in pathological hypersecretory conditions including Zollinger-Ellison (ZE) syndrome, and short-term treatment and maintenance of duodenal ulcers.

[0044] As per one embodiment of the present invention, the powder composition comprises: a) 0.01% w / w to about 5% w / w, preferably in the range from about 0.05% w / w to about 3.5% w / w of Lansoprazole or pharmaceutically acceptable salts thereof; b) a combination of mannitol and xylitol present in the range from about 20% w / w to about 80% w / w, preferably in the range from about 30% w / w to about 70% w / w; c) 0.0010% w / w to about 2.0% w / w, preferably in the range from about 0.0015% w / w to about 1.5% w / w of xanthan gum; d) a first buffering agent is sodium carbonate anhydrous present in the range from about 0.45% w / w to about 2% w / w, preferably in the range from about 0.5% w / w to about 1.5% w / w, a second buffering agent is a combination of sodium carbonate anhydrous and potassium hydrogen carbonate present in the range from about 15% w / w to about 65% w / w, preferably in the range from about 25% w / w to about 55% w / w; e) 0.05% w / w to about 12.5% w / w, preferably in the range from about 0.075% w / w to about 8.5% w / w of sodium alginate; f) a combination of sodium benzoate and sodium methyl para hydroxy benzoate present in the range from about 0.05% w / w to about 4% w / w, preferably in the range from about 0.075% w / w to about 3% w / w; g) 0.05% w / w to about 8.5% w / w, preferably in the range from about 0.1% w / w to about 7% w / w of sucralose; and h) 0.01% w / w to about 2.5% w / w, preferably in the range from about 0.025% w / w to about 1.5% w / w of natural mint flavour.

[0045] As per one embodiment of the present invention, the powder composition comprises: a) 0.05% w / w to about 5% w / w, preferably in the range from about 0.1% w / w to about 3.5% w / w of Esomeprazole or pharmaceutically acceptable salts thereof; b) a combination of mannitol and maltitol present in the range from about 20%w / w to about 80% w / w, preferably in the range from about 30% w / w to about 70% w / w; c) 0.0010% w / w to about 2.0% w / w, preferably in the range from about 0.0015% w / w to about 1.5% w / w of xanthan gum; d) a first buffering agent is sodium carbonate anhydrous present in the range from about 0.45% w / w to about 2% w / w, preferably in the range from about 0.5% w / w to about 1.5% w / w, a second buffering agent is a combination of sodium carbonate anhydrous and potassium hydrogen carbonate present in the range from about 15% w / w to about 65% w / w, preferably in the range from about 25% w / w to about 55% w / w; e) 0.05% w / w to about 12.5% w / w, preferably in the range from about 0.075% w / w to about 8.5% w / w of sodium alginate; f) a combination of sodium benzoate and sodium methyl para hydroxy benzoate present in the range from about 0.05% w / w to about 4% w / w, preferably in the range from about 0.075% w / w to 3% w / w; g) a combination of sucralose and sodium saccharin dihydrate present in the range from about 0.05% w / w to about 8.5% w / w, preferably in the range from about 0.1% w / w to about 7% w / w; and h) 0.01% w / w to about 2.5% w / w, preferably in the range from about 0.025% w / w to about 1.5% w / w of natural mint flavour.

[0046] As per one embodiment of the present invention, there is provided a process for preparation for a powder composition for oral suspension comprising Proton Pump Inhibitor or its pharmaceutically acceptable salts thereof, wherein a manufacturing process comprises the following steps:

[0047] Part-I

[0048] (i) Sift a proton pump Inhibitor, a first buffering agent, and at least one diluent together through a 40# sieve.

[0049] (ii) Dry mixing of the sifted ingredients of Step-(i) for 10 minutes in the rapid mixer granulator with the impeller at slow speed and chopper off.

[0050] (iii) Adding binding agent in 70% of total purified water and stirring for about 45 minutes and dissolving to prepare the clear viscous solution.

[0051] (iv) Continuous mixing of the binder solution of Step (iii) in the dry mix of step (ii) in a rapid mixer granulator at slow impeller speed for 1-2 minutes.

[0052] (v) Continuous mixing of ingredients of Step-(iv) and water for a minute at slow impeller speed and continuous kneading of wet mass for a minute with a chopper off during all process, further check the dough mass for proper granulation characteristics. (vi) Scarp the side of the rapid mixer granulator and impeller blades for raking the mass obtained in Step-(v). Then, discharge the wet mass into the fluid bed drier blow by opening the discharge port and operating the sampling and chopper at a slow speed.

[0053] (vii) Dry and sift the wet mass of Step- (vi) in FBD, these dried granules passed through a 40# sieve, and the retained granules are milled through the multi mill by 1.0 mm screen, transfer the remaining milled granules through 40# sieve, the final blending of the granules in a blender for 10 minutes. The obtained first powder mixture contains a moisture content of not more than 5.0%.

[0054] Part-II

[0055] (viii) Milling of the second buffering agent through the multi mill with 3 mm screen, adding this milled second buffering agent with previously sifted viscosity enhancer agent, sweetener, flavor, preservative, and passed through 30 # sieve.

[0056] (ix) Mixing of diluent and preservatives in the blender for 10 minutes and pass through 30# sieve. This final sifted material is mixed with the above-sifted material in the blender for 20 min.

[0057] Part-Ill

[0058] (x) Fill separately the API part in Plunger (Powder Holding Cap) and the dry mix blend in a 150 ml PET amber bottle, closed by a white outer cap.

[0059] As per one embodiment of the present invention, the stability study of a powder composition for oral Suspension of Proton Pump Inhibitors was carried out by placing a dry mix blend in a 150 ml PET amber bottle and API part in Plunger (Powder Holding Cap), said packing material was closed with white outer cap and this powder containing packaging was stored at 25°C / 60% RH and at 40°C / 75% RH for 3 months and 6 months. The powder composition for oral suspension of proton pump Inhibitors provided good physicochemical parameters in stability studies with said packaging and storage conditions.

[0060] As per one embodiment of the present invention is a method for assessing therapeutic equivalence and bioequivalence of Proton Pump Inhibitor comprising the steps of: a) administering a predetermined dose of the reference product (R) or test product (T) to a number of human subjects; b) collecting gastric juice samples from the human subjects by inserting the tube through the subject’s nose; c) measuring the pH of the collected gastric juice samples and storing collected gastric juice samples at -70 +15 °C for 6 months; d) collecting blood samples from the human subjects; e) determining the concentration of drug in the blood samples, preferably by High Performance-Electrospray- Liquid Chromatography-Mass Spectrometry / Mass Spectrometry (HPLC-ESI-MS / MS); and f) comparing the pharmacokinetic parameters of test product formulation with a reference formulation but not limited to Cmax (ng / mL), AUCO-t (hr*ng / mL), AUCO-inf (hr*ng / mL), Tmax (hr), Kel ( 1 / hr), t’A (hr), ALIC ratio, residual area (%).

[0061] As per one embodiment of the present invention, administering a predetermined dose of the reference product (R) or test product (T) to 52 human subjects for the omeprazole and 41 subjects for the lansoprazole Bio-therapeutics and Bioequivalence study; wherein test product is omeprazole 4 mg / ml, powder for oral suspension, and Lansoprazole 30mg / 5mL powder for oral suspension and their reference product is Losec® 20 mg capsules duras gastro resistances (Hard gastro-resistant capsules) and OGAST ORO 30 mg, comprime orodispersible (orodispersible tablet) respectively

[0062] As per one embodiment of the present invention, collecting gastric juice samples of Omeprazole and Lansoprazole from the human subjects by inserting the tube through the subject’s nose: i) from 25.00 hrs pre-dose and up to 24.00 hrs post-dose for omeprazole, as follows:

[0063] Day 0 (Housing day): After nasogastric tube insertion [(-25.00) ± of scheduled time], -23.00, - 22.00, -21.00, -20.00, -18.00, -16.00, -14.00, -12.00, -10.00, -07.00, -05.00, - 03.00, -1.00 hrs pre-dose (± 15 minutes of scheduled time), and Day 1 (Dosing day): Pre-dose (collected within 45 minutes prior to dosing) (0.00), 01.00, 02.00, 03.00, 04.00, 05.00, 07.00, 09.00, 11.00, 13.00, 15.00, 18.00, 20.00, 22.00, 23.00 hrs post dose (± 15 minutes of scheduled time); ii) from -24.00 hrs pre-dose and up to 23.00 hrs post-dose for lansoprazole, as follows:

[0064] Day 0 (Housing day): After nasogastric tube insertion -24.00, -23.00, -22.00, -21.00, -20.00, - 19.00, -17.00, -15.00, -13.00, -11.00, -09.00, -06.00, -04.00, -02.00, -01.00 hrs pre-dose (± 15minute o scheduled times), and Day 1 (Dosing day): Pre-dose (collected within ± 45 minutes prior to dosing) (00.00), 01.00, 02.00, 03.00, 04.00, 05.00, 07.00, 09.00, 11.00, 13.00, 15.00, 18.00, 20.00, 22.00, 23.00 hrs post-dose (±15 minutes of scheduled time).

[0065] As per one embodiment of the present invention, therapeutic equivalence study data of proton pump inhibitor of Omeprazole: pH value for Day 0 is 2 to 6 (Median>3), preferably 3.58 ± 0.11(Median>3); the pH value for Day 1 is 2 to 6 (Median>3), preferably 3.67 ± 0.28(Median>3); the pH value for Day 0 is 2 to 6 (Median>4), preferably 4.76 ± 0.47 (Median>4); the pH value for Day 1 is 2 to 6 (Median>4), preferably 4.65 ± 0.46 (Median>4); the AUC of pH data for Day 0 is 50 to 60, preferably 53.48±19.50; and the AUC of pH data for Day 1 is 50 to 60, preferably 52.39±16.64

[0066] As per one embodiment of the present invention, therapeutic equivalence study data of proton pump inhibitor of Lansoprazole: pH value for Day 0 is 2 to 6 (Median>3), preferably 3.90±0.14(Median>3); the pH value for Day 1 is 2 to 6 (Median>3), preferably 3.74 ± 0.28 (Median>3); the pH value for Day 0 is 3 to 6 (Median>4), preferably 4.98 ± 0.22 (Median>4), the pH value for Day 1 is 3 to 6 (Median>4), preferably 4.52 ± 0.47 (Median>4); the AUC of pH data for Day 0 is 60 to 70, preferably 64.338±23.807, and the AUC of pH data for Day 1 is 80 to 90, preferably 85.328 ±19.725

[0067] As per one embodiment of the present invention, the pharmacokinetic data of proton pump inhibitor of Omeprazole: AUCO-t is 2100 to 2900 (hr*ng / mL), preferably 2500.358 ± 2194.657 (hr*ng / mL); AUCO-inf is 2100 to 2900 (hr*ng / mL), preferably 2528.279 ± 2223.897(hr*ng / mL); the maximum plasma concentration (Cmax) is 700 to 1200 (ng / mL), preferably 1006.336 ± 451.539 (ng / mL); the time to reach maximum concentration (Tmax) is 0.25 to 1 hours, preferably 0.50 hour; the elimination rate constant (Kel) is 0.20 to 0.90 (1 / hr), preferably 0.55 ± 0.27 (1 / hr); and the t’A is 0.5 to 3 (hr), preferably 1.75 ± 1.17 (hr).

[0068] As per one embodiment of the present invention, the pharmacokinetic data of proton pump inhibitor of Lansoprazole: AUCO-t is 3000 to 4000 (hr*ng / mL), preferably 3464.891 ± 2521.249 (hr*ng / mL); the AUCO-inf is 3000 to 4000 (hr*ng / mL), preferably 3576.389 ± 2668.482 (hr*ng / mL); the maximum plasma concentration (Cmax) is 200 to 1000 (ng / ml), preferably 590.078 ± 229.778 (ng / mL); the time to reach maximum concentration (Tmax) is 0.1 to 2.50 hours, preferably 0.75 hours; the elimination rate constant (Kel) is 0.1 to 1 (1 / hr), preferably 0.25± 0.11 (1 / hr); and the t’A is 1 to 10 hr, preferably 3.32 ± 1.45 (hr). The invention is further defined by reference to the following examples describing in detail the method for the preparation and testing parameters of Proton Pump Inhibitor drugs in Powder composition to be reconstituted to form an oral suspension, which is by no means intended to limit the scope of the invention but are given by way of illustration.

[0069] Example 1:

[0070] The manufacturing of a Powder composition for oral Suspension of Omeprazole was conducted according to the method defined below having the ingredients shown in Table-I:

[0071] Table-I

[0072] Manufacturing process:

[0073] Part - 1

[0074] (i) Sift the omeprazole, sodium hydrogen carbonate, and mannitol together through a 40# sieve.

[0075] (ii) Dry mixing of the sifted ingredients of Step-(i) for 10 minutes in the rapid mixer granulator with the impeller at slow speed and chopper off. (iii) Adding xanthan gum in 70% of the total purified water and stirring for about 45 minutes and dissolve to prepare the clear viscous solution.

[0076] (iv) Continuous mixing of the binder solution of Step (iii) in a dry mix of step (ii) in a rapid mixer granulator at slow impeller speed.

[0077] (v) Discharge the wet mass into the fluid bed drier blow by opening the discharge port and operating the sampling and chopper at a slow speed.

[0078] (vi) Dry and sift the wet mass of Step- (v) in FBD, these dried granules are passed through a 40# sieve and the retained granules are milled through the multi mill by 1.0 mm screen, transfer the remaining milled granules through 40# sieve, the final blending of the granules in a blender for 10 minutes. The obtained first powder mixture contains a moisture content of not more than 4.0%.

[0079] Part-II

[0080] (viii) Milling potassium hydrogen carbonate through the multi mill with a 3mm screen, adding this milled potassium hydrogen carbonate with previously sifted sodium hydrogen carbonate, sodium alginate, mint spray dried flavor, sodium methyl para hydroxy benzoate and passing through 30# sieve.

[0081] (ix) Mixing of maltitol and sodium benzoate in the blender for 10 minutes and pass through a 30# sieve. This final sifted mixture is mixed with the above-sifted material in the blender for 20 min.

[0082] Part-Ill

[0083] (ix) Fill separately the API part in Plunger (Powder Holding Cap) and the dry mix blend in a 150 ml PET amber bottle, closed by a white outer cap.

[0084] Suspension after reconstitution was not properly pourable due to lower viscosity. Hence, a viscosity enhancer was added in subsequent trials.

[0085] Example 2:

[0086] The manufacturing of a Powder composition for oral suspension of Omeprazole was conducted according to the method defined below having the ingredients shown in table-II:

[0087] Table-II

[0088] Manufacturing process:

[0089] Part - 1

[0090] (i) Sift the omeprazole, sodium hydrogen carbonate, and mannitol together through a 40# sieve.

[0091] (ii) Dry mix the sifted ingredients of Step-(i) for 10 minutes in the rapid mixer granulator with the impeller at slow speed and chopper off.

[0092] (iii) Adding xanthan gum in 70% of the total purified water and stirring for about 45 minutes and dissolve to prepare the clear viscous solution.

[0093] (iv) Continuous mixing of the binder solution of Step (iii) in the dry mix of step (ii) in a rapid mixer granulator at slow impeller speed.

[0094] (v) Discharge the wet mass into the fluid bed drier blow by opening the discharge port and operating the sampling and chopper at a slow speed.

[0095] (vi) Dry and sift the wet mass of Step- (v) in FBD, these dried granules are passed through a 40# sieve and the retained granules are milled through the multi mill by 1.0 mm screen, transfer the remaining milled granules through 40# sieve, the final blending of the granules in the blender for 10 minutes. The obtained first powder mixture contains a moisture content of not more than 4.0%.

[0096] Part-II

[0097] (viii) Milling Potassium hydrogen carbonate through the multi mill with a 3mm screen, adding this milled potassium hydrogen carbonate with previously sifted sodium hydrogen carbonate, sodium alginate, mint spray dried flavor, sodium methyl para hydroxy benzoate passed through 30 # sieve.

[0098] (ix) Mixing of maltitol and sodium benzoate in the blender for 10 minutes and pass through 30# sieve. This final sifted mixture is mixed with the above-sifted material in the blender for 20 min.

[0099] Part-Ill

[0100] (ix) Fill separately the API part in Plunger (Powder Holding Cap) and the Dry Mix Blend in a 150 ml PET amber bottle, closed by a white outer cap.

[0101] Suspension after reconstitution has satisfactory pourability. It was further evaluated for palatability as suspension after reconstitution had a bitter taste. Hence, there was a need to improve palatability by adding sweetener.

[0102] Example -3

[0103] The manufacturing of a Powder composition for oral suspension of Omeprazole was conducted according to the method defined below having the ingredients shown in table-III:

[0104] Table-Ill Manufacturing process:

[0105] Part - 1

[0106] (i) Sift the omeprazole, sodium hydrogen carbonate, and mannitol together through a 40# sieve.

[0107] (ii) Dry mixing the previously sifted ingredients of Step-(i) for 10 minutes in the rapid mixer granulator with the impeller at slow speed and chopper off.

[0108] (iii) Adding xanthan gum in 70% of the total purified water and stirring for about 45 minutes and dissolve to prepare the clear viscous solution.

[0109] (iv) Continuous mixing of the binder solution of Step (iii) in the dry mix of step (ii) in a rapid mixer granulator at slow impeller speed.

[0110] (v) Discharge the wet mass into the fluid bed drier blow by opening the discharge port and operating the sampling and chopper at a slow speed.

[0111] (vi) Dry and sift the wet mass of Step- (v) in FBD, these dried granules passed through a 40# sieve, and the retained granules are milled through the multi mill by 1.0 mm screen, transfer the remaining milled granules through 40# sieve, the final blending of the granules in the blender for 10 minutes. The obtained first powder mixture contains a moisture content of not more than 4.0%.

[0112] Part-II

[0113] (viii) Milling the Potassium hydrogen carbonate through the multi mill with a 3mm screen, adding this milled potassium hydrogen carbonate with previously sifted sodium hydrogen carbonate, sodium alginate, sucralose, mint spray dried flavor, sodium methyl para hydroxy benzoate passed through 30 # sieve.

[0114] (ix) Mixing of maltitol and sodium benzoate in the blender for 10 minutes and pass through 30# sieve. This final sifted mixture is mixed with the above-sifted material in the blender for 20 min.

[0115] Part-Ill

[0116] (ix) Fill separately the API part in Plunger (Powder Holding Cap) and the dry mix blend in a 150 ml PET amber bottle, closed by a white outer cap.

[0117] Suspension after reconstitution has satisfactory pourability. It was evaluated further for palatability as suspension after reconstitution had a bitter taste. Hence, there was a need to improve palatability by adding sweetener. Therefore, the next trial was performed by increasing sucralose by 0.39% to mask the taste. Example -4

[0118] The manufacturing of a Powder composition for oral suspension of Omeprazole was conducted according to the method defined below having the ingredients shown in Table IV:

[0119] Table-IV

[0120] Manufacturing process:

[0121] Part-I

[0122] (i) Sift the omeprazole, sodium hydrogen carbonate, and mannitol together through a 40# sieve.

[0123] (ii) Dry mixing of the sifted ingredients of Step-(i) for 10 minutes in the rapid mixer granulator with the impeller at slow speed and chopper off.

[0124] (iii) Adding xanthan gum in 70% of the total purified water and stirring for about 45 minutes and dissolve to prepare the clear viscous solution.

[0125] (iv) Continuous mixing of the binder solution of Step (iii) in the dry mix of step (ii) in a rapid mixer granulator at slow impeller speed for 2-5 minutes. (v) Continuous mixing of ingredients of Step-(iv) and water for a minute at slow impeller speed and continuous kneading of wet mass for a minute with a chopper off during all process, further checking the dough mass for proper granulation characteristics.

[0126] (vi) Scarp the sides of the rapid mixer granulator and impeller blades for raking the mass obtained in Step-(v). Then, the wet mass is discharged into the fluid bed drier blow by opening the discharge port and operating the sampling and chopper at a slow speed.

[0127] (vii) Dry and sift the wet mass of Step- (vi) in FBD, these dried granules are passed through a 40# sieve and the retained granules are milled through the multi mill by 1.0 mm screen, transfer the remaining milled granules through 40# sieve, the final blending of the granules in the blender for 10 minutes. The obtained first powder mixture contains a moisture content of not more than 4.0%.

[0128] Part-II

[0129] (viii) Milling of the Potassium hydrogen carbonate through the multi mill with a 3 mm screen, adding this milled potassium hydrogen carbonate with previously sifted sodium hydrogen carbonate, sodium alginate, sucralose, mint spray dried flavor, sodium methyl para hydroxy benzoate and passed through 30 # sieve.

[0130] (ix) Mixing of maltitol and sodium benzoate in the blender for 10 minutes and pass through 30# sieve. This final sifted mixture is mixed with the above-sifted material in the blender for 20 min.

[0131] Part -III

[0132] (x) Fill separately the API part in Plunger (Powder Holding Cap) and the dry mix blend in a 150 ml PET amber bottle, closed by a white outer cap.

[0133] Example -5

[0134] The manufacturing of a Powder composition for oral suspension of Esomeprazole was conducted according to the method defined below having the ingredients shown in Table-V for dose Strengths 40mg / 5ml and 20mg / 5ml:

[0135] Table-VA

[0136]

[0137] Table- VB

[0138] Manufacturing process:

[0139] Part-I

[0140] (i) Sift the Esomeprazole, mannitol, and sodium carbonate anhydrous together through a 40# sieve.

[0141] (ii) Dry mixing of sifted ingredients of Step-(i) for 10 minutes in the rapid mixer granulator with the impeller at slow speed and chopper off.

[0142] (iii) Adding xanthan gum in 70% of the total purified water and stirring for about 45 minutes and dissolved to prepare the clear viscous solution.

[0143] (iv) Continuous mixing of the binder solution of Step (iii) in the dry mix of step (ii) in a rapid mixer granulator at slow impeller speed for 1-2 minutes.

[0144] (v) Continuous mixing of ingredients of Step-(iv) and water for a minute at slow impeller speed and continuous kneading of wet mass for a minute with a chopper off during all process, further checking the dough mass for proper granulation characteristics.

[0145] (vi) Scarp the side of the rapid mixer granulator and impeller blades for raking the mass obtained in Step-(v). Then, discharge the wet mass into the fluid bed drier blow by opening the discharge port and operating the sampling and chopper at a slow speed.

[0146] (vii) Dry and sift the wet mass of Step- (vi) in FBD, these dried granules are passed through a 40# sieve and the retained granules are milled through the multi mill by 1.0 mm screen, transfer the remaining milled granules through 40# sieve, the final blending of the granules in the blender for 10 minutes. The obtained first powder mixture contains a moisture content of not more than 2%.

[0147] Part-II

[0148] (viii) Milling potassium hydrogen carbonate through the multi mill with a 3mm screen, adding this milled potassium hydrogen carbonate with previously sifted sodium carbonate anhydrous, mannitol, sodium alginate, sodium saccharin dihydrate, sucralose, mint spray dried flavor, sodium methyl para hydroxy benzoate and these milled ingredients are passed through 30#sieve. Also, maltitol and sodium benzoate are sifted through a 30# sieve.

[0149] (ix) Mixing the previously sifted maltitol and sodium benzoate in the blender for 10 min. The final sifted mixture is mixed with the above-sifted material in the blender for 20 min.

[0150] Part-Ill

[0151] (x) Fill separately the API part in Plunger (Powder Holding Cap) and the Dry Mix Blend in a 150 ml PET amber bottle, closed by a white outer cap.

[0152] Example -6

[0153] The manufacturing of a Powder composition for oral Suspension of Lansoprazole was conducted according to the method defined below having the ingredients shown in Table VI for dose strengths 30mg / ml and 15mg / 5ml:

[0154] Table- VIA Table- VIB

[0155] Manufacturing process:

[0156] Part-I

[0157] (i) Sift the Lansoprazole, mannitol, and sodium carbonate anhydrous together through a 40# sieve.

[0158] (ii) Dry mix the sifted ingredients of Step-(i) for 10 minutes in the rapid mixer granulator with the impeller at slow speed and chopper off.

[0159] (iii) Adding xanthan gum in 70% of the total purified water and stirring for about 45 minutes and dissolve to prepare the clear viscous solution.

[0160] (iv) Continuous mixing of the binder solution of Step (iii) in a dry mix of step (ii) in a rapid mixer granulator at slow impeller speed for 1-2 minutes. (v) Continuous mixing of ingredients of Step-(iv) and water for a minute at slow impeller speed and continuous kneading of wet mass for a minute with a chopper off during all process, further checking the dough mass for proper granulation characteristics.

[0161] (vi) Scarp the side of the rapid mixer granulator and impeller blades for raking the mass obtained in Step-(v). Then, discharge the wet mass into the fluid bed drier blow by opening the discharge port and operating the sampling and chopper at a slow speed.

[0162] (vii) Dry and sift the wet mass of Step- (vi) in FBD, these dried granules passed through a 40# sieve, and the retained granules are milled through the multi mill by 1.0 mm screen, transfer the remaining milled granules through 40# sieve, final blending the granules in the blender for 10 minutes. The obtained first powder mixture contains a moisture content of not more than 2%.

[0163] Part-II

[0164] (viii) Milling the potassium hydrogen carbonate through the multi mill with a 3 mm screen, adding this milled potassium hydrogen carbonate with previously sifted sodium carbonate anhydrous, mannitol, sodium alginate, sucralose, mint spray dried flavor, sodium methyl para hydroxyl benzoate, and this milled ingredient are passed through 30# sieve. In addition to this xylitol and sodium benzoate are sieved through a 30# sieve.

[0165] (ix) Mixing the previously sifted maltitol and sodium benzoate in the blender for 10 minutes and the final sifted mixture is mixed with the above-sifted material in the blender for 20min.

[0166] Part-Ill

[0167] (x) Fill separately the API part in Plunger (Powder Holding Cap) and the dry mix blend in a 150 ml PET amber bottle, closed by a white outer cap.

[0168] Example 7

[0169] The Dissolution condition of Powder composition for oral Suspension of a Proton Pump Inhibitor was prepared for Example 4.

[0170] The conditions of the dissolution system are as follows:

[0171] Product Name: Omeprazole Powder Composition

[0172] Strengths: 20mg / ml

[0173] Media: pH 6.8 phosphate buffer

[0174] Apparatus: Paddle

[0175] Rate of rotation: 100 RPM

[0176] Volume: 900 ml Example 8

[0177] A powder composition of Omeprazole for its dissolution profile was analyzed in 900 ml of pH 6.8 phosphate buffer at 100 RPM in USP II (Paddle) apparatus and subjected to a stability study of 25°C / 60%RH and 40°C / 75%RH for 3 months. Results are tabulated below:

[0178] A Powder composition for oral suspension of Omeprazole

[0179] Example 9

[0180] The Dissolution condition of Powder composition for oral suspension of a Proton Pump

[0181] Inhibitor was prepared for Example 5-A.

[0182] The conditions of the dissolution system are as follows: Product Name: Esomeprazole powder composition

[0183] Strengths: 40mg / 5ml

[0184] Media: pH 6.8 phosphate buffer

[0185] Apparatus: Paddle

[0186] Rate of rotation: 100 RPM

[0187] Volume: 900 ml

[0188] Example 10

[0189] A powder composition of Esomeprazole for its dissolution profile was analyzed in 900 ml of pH 6.8 phosphate buffer at 100 RPM in USP II (Paddle) apparatus and subjected to a stability study of 25°C / 60%RH and 40°C / 75% RH for 3 months. Results are tabulated below:

[0190] A Powder composition for oral suspension of Esomeprazole Example 11

[0191] The Dissolution condition of Powder composition for oral suspension of a Proton Pump

[0192] Inhibitor was prepared for Example 6-A.

[0193] The conditions of the dissolution system are as follows:

[0194] Product Name: Lansoprazole powder composition

[0195] Strengths: 30mg / 5ml

[0196] Media: pH 6.8 phosphate buffer

[0197] Apparatus: Paddle

[0198] Rate of rotation: 150 RPM

[0199] Volume: 900 ml

[0200] Example 12

[0201] A powder composition of Lansoprazole for its dissolution profile was analyzed in 900ml of pH 6.8 phosphate buffer at 150 RPM in USP II (Paddle) apparatus and subjected to a stability study of 25°C / 60%RH and 40°C / 75%RH for 6 months. Results are tabulated below:

[0202] A Powder composition for oral suspension of Lansoprazole

[0203]

[0204] Example 13

[0205] An open label, balanced, randomized, two-treatment, two-sequence, two-period, crossover, single oral dose comparative bioavailability study was conducted to compare an omeprazole composition of the present invention with a known omeprazole dosage form with market approval, in normal, healthy, adult, human subjects under fasting conditions.

[0206] The Reference Product (R) was: PrLosec® 20 mg capsulas duras gastrorresistentes (Hard gastro-resistant capsules). The Test Product (T) was: omeprazole 4 mg / ml, powder for oral suspension having the following composition:

[0207] 1.0 INVESTIGATIONAL PRODUCTS

[0208] Test product: omeprazole 4 mg / ml, powder for oral suspension.

[0209] 1.1 SELECTION AND WITHDRAWAL OF SUBJECTS

[0210] All study subjects were screened based on clinical examination, recording of ECG and laboratory investigations of blood, urine, urine pregnancy test (only for female subjects) not more than 21 days prior to first dosing. Chest X-Ray (PA view) taken within 180 days prior to dosing in the first study period for each volunteer was considered for assessment. For all subjects urine screen for drugs of abuse and alcohol breath test were done on the day of checkin of each study period. Additionally, serum P-hCG test for female subjects was done before check-in of each study period. In addition to this, oropharyngeal examination was done during screening or before check in of period 01. The buccal area was examined and lateral, superior, and inferior walls were inspected. The evaluation of peptic ulcer was done during screening or before check in of period 01. (The Questionnaire to evaluate symptoms of peptic ulcer was used). Study subjects were selected based on the following inclusion and exclusion criteria.

[0211] 1.1.1 Inclusion Criteria

[0212] Subjects were selected to participate in the study, if they meet all of the following criteria:

[0213] 1. Subjects aged between 18 and 45 years (both inclusive).

[0214] 2. Subject’s weight within normal range according to normal values for Body Mass Index (18.50 to 29.99 kg / m2) (both inclusive) with minimum of 50 kg weight.

[0215] 3. Subjects with normal health based on personal medical history, medication history, clinical examination and laboratory examinations within clinically acceptable limits.

[0216] 4. Subject having vital signs parameters (blood pressure, body temperature, pulse rate and respiratory rate) within acceptable limits.

[0217] 5. Subjects having clinically acceptable 12-lead electrocardiogram (ECG). 6. Subjects having clinically acceptable chest X-Ray (PA view).

[0218] 7. Subjects having negative urine screen for drugs of abuse (including amphetamines, barbiturates, benzodiazepines, marijuana, cocaine, and morphine).

[0219] 8. Subjects having negative alcohol breath test.

[0220] 9. Subjects (available for entire study duration) willing to adhere to the protocol requirements and to provide written informed consent.

[0221] 10. Subjects comply with oropharyngeal examination and peptic ulcer evaluation during screening or before check in of period 01.

[0222] 11. For Female Subjects:

[0223] • Subjects having negative Urine pregnancy test at screening and Serum P-hCG (pregnancy test) on admission of each study period.

[0224] • Female of child bearing potential agrees to practice for the duration of the study an acceptable method of birth control as judged by the investigator(s), such as intrauterine device (IUD), abstinence or double barrier contraception, i.e., condom + diaphragm, condom + spermicidal or foam.

[0225] 1.1.2 Exclusion Criteria

[0226] Subjects were excluded from the study, if they meet any one of the following criteria:

[0227] 1. Hypersensitivity to study drug or related class of drugs or to the inactive ingredients of the Test (T) and Reference (R) formulation.

[0228] 2. History or presence of significant cardiovascular, pulmonary, hepatic, renal, gastrointestinal, endocrine, immunological, dermatological, neurological disease or disorder.

[0229] 3. Use of any treatment which could bring about induction or inhibition of hepatic microsomal enzyme system within 1 month prior to dosing of Period 01.

[0230] 4. History or presence of drug abuse in the past one year.

[0231] 5. History or presence of smoking in the past one year.

[0232] 6. History or presence of alcohol abuse in the past one year [alcohol abuse >14 drinks per week (1 drink = 360 mL beer, 150 mL wine, or 45 mL hard liquor)]. 7. History or presence of asthma, urticaria or other significant allergic reactions.

[0233] 8. History or presence of significant gastric and / or duodenal ulceration.

[0234] 9. Difficulty with donating blood.

[0235] 10. Difficulty in swallowing solid dosage forms like tablets or capsules.

[0236] 11. Use of any prescribed medication or OTC medication including vitamins and herbal remedies during last 14 days prior to dosing in period 01.

[0237] 12. Major illness or hospitalization within past 3 months.

[0238] 13. Volunteer / s who have donated 1 unit blood (> 300 mL) or participated in a clinical study involving blood sampling within 90 days prior to the first dose of the study drug.

[0239] 14. Consumption of grapefruit juice within 72 hours prior to dosing and xanthine containing products, tobacco containing products or any alcoholic products within 48 hours prior to dosing.

[0240] 15. Positive screening test for any one or more: HIV, Hepatitis B and Hepatitis C.

[0241] 16. History or presence of significant easy bruising or bleeding.

[0242] 17. History or presence of significant recent trauma.

[0243] 18. Female volunteer who has used implanted or injected hormonal contraceptives anytime during the 6 months prior to study or used hormonal contraceptives within 14 days before dosing.

[0244] 19. Female subjects who are currently breast feeding.

[0245] 20. Pregnant female volunteers.

[0246] 2.0 SUBJECT TREATMENT

[0247] 2.1 Dosing

[0248] Test product: Dosing was done using syringe of appropriate capacity. The prelabelled syringe containing 5 mL Oral suspension was kept in the beaker after dispensing. Prior to drug administration, the syringe was held at upright position. The product was administered with a syringe directly into the subject's mouth. The syringe was rinsed with water utilizing the same beaker used during dispensing. For rinsing of the syringe, water in excess of the volume of drug used for dosing was withdrawn in the syringe from the beaker and then the entire contents of the syringe were emptied back in the beaker. This procedure was done twice to ensure the complete rinsing of the syringe. The rinse was administered to the subjects. The beaker used for rinsing the syringe was rinsed once with adequate quantity of water and this was administered to the subj ects. The total quantity of water used for rinsing the syringes and beaker for dosing did not exceed 240 mL ± 2 mL. The beginning of drug administration with syringe and completion of water intake was considered as dosing start time and dosing completion time respectively. The dose was administered in a staggered manner to maintain subsequent blood collection schedule. The QA person ensured that the dosing is done as per the dosing schedule and as mentioned in the protocol. Compliance for dosing was assessed by a thorough check of the oral cavity by using a tongue depressor and torch immediately after dosing by Principal Investigator / Authorized trained person / Medical Officer. Record of dosing for individual subject was maintained in Case Report Form.

[0249] Reference product: Dose administration was done with 240 mL ± 2 mL of water at ambient temperature by trained personnel, under the supervision of Principal Investigator / authorized trained person in accordance with current version of SOP for ‘Dosing’. Dosing was done by trained study personnel, under the supervision of the Pl / designee in accordance with the current version of the SOP on ‘Administration of Investigational products’. Subjects were instructed not to chew or crush or break or bite the IP but to consume it as a whole. The dose was administered in a staggered manner to maintain subsequent blood collection schedule. Dosing was done in presence of QA. Compliance for dosing was assessed by a thorough check of the oral cavity using a disposable wooden spatula and torch immediately after dosing. Record of dosing of individual subjects was maintained in the CRF. Dosing compliance was based on the current version of the SOP for ‘Administration of Investigational products’.

[0250] 2.2 Monitoring for subject compliance

[0251] 2.1.1 Diet

[0252] In each study period, all subjects fasted overnight for at least 10.00 hrs before dosing and for at least 04.00 hrs after dosing. Subjects were given standardized meals during check-in night and scheduled at around -24.00, -20.00, -16.00, -12.00 hrs (to maintain at least 10.00 hrs. of fasting prior to dosing) before dosing and at around 4.00, 8.00 and 12.00 hrs post-dose in each study period. Record of food served and consumed was documented in the meal consumption record.

[0253] 2.1.2 Fluid Restriction

[0254] Water was not allowed to subjects from at least 01.00 hr pre-dose to at least 01.00 hr post dose except 240 ± 2 mL of water at room temperature given during dosing in each study period. At all other times drinking water was given ad-libitum.

[0255] 2.1.3 Physical Activity / Posture

[0256] Subjects remained in semi recumbent position for first 4.00 hrs post-dose except for any procedure / s. During an AE / s, subject / s were given appropriate (supine / semisupine) position in each study period as recommended by the principal investigator. This was be considered as a protocol deviation.

[0257] 2.1.4 Other

[0258] Subjects were instructed during screening to refrain from chewing tobacco, smoking, pan or pan masala, gutkha, masala (containing beetle nut and tobacco) and consumption of any alcoholic products, xanthine-containing foods or beverages for 48 hours prior to dosing and grapefruit juice for 72 hours prior to dosing until after the last blood sample is collected in each study period. They were not allowed to chew tobacco, pan or pan masala, gutkha, masala (containing tobacco and supari (beetle nut), smoke and to have any xanthine-containing food and / or beverages (like chocolate, tea, coffee or cola drinks) or any fruit juice including grapefruit juice from admission till discharge in each study period.

[0259] For Male subjects: Male subjects must use an approved form of birth control while in the study and for 30 days after the last dose of the study medication as a birth control restriction. Approved birth control methods (a double barrier method) during this period are: condom with spermicide or condom with diaphragm. Men should also not donate sperm during this time. Even if birth control is used during the study, there is a chance of their partner becoming pregnant.

[0260] For Female subjects: Female subjects should not be in the study if, they are pregnant or are breastfeeding. Females should not have unprotected sex with any non-sterile male (i.e., non vasectomised male for at least 06 months) from screening till the end of the study. Moreover, they must use an acceptable method of birth control like condoms, foams, jellies, diaphragm, intrauterine device (IUD), or abstinence during study. If they are pregnant or become pregnant during the study, the study drug or procedures may involve risks to the unborn baby, which are currently unforeseeable. If they become pregnant during the study, they must be instructed to inform the study doctor immediately. It is not known whether the study drug is safe for breast fed babies. If female study subject / s are breastfeeding a child then it may not be safe for them to participate in the study.

[0261] 3.0 Sampling Schedule

[0262] Gastric pH Collection:

[0263] A nasogastric tube was inserted through the subject’s nose for collection of Gastric Juice samples from 25.00 hrs pre-dose and up to 24.00 hrs post-dose.

[0264] A total of twenty nine (29) gastric Juice samples was collected in each study period.

[0265] Day 0 (Housing day): After nasogastric tube insertion [(-25.00) ± of scheduled time], -23.00, - 22.00, -21.00, -20.00, -18.00, -16.00, -14.00, -12.00, -10.00, -07.00, -05.00, - 03.00, -1.00 hrs pre-dose (± 15 minutes of scheduled time).

[0266] Day 1 (Dosing day): Pre-dose (collected within 45 minutes prior to dosing) (0.00), 01.00, 02.00, 03.00, 04.00, 05.00, 07.00, 09.00, 11.00, 13.00, 15.00, 18.00, 20.00, 22.00, 23.00 hrs post dose (± 15 minutes of scheduled time).

[0267] Blood Sample Collection:

[0268] An intravenous cannula was inserted in the subject’ s arm for collection of blood samples before pre-dose blood sample and up to 24.00 hrs post-dose. If there was any difficulty in collecting blood or if the subject is not comfortable with the cannula, the cannula was removed before 24.00 hrs post-dose and the remaining blood samples were collected through fresh vein puncture or by re-cannulation. For any activities coinciding with blood sample collection, blood sample collection was given preference and other activities followed. Before each blood sample collection, 0.3 mL of saline mixed blood from the intravenous cannula was discarded during the use of the intravenous cannula. After every blood sample collection, 0.3 mL of saline was injected in the intravenous cannula to maintain the patency of cannula.

[0269] A total of twenty five (25) blood samples were collected in pre-labelled vacutainer containing K2EDTA as an anticoagulant in each study period. Blood samples (5.0 mL) were collected at pre-dose (00.00 hr) in morning on dosing day within 01.00 hour prior to dosing and at 00.17, 00.25, 00.50, 00.75, 01.00, 01.25, 01.50, 01.75, 02.00, 02.25, 02.50, 02.75, 03.00, 03.50, 04.00, 04.50, 05.00, 06.00, 08.00, 10.00, 12.00, 14.00, 16.00 and 24.00 hours post dose in each study period. Blood samples were kept in ice cold water bath from time of collection up to centrifugation.

[0270] Post dose blood samples were collected within +2 min of schedule time.

[0271] A deviation of more than permissible window for sample collection time was not reported as protocol deviation. It was communicated to the concerned department by format no. CL-015- FT01 “Sampling Deviation Record” and was reported in the final report. The actual time of collection of each blood sample was recorded in the CRF and considered for PK analysis.

[0272] Approximate volume of blood loss during the study:

[0273] Additionally, 6.0 mL blood can be collected if recommended by the Investigator, compensation for same was paid as per in-house SOP.

[0274] 3.1 Sample Handling & Processing

[0275] Samples were centrifuged within 60 minutes after sample collection of respective time point. Following centrifugation at 4000 RPM for 10 minutes at 4°C (short term excursion permitted up to 8°C), the separated plasma was transferred in appropriate sized polypropylene screw top (previously labelled with project no., period no., subject no. and sample time point) biological sample storage vials in approximately equal volume, in duplicate (one aliquot as control sample and one aliquot for analysis). Two separate cryo boxes were used to store the plasma samples, one for analytical and the other for control (back up) samples. All plasma samples were stored at -70° ± 15°C for interim storage at the clinical site until shipped to analytical site. 3.2 Method Validation

[0276] 3.2.1 Sample Assay

[0277] Samples were assayed for Omeprazole using a validated bioanalytical method at the bioanalytical department of Enem Nostrum Remedies Pvt. Ltd. All samples from a subject were analyzed in a single run. Quality control samples were distributed through each batch of study samples assayed as per SOP of Enem Nostrum Remedies Pvt. Ltd. Samples with drug concentrations greater than upper limit of validation range of assay were diluted with appropriate drug free biological fluid and reassayed. Samples below the lower limit of this range were reported as BLQ. Analysts did not have access to the randomization schedule, used for drug dispensing. Samples from subjects completing both the study periods were analyzed. Samples from subject withdrawn due to adverse event were assayed and presented. Repeat analysis was done based on repeat analysis SOPs of Enem Nostrum Remedies Pvt. Ltd.

[0278] Repeat analysis was done in the following cases: rejected analytical batch, lost in processing / analysis, poor chromatography, value above upper limit of standard curve, improper / inconsistent internal standard area and improper sample processing. Both initial and repeat analysis concentrations were reported in tabular form and the value used forPK analysis was reported. Incurred sample re-analysis was done based on the bio-analytical laboratory’s applicable SOP and regulatory requirements.

[0279] 4.0 Safety Evaluation

[0280] Study subjects were monitored for occurrence of adverse events and serious adverse events throughout the study. Safety evaluation was done based on the outcomes of general examination, vital signs measurement, and clinical laboratory results which was done during each study period as detailed below.

[0281] *Well-being assessment, clinical examination [general examination, systemic examination and vital signs (including blood pressure, radial pulse rate, body temperature and respiratory rate)] done during check-out of last study period were considered for post study evaluation as well.

[0282] Additionally, any other assessment including laboratory test(s) were done if judged necessary by the PI or Clinical-Investigator at any time during the study. If subject fails to complete the study or is discontinued from the study, the post-study evaluation was done either on the day of discontinuation or after resolution of AEs. The reason for not completing the study was specified in the subject specific CRF and clinical report.

[0283] 5.0 PHARMACOKINETICS AND STATISTICAL ANALYSIS

[0284] 5.1.1 Pharmacokinetic Parameters

[0285] Data analysis and statistical evaluation pH data:

[0286] Individual pH values were collected at Day 0 and Day 1 for all the subjects for each treatment separately.

[0287] This data was analyzed as below:

[0288] 1. The Median pH values for all 24 hours were analyzed using Wilcoxon's signed rank test at significance level of 5%. The p-values less than 5% were considered as significant and p-values greater than 5% were considered as insignificant.

[0289] 2. This pH data was considered for calculation of AUC values at Day 1 and Day 0 for all the subjects for each treatment separately.

[0290] 3. The comparative data was presented. For Test and Reference products, AUC at Day 1 - AUC at Day 0 was calculated and presented.

[0291] 4. Median (%) of time above pH > 3 and pH > 4 was calculated for all the subjects for each treatment separately and considered as secondary parameter. The median values above pH > 3 and pH > 4 were tabulated and considered for calculation of Median (%).

[0292] 5.1.2 Subject Population

[0293] 60 healthy, adult, human subjects were enrolled in the study.

[0294] Based on the Literature, the maximum intra-subject coefficient of variation (ISCV) for the primary PK parameter was found to be around 32.6%.

[0295] Considering the ISCV not exceeding 32.6%; the sample size computation was determined by considering the following assumptions: a. T / R ratio = 95.0%- 105.0% b. Intra- Subject C.V (%) = 32.6% c. Significance Level = 5% d. Power = 85% e. Bioequivalence Limits = 80.00%-125.00%

[0296] Based on the above estimate, a sample size of 51 subjects would be sufficient to establish comparative bioavailability between products with adequate power. By considering 20% dropouts, 60 subjects were randomized and dosed.

[0297] 5.1.3 Statistical Analysis

[0298] 5.1.3.1 Comparative bioavailability criteria

[0299] For Omeprazole, based on the statistical results of 90% confidence intervals for the geometric least square means ratio of test to reference product for the pharmacokinetic parameters Cmax and AUCO-t, conclusions can be drawn whether test product is bioequivalent to reference product under fasting conditions. Acceptance range for comparative bioavailability is 80.00% - 125.00% for 90% confidence intervals of the geometric least square means ratio of test to reference product for Cmax and AUCO-t.

[0300]

[0301] *Well-being assessment, clinical examination [general examination, systemic examination and vital signs (including blood pressure, radial pulse rate, body temperature and respiratory rate)] done during check-out of last study period were considered for post study evaluation.

[0302] Method and process for data analysis and statistical evaluation pH data:

[0303] Individual pH values were collected at Day 0 and Day 1 for all the subjects for each treatment separately.

[0304] This data was analyzed as below:

[0305] 1. The Median pH values for all 24 hours was analyzed using Wilcoxon's signed rank test at significance level of 5%. The p-values less than 5% were considered as significant and p- values greater than 5% were considered as insignificant for Day 0 and Day 1 respectively. The p value from Day 0 vs Day 1 was calculated treatment wise (Day 0 test vs Day 1 test) and (Day 0 Reference vs Day 1 reference). P value was calculated as significant if it is less than 5% and insignificant If it is greater than 5%.

[0306] 2. This pH data was considered for calculation of AUC values at Day 1 and Day 0 for all the subjects for each treatment separately.

[0307] 3. The comparative data was presented. For Test and Reference products, AUC at Day 1 - AUC at Day 0 was calculated and presented.

[0308] 4. Median (%) of time above pH > 3 and pH > 4 was calculated for all the subjects for each treatment separately and considered as secondary parameter. The median values above pH > 3 and pH > 4 was tabulated and considered for calculation of Median (%).

[0309] Pharmacokinetic Results:

[0310] Descriptive Statistics of Day 0 for pH values [Median>3]

[0311] Descriptive Statistics of Day 0 for pH values [Median>4]

[0312] Descriptive Statistics of Day 1 for pH values [Median>3]

[0313] Descriptive Statistics of Day 1 for pH values [Median>4] Descriptive Statistics of AUC of pH data for Day 0

[0314] Descriptive Statistics of AUC of pH data for Day 1

[0315] Wilcoxon Signed Rank Test Results:

[0316] * Significant P value < 0.05

[0317] Evaluation of Bioequivalence:

[0318] 60 subjects were enrolled in the study and 52 subjects completed clinical phase of the study.

[0319] Pharmacokinetic parameters and statistical analysis were performed over 52 subjects.

[0320] Pharmacokinetic results:

[0321] Statistical analysis:

[0322] The 90% confidence intervals for the geometric least square means ratio [T / R] for the pharmacokinetic parameters Cmax and AUCO-t was calculated and presented.

[0323] Discussion:

[0324] The statistical analysis of Median pH values for all 24 using wilcoxon signed rank test was performed for Day 0. The p values were found to be insignificant as the p values was greater than 5%. The statistical analysis of Median pH values for all 24 using wilcoxon signed rank test was performed for Day 1. The p values were found to be insignificant as the p values was greater than 5%. The statistical analysis of Median pH values for all 24 using wilcoxon signed rank test was performed for Day 0 (Test product) vs Day 1 (Test product). The p values were found to be significant as the p values was greater than 5%. The statistical analysis of Median pH values for all 24 using wilcoxon signed rank test was performed for Day 0 (Reference product) vs Day 1 (Reference product). The p values were found to be significant as the p values was greater than 5%.

[0325] Conclusion:

[0326] Based on the data analysis and statistical evaluation of pH based on the result obtained for Day 1 within treatment proves therapeutic equivalence between the Test Product (T) (Omeprazole 4 mg / ml, powder for oral suspension manufactured for Orbit Pharma Limited, UK) when compared with the Reference Product (R) [Losec® 20 mg capsulas duras gastrorresistentes (Hard gastro-resistant capsules) MAH Holder CHEPLAPHARM Arzneimittel GmbH, Ziegelhof 24, 17489 Greifswald, Alemania].

[0327] This test formulation (T) Omeprazole 4 mg / ml, powder for oral suspension represents an option for patients who have difficulty in swallowing oral solid dosage forms.

[0328] Example 14

[0329] An open label, balanced, randomized, two-treatment, two-sequence, two-period, crossover, single oral dose comparative bioavailability study was conducted to compare a lansoprazole composition of the present invention with a known lansoprazole dosage form with market approval, in normal, healthy, adult, human subjects under fasting conditions.

[0330] The Reference Product (R) was: OGAST ORO 30 mg, comprime orodispersible (orodispersible tablet). The Test Product (T) was: Lansoprazole 30mg / 5mL powder for oral suspension having the following composition:

[0331] 1.0 INVESTIGATIONAL PRODUCTS

[0332] Test product: Lansoprazole 30mg / 5ml powder for oral suspension.

[0333] 1.1 SELECTION AND WITHDRAWAL OF SUBJECTS

[0334] All study subjects were screened based on clinical examination, recording of ECG and laboratory investigations of blood, urine, urine pregnancy test (only for female subjects) not more than 21 days prior to first dosing. Chest X-Ray (PA view) taken within 180 days prior to dosing in the first study period for each volunteer was considered for assessment. For all subjects urine screen for drugs of abuse and alcohol breath test were done on the day of checkin of each study period. Additionally, serum P-hCG test for female subjects was done before check-in of each study period. In addition to this, oropharyngeal examination was done during screening or before check in of period 01. The buccal area was examined and lateral, superior, and inferior walls were inspected. The evaluation of peptic ulcer was done during screening or before check in of period 01. (The Questionnaire to evaluate symptoms of peptic ulcer was used). Study subjects were selected based on the following inclusion and exclusion criteria.

[0335] 1.1.1 Inclusion Criteria and Exclusion Criteria

[0336] The Inclusion Criteria and Exclusion Criteria for the Omeprazole bioequivalence study mentioned in 1.1.1 and 1.1.2, respectively, are the same for Lansoprazole. 2.0 SUBJECT TREATMENT

[0337] 2.1 Dosing

[0338] Test product: Dosing was done using syringe of appropriate capacity. The prelabelled syringe containing 5 mL Oral suspension was kept in the beaker after dispensing. Prior to drug administration, the syringe was held at upright position. The product was administered with a syringe directly into the subject's mouth. The syringe was rinsed with water utilizing the same beaker used during dispensing. For rinsing of the syringe, water in excess of the volume of drug used for dosing was withdrawn in the syringe from the beaker and then the entire contents of the syringe were emptied back in the beaker. This procedure was done twice to ensure the complete rinsing of the syringe. The rinse was administered to the subjects. The beaker used for rinsing the syringe was rinsed once with adequate quantity of water and this was administered to the subj ects. The total quantity of water used for rinsing the syringes and beaker for dosing did not exceed 240 mL ± 2 mL. The beginning of drug administration with syringe and completion of water intake was considered as dosing start time and dosing completion time respectively. The dose was administered in a staggered manner to maintain subsequent blood collection schedule. The QA person ensured that the dosing is done as per the dosing schedule and as mentioned in the protocol. Compliance for dosing was assessed by a thorough check of the oral cavity by using a tongue depressor and torch immediately after dosing by Principal Investigator / Authorized trained person / Medical Officer. Record of dosing for individual subject was maintained in Case Report Form.

[0339] Reference product: Dose administration was done with 240 mL ± 02 mL of water at ambient temperature by trained personnel, under the supervision of Principal Investigator / authorized trained person in accordance with current version of SOP for ‘Dosing’. Subjects were instructed not to chew or crush the IMPs but to consume it as a whole. The dose was administered in a staggered manner to maintain subsequent blood collection schedule. The QA person ensured that the dosing is done as per the dosing schedule and as mentioned in the protocol. Compliance for dosing was assessed by a thorough check of the oral cavity by using a tongue depressor and torch immediately after dosing by Principal Investigator / Authorized trained person / Medical Officer. Record of dosing for individual subject was maintained in Case Report Form. 2.2 Monitoring for subject compliance

[0340] The monitoring for subject compliance for the Omeprazole bioequivalence study mentioned in 2.2 (Example 13) is the same for Lansoprazole.

[0341] 3.0 Sampling Schedule

[0342] Gastric pH Collection:

[0343] A total of thirty (30) Gastric Juice samples were collected in each study period.

[0344] A nasogastric tube was inserted through the subject’s nose for collection of Gastric Juice samples from -24.00 hrs pre-dose and up to 23.00 hrs post-dose.

[0345] Day 0 (Housing day): After nasogastric tube insertion -24.00, -23.00, -22.00, -21.00, - 20.00, - 19.00, -17.00, -15.00, -13.00, -11.00, -09.00, -06.00, -04.00, -02.00, -01.00 hrs pre-dose (± 15 minutes of scheduled time).

[0346] Day 1 (Dosing day): Pre-dose (collected within ± 45 minutes prior to dosing) (00.00), 01.00, 02.00, 03.00, 04.00, 05.00, 07.00, 09.00, 11.00, 13.00, 15.00, 18.00, 20.00, 22.00, 23.00 hrs post dose (± 15 minutes of scheduled time).

[0347] For Collected Gastric Juice samples pH was measured. The collected Gastric Juice samples were stored along with plasma samples at -70 ± 15oC for 6 months.

[0348] Blood Sample Collection: An intravenous cannula was inserted in the subject’s arm for collection of blood samples before pre-dose blood sample and up to 24.00 hrs post-dose. If there is any difficulty in collecting blood or if the subject is not comfortable with the cannula, the cannula was removed before 24.00 hrs post-dose and the remaining blood samples were collected through fresh vein puncture or by re-cannulation. For any activities coinciding with blood sample collection, blood sample collection was given preference and other activities followed. Before each blood sample collection, 0.3 mL of saline mixed blood from the intravenous cannula was discarded during the use of the intravenous cannula. After every blood sample collection, 0.3 mL of saline was injected in the intravenous cannula to maintain the patency of cannula. A total of Nineteen (19) blood samples were collected in pre-labeled vacutainer containing K2EDTA as an anticoagulant in each study period.

[0349] Blood samples (5.0 mL) were collected at pre-dose (00.00 hr) in morning on dosing day within 01.00 hour prior to dosing and at 00.25, 00.50, 00.75, 01.00, 01.50, 02.00, 02.50, 03.00, 03.50, 04.00, 05.00, 06.00, 08.00, 10.00, 12.00, 14.00, 16.00 and 24.00 hours post dose in each study period. Blood samples were kept in ice cold water bath from time of collection up to centrifugation. Post dose blood samples were collected within +2 min of schedule time.

[0350] A deviation of more than permissible window for sample collection time was be reported as protocol deviation. It was communicated to the concerned department by format no. CL-015- FT01 “Sampling Deviation Record” and was reported in the final report. The actual time of collection of each blood sample was recorded in the CRF and considered for PK analysis.

[0351] Approximate volume of blood loss during the study:

[0352] Additionally, 6.0 mL blood can be collected if recommended by the Investigator, compensation for same was paid as per in-house SOP.

[0353] 3.1 Sample Handling & Processing

[0354] Samples were centrifuged within 60 minutes after sample collection of respective time point. Following centrifugation at 4000 RPM for 10 minutes at 4°C (short term excursion permitted up to 8°C), the separated plasma was transferred in appropriate sized polypropylene screw top (previously labelled with project no., period no., subject no. and sample time point) biological sample storage vials in approximately equal volume, in duplicate (one aliquot as control sample and one aliquot for analysis). Two separate cryo boxes were used to store the plasma samples, one for analytical and the other for control (back up) samples. All plasma samples were stored at -70° ± 15°C for interim storage at the clinical site until shipped to analytical site. 3.2 Method Validation

[0355] 3.2.1 Sample Assay

[0356] Samples were assayed for Lansoprazole using a validated bioanalytical method at the bioanalytical department of Enem Nostrum Remedies Pvt. Ltd. All samples from a subject were analyzed in a single run. Quality control samples were distributed through each batch of study samples assayed as per SOP of Enem Nostrum Remedies Pvt. Ltd. Samples with drug concentrations greater than upper limit of validation range of assay were diluted with appropriate drug free biological fluid and reassayed. Samples below the lower limit of this range were reported as BLQ. Analysts did not have access to the randomization schedule, used for drug dispensing. Samples from subjects completing both the study periods were analyzed. Samples from subject withdrawn due to adverse event were be assayed and presented. Repeat analysis were done based on repeat analysis SOPs of Enem Nostrum Remedies Pvt. Ltd. Repeat analysis were done in the following cases: rejected analytical batch, lost in processing / analysis, poor chromatography, value above upper limit of standard curve, improper / inconsi stent internal standard area and improper sample processing. Both initial and repeat analysis concentrations were reported in tabular form and the value used for PK analysis was also be reported. Incurred sample re-analysis was done based on the bio-analytical laboratory’s applicable SOP and regulatory requirements.

[0357] 4.0 Safety Evaluation

[0358] The safety evaluation mentioned in the above bioequivalence study of omeprazole (4.0 in example 13) is also the same for lansoprazole.

[0359] 5.0 PHARMACOKINETICS AND STATISTICAL ANALYSIS

[0360] 5.1.1 Subject population

[0361] 46 healthy, adult, human subjects were enrolled in the study.

[0362] Based on the Literature, the maximum intra-subject coefficient of variation (ISCV) for the primary PK parameter was found to be around 18%.

[0363] Considering the ISCV not exceeding 18%; the sample size computation was determined by considering the following assumptions: a. T / R ratio = 90.0%-105.0% b. Intra-Subject C.V (%) = 18% c. Significance Level = 5% d. Power = 90% e. Bioequivalence Limits = 80.00%-125.00%

[0364] Based on the above estimate, a sample size of 42 subjects would be sufficient to establish therapeutic bioequivalence between products with adequate power. By considering 10% dropouts, 46 subjects were randomized and dosed.

[0365] 5.1.2 Therapeutic bioequivalence criteria

[0366] Data analysis and statistical evaluation pH data:

[0367] Individual pH values were collected at Day 0 and Day 1 for all the subjects for each treatment separately.

[0368] This data was analyzed as below:

[0369] 1. The Median pH values for all 24 hours were analyzed using Wilcoxon's signed rank test at significance level of 5%. The p-values less than 5% were considered as significant and p-values greater than 5% were considered as insignificant.

[0370] 2. This pH data was considered for calculation of AUC values at Day 1 and Day 0 for all the subjects for each treatment separately.

[0371] 3. The comparative data were presented. For Test and Reference products, AUC at Day 1 - AUC at Day 0 were calculated and presented. Median (%) of time above pH > 3 and pH > 4 were calculated for all the subjects for each treatment separately and considered as secondary parameter. The median values above pH > 3 and pH > 4 were tabulated and considered for calculation of Median (%). E OF EVENTS

[0372] Method and process for data analysis and statistical evaluation pH data:

[0373] Individual pH values were collected at Day 0 and Day 1 for all the subjects for each treatment separately.

[0374] This data was analyzed as below:

[0375] 5. The Median pH values for all 24 hours were analyzed using Wilcoxon's signed rank test at significance level of 5%. The p-values less than 5% were considered as significant and p- values greater than 5% were considered as insignificant.

[0376] 6. This pH data was considered for calculation of AUC values at Day 1 and Day 0 for all the subjects for each treatment separately.

[0377] 7. The comparative data was presented. For Test and Reference products, AUC at Day 1 - AUC at Day 0 was calculated and presented.

[0378] 8. Median (%) of time above pH > 3 and pH > 4 was calculated for all the subjects for each treatment separately and considered as secondary parameter. The median values above pH

[0379] > 3 and pH > 4 were tabulated and considered for calculation of Median (%).

[0380] Pharmacokinetic Results:

[0381] Descriptive Statistics of Day 0 for pH values [Median>3]

[0382] Descriptive Statistics of Day 0 for pH values [Median>4]

[0383] Descriptive Statistics of Day 1 for pH values [Median>3] Descriptive Statistics of Day 1 for pH values [Median>4]

[0384] Descriptive Statistics of AUC of pH data for Day 0

[0385] Descriptive Statistics of AUC of pH data for Day 1

[0386] Wilcoxon Signed Rank Test Results:

[0387] * Significant P value < 0.05

[0388] Safety Results:

[0389] The subjects were monitored for occurrence of adverse events and serious adverse events throughout the study. Safety evaluation was done on the basis of outcomes of physical examination, vital signs measurement during each cohort of each study period and clinical laboratory test results performed during post study safety assessments (at the time of collection of last PK sample in last study period of each cohort). During entire study, nine (9) laboratory adverse events reported for seven (7) subjects (subject nos. 02, 09, 10, 11, 19R, 20 and 23) in post study safety assessment which were mild in severity. Out of nine (9) adverse event, eight (8) adverse events were not related and one (1) adverse event (subject no. 10) was related to the study medication administered to the subject. Subject no. 02 had showed decreased Lymphocyte, subject nos. 09, 11, 20 and 23 had showed increased SGPT, subject no. 10 had showed increased eosinophil, subject no. 19R had showed increased Total WBC count and subject no. 23 had showed increased SGOT and bilirubin total during post study safety assessment. All nine (9) laboratory adverse events were resolved. No serious or significant adverse event occurred during the conduct of the study.

[0390] Evaluation of Bioequivalence:

[0391] Evaluation of bioequivalence was demonstrated for purpose of presentation while it was not considered for evaluation of bioequivalence. 46 subjects were enrolled in the study and 41 subjects completed all the periods of the study. Pharmacokinetic parameters and statistical analysis was performed over 41 subjects. Pharmacokinetic results: Statistical analysis:

[0392] The 90% confidence intervals for the geometric least square means ratio [T / R] for the pharmacokinetic parameters Cmax and AUCO-t was calculated and presented.

[0393] Discussion:

[0394] The statistical analysis of Median pH values for all 24 using wilcoxon signed rank test was performed for Day 0. The p values were found to be insignificant as the p values was greater than 5%. The statistical analysis of Median pH values for all 24 using wilcoxon signed rank test was performed for Day 1. The p values were found to be insignificant as the p values was greater than 5%. The statistical analysis of Median pH values for all 24 using wilcoxon signed rank test was performed for Day 0 (Test product) vs Day 1 (Test product). The p values were found to be significant as the p values was less than 5%. The statistical analysis of Median pH values for all 24 using wilcoxon signed rank test was performed for Day 0 (Reference product) vs Day 1 (Reference product). The p values were found to be significant as the p values was less than 5%.

[0395] Conclusion:

[0396] Based on the data analysis and statistical evaluation of pH based on the result obtained for Day 1 within treatment proves therapeutic equivalence between the Test Product (T) (Lansoprazole 30mg / 5ml Powder for oral Suspension Manufactured for: Orbit Pharma Limited, UK) when compared with the Reference Product (R) [OGAST ORO 30 mg, comprime orodispersible (orodispersible tablet) marketing authorization holder TAKEDA FRANCE, 112 Avenue Kleber, 75116 Paris], As both treatments showed significant improvement in pH results from day 0 to day 1 and supported by Statistical test ANOVA that both treatments showed p value less than 0.05. Hence it is considered therapeutic bio-equivalent. From the results of the safety evaluation, it can be concluded that both test (T) and reference (R) treatments were safe and well tolerated by the subjects.

[0397] Difference with the Invention & Advantages:

[0398] The therapeutic equivalence of the Test Product was assessed in this clinical investigation by statistical analysis of the Median pH values for Days 0 and 01, which revealed a significant p- value of less than -0.05 for the Test Product in comparison to the Reference product. This demonstrates that it inhibits the last stage of gastric acid formation by inhibiting the activity of the H+ / K+ ATPase proton pump in the parietal cells of the stomach. The inhibition is reversible and dose dependent. Its effects are exerted on both basal and stimulated gastric acid secretions. Lansoprazole concentrates in parietal cells and becomes active in their acidic environment and reacts with the hydrosulfide group of the proton pump H+ / K+ ATPase resulting in inhibition of enzyme activity. Test product's proton pump inhibition activity was therapeutically equivalent to the Reference product and that the Test (T) Lansoprazole 30 mg / 5 ml powder for oral solution had a proton pump inhibition capability that was equivalent to the Reference Product.

[0399] This test formulation (T) Lansoprazole 30mg / 5ml powder for oral suspension represents an option for patients who have difficulty in swallowing oral solid dosage forms.

Claims

Claims:

1. A Powder composition for oral suspension comprising a two phase powder mixture, where the first phase is in powder form comprising:(a) a Proton Pump Inhibitor or pharmaceutically acceptable salts thereof, present in the range from about 0.01% w / w to about 7.5% w / w, preferably in the range from about 0.05% w / w to about 6.5% w / w;(b) at least one diluent;(c) a first buffering agent;(d) at least binding agent present in the range from about 0.0010% w / w to about 2.0% w / w, preferably in the range from about 0.0015% w / w to about 1.5% w / w;(e) the second phase is in powder form comprising a second buffering agent;(f) at least a viscosity enhancer present in the range from about 0.05% w / w to about 12.5% w / w, preferably in the range from about 0.075% w / w to about 8.5% w / w;(g) at least one diluent;(h) at least one preservative; and(i) at least one or more pharmaceutically acceptable excipients; wherein the first phase powder mixture contains a moisture content of not more than 5.0%.

2. The powder composition for oral suspension of Proton Pump Inhibitors according to claim1, wherein the diluents are selected from the group consisting of lactitol, mannitol, maltitol, xylitol, sorbitol, erythritol, isomalt, or any combinations thereof.

3. The powder composition for oral suspension of Proton Pump Inhibitors according to claim2, wherein the diluents are sugar alcohols or a combination thereof present in the range from about 20 % w / w to about 80 % w / w, preferably in the range from about 30 % w / w to about 70 % w / w.

4. The powder composition for oral suspension of Proton Pump Inhibitors according to claim3, wherein the sugar alcohols diluent is selected from mannitol, maltitol, and xylitol or combinations thereof.

5. The powder composition for oral suspension of Proton Pump Inhibitors according to claim 1, wherein the first and second buffering agents are selected from the group consisting of acetic acid, sodium acetate, citric acid, sodium citrate, sodium phosphate, sodium hydrogen carbonate,potassium hydrogen carbonate, gluconates, tartrates, L-methionine, potassium citrate, sodium carbonate anhydrous, potassium bicarbonate, sodium dihydrogen phosphate, disodium hydrogen phosphate, sodium hydroxide, potassium dihydrogen phosphate, fumaric acid, tartaric acid or any combinations thereof.

6. The powder composition for oral suspension of Proton Pump Inhibitors according to claim 5, wherein the first buffering agent is sodium hydrogen carbonate present in the range from about 0.45% w / w to about 2% w / w, preferably in the range from about 0.5% w / w to about 1.5% w / w.

7. The powder composition for oral suspension of Proton Pump Inhibitors according to claim 5, wherein the second buffering agent is selected from the group consisting of sodium hydrogen carbonate, potassium hydrogen carbonate, and sodium carbonate anhydrous or any combinations thereof present in the range from about 15% w / w to about 65% w / w, preferably in the range from about 25% w / w to about 55% w / w.

8. The powder composition for oral suspension of Proton Pump Inhibitors according to claim 5, wherein the pH of the reconstituted suspension is in the range from 7.0 to 11.0, preferably it is in the range from 7.5 to 10.5.

9. The powder composition for oral suspension of Proton Pump Inhibitors according to claim 1, wherein the binding agent is selected from the group consisting of povidone, starch, pregelatinized starch, tragacanth, dextrin, sucrose, glucose, dextrose, molasses, mannitol, sorbitol, xylitol, lactose, acacia, tragacanth, ghatti gum, xanthan gum, polyvinylpyrrolidone, carboxymethylcellulose, methylcellulose, microcrystalline dextrose, amylose, magnesium aluminum silicate, polysaccharide acids, bentonites, gelatin or any combinations thereof.

10. The powder composition for oral suspension of Proton Pump Inhibitors according to claim 9, wherein the binding agent is xanthan gum.

11. The powder composition for oral suspension of Proton Pump Inhibitors according to claim 1, wherein the viscosity enhancer is selected from the group consisting of sodium alginate, carrageenan, gum acacia, gum tragacanth, sodium carboxymethyl cellulose, methyl cellulose, bentonite, veegum, carbomers, colloidal silicon dioxide, glucose, fructose, acacia, bentonite,carboxy methyl cellulose sodium, gelatin, guar gum, hydroxyl ethyl cellulose, hydroxyl propyl methylcellulose, polyvinyl pyrrolidone, polyvinyl alcohol, and poloxamer or any combinations thereof.

12. The powder composition for oral suspension of Proton Pump Inhibitors according to claim 11, wherein the viscosity enhancer is sodium alginate that contains a percentage of moisture from about 6% to about 12%, preferably in the range from about 8% to about 10%.

13. The powder composition for oral suspension of Proton Pump Inhibitors according to claim 1, wherein the preservatives are selected from the group consisting of ethanol, propylene glycol, benzyl alcohol, quaternary amines, benzalkonium chloride, sorbic acid, benzoic acid, methyl paraben, propyl paraben, glycerin, propylene glycol, sodium propionate, cetrimide, chlorobutanol, phenylmercuric acetate, potassium sorbate, sodium benzoate, disodium edetate, butylparaben, phenyl ethyl alcohol, phenoxetol or any combinations thereof in the range from about 0.05% w / w to about 4% w / w, preferably in the range from about 0.075% w / w to about 3% w / w.

14. The powder composition for oral suspension of Proton Pump Inhibitors according to claim 13, wherein the preservative is the combination of sodium benzoate and sodium methyl para hydroxy benzoate.

15. The powder composition for oral suspension of Proton Pump Inhibitors according to claim 1, wherein the pharmaceutical composition further comprises at least one or more pharmaceutically acceptable excipients selected from the group consisting of sweeteners and flavours.

16. The powder composition for oral suspension of Proton Pump Inhibitors according to claim 1, wherein the ratio of a Proton Pump Inhibitor to Viscosity enhancer is in the range from about 1 : 1 to about 1 : 12 and preferably it is in the range from about 1 :2 to about 1 : 10.

17. The powder composition for oral suspension of Proton Pump Inhibitors according to claim 1, is for the treatment or prevention of a variety of disorders including the healing of erosive esophagitis, maintenance of healed erosive esophagitis, treatment of gastroesophageal reflux disease, for gastric ulcers associated with nonsteroidal anti-inflammatory drugs, to reduce therisk of duodenal ulcer recurrence by eradication of helicobacter pylori, in pathological hypersecretory conditions including Zollinger-Ellison (ZE) syndrome, and in short-term treatment and maintenance of duodenal ulcers.

18. The powder composition for oral suspension of Proton Pump Inhibitors according to claim 1, wherein a Proton Pump Inhibitor is selected from the group consisting of Omeprazole, Pantoprazole, Lansoprazole, Rabeprazole, Dexlansoprazole, Esomeprazole, Ilaprazole, Tenetoprazole, Azeloprazole, Anaprazole or pharmaceutically acceptable salts thereof.

19. The powder composition for oral suspension of Proton Pump Inhibitors according to claim18, wherein a Proton Pump Inhibitor or pharmaceutically acceptable salts thereof is Omeprazole, Esomeprazole, and Lansoprazole in non-micronized form.

20. The powder composition for oral suspension of Proton Pump Inhibitors according to claim19, wherein the D50 particle size of Omeprazole or a pharmaceutically acceptable salt thereof is in the range from about 1.5 pm to 5.5 pm, preferably in the range from about 2.5 pm to 4.5 pm, the D50 particle size of Esomeprazole or a pharmaceutically acceptable salt thereof is in the range from about 0.5 pm to 4.5 pm, preferably in the range from about 1.5 pm to 3.5 pm, the D50 particle size of Lansoprazole or a pharmaceutically acceptable salt thereof is in the range from about 4 pm to 16 pm, preferably in the range from about 9 pm to 11 pm.

21. The powder composition for oral suspension of Proton Pump Inhibitors according to claim 19, wherein the D90 particle size of Omeprazole or a pharmaceutically acceptable salt thereof is in the range from about 5 pm to 15 pm, preferably in the range from about 8 pm to 10 pm, the D90 particle size of Esomeprazole or a pharmaceutically acceptable salt thereof is in the range from about 1 pm to 15 pm, preferably in the range from about 4 pm to 8 pm, the D90 particle size of Lansoprazole or a pharmaceutically acceptable salt thereof is in the range from about 15 pm to 45 pm, preferably in the range from about 20 pm to 30 pm.

22. The powder composition for oral Suspension of Proton Pump Inhibitors according to claim 1, wherein the powder composition comprising: a) 0.01% w / w to about 2.5% w / w, preferably in the range from about 0.05% w / wto about 1.5% w / w of omeprazole or pharmaceutically acceptable salts thereof;b) a combination of mannitol and maltitol present in the range from about 20% w / w to about 80% w / w, preferably in the range from about 30% w / w to about 70% w / w; c) 0.0010% w / w to about 2% w / w, preferably in the range from about 0.0015% w / w to about 1.5% w / w of xanthan gum; d) a first buffering agent is sodium hydrogen carbonate present in the range from about 0.45% w / w to about 2% w / w, preferably in the range from about 0.5% w / w to about 1.5% w / w, a second buffering agent is a combination of sodium hydrogen carbonate and potassium hydrogen carbonate present in the range from about 15% w / w to about 65% w / w, preferably in the range from about 25% w / w to about 55% w / w; e) 0.05% w / w to about 12.5% w / w, preferably in the range from about 0.075% w / w to about 8.5% w / w of sodium alginate; f) a combination of sodium benzoate and sodium methyl parahydroxy benzoate present in the range from about 0.05% w / w to about 4% w / w, preferably from about 0.075% w / w to about 3% w / w; g) 0.05% w / w to about 8.5% w / w, preferably in the range from about 0.10% w / w to about 7% w / w of sucralose; and h) 0.010% w / w to about 2.5% w / w, preferably in the range from about 0.025% w / w to about 1.5% w / w of mint spray dried flavour.

23. The powder composition for oral suspension of Proton Pump Inhibitors according to claim 1, wherein the powder composition comprising: a) 0.05% w / w to about 5% w / w, preferably in the range from about 0.1% w / w to about 3.5% w / w of Esomeprazole or pharmaceutically acceptable salts thereof; b) a combination of mannitol and maltitol present in the range from about 20%w / w to about 80% w / w, preferably in the range from about 30% w / w to about 70% w / w; c) 0.0010% w / w to about 2.0% w / w, preferably in the range from about 0.0015% w / w to about 1.5% w / w of xanthan gum; d) a first buffering agent is sodium hydrogen carbonate present in the range from about 0.45% w / w to about 2% w / w, preferably in the range from about 0.5% w / w to about 1.5% w / w, a second buffering agent is a combination of sodium carbonate anhydrous and potassium hydrogen carbonate present in the range from about 15% w / w to about 65% w / w, preferably in the range from about 25% w / w to about 55% w / w; e) 0.05% w / w to about 12.5% w / w, preferably in the range from about 0.075% w / w to about 8.5% w / w of sodium alginate;f) a combination of sodium benzoate and sodium methyl para hydroxy benzoate present in the range from about 0.05% w / w to about 4% w / w, preferably in the range from about 0.075% w / w to 3% w / w; g) a combination of sucralose and sodium saccharin dihydrate present in the range from about 0.05% w / w to about 8.5% w / w, preferably in the range from about 0.1% w / w to about 7% w / w; and h) 0.01% w / w to about 2.5% w / w, preferably in the range from about 0.025% w / w to about 1.5% w / w of natural mint flavour.

24. The powder composition for oral suspension of Proton Pump Inhibitors according to claim 1, wherein the powder composition comprising: a) 0.01% w / w to about 5% w / w, preferably in the range from about 0.05% w / w to about 3.5% w / w of Lansoprazole or pharmaceutically acceptable salts thereof; b) a combination of mannitol and xylitol present in the range from about 20% w / w to about 80% w / w, preferably in the range from about 30% w / w to about 70% w / w; c) 0.0010% w / w to about 2.0% w / w, preferably in the range from about 0.0015% w / w to about 1.5% w / w of xanthan gum; d) a first buffering agent is sodium hydrogen carbonate present in the range from about 0.45% w / w to about 2% w / w, preferably in the range from about 0.5% w / w to about 1.5% w / w, a second buffering agent is a combination of sodium carbonate anhydrous and potassium hydrogen carbonate present in the range from about 15% w / w to about 65% w / w, preferably in the range from about 25% w / w to about 55% w / w; e) 0.05% w / w to about 12.5% w / w, preferably in the range from about 0.075% w / w to about 8.5% w / w of sodium alginate; f) a combination of sodium benzoate and sodium methyl para hydroxy benzoate present in the range from about 0.05% w / w to about 4% w / w, preferably in the range from about 0.075% w / w to about 3% w / w; g) 0.05% w / w to about 8.5% w / w, preferably in the range from about 0.1% w / w to about 7% w / w of sucralose; and h) 0.01% w / w to about 2.5% w / w, preferably in the range from about 0.025% w / w to about 1.5% w / w of natural mint flavour.

25. The powder composition for oral suspension of Proton Pump Inhibitors according to claim 18, wherein a Proton Pump Inhibitor or pharmaceutically acceptable salts thereof is Omeprazole, Esomeprazole, and Lansoprazole in micronized form.

26. The powder composition for oral Suspension of Proton Pump Inhibitors according to claim 1, wherein the powder composition comprising: a) 0.78% w / w of omeprazole or pharmaceutically acceptable salts thereof; b) 4.86% w / w of mannitol and 52.30% w / w of malitol; c) 0.01% w / w of xanthan gum; d) a first buffering agent is sodium hydrogen carbonate present in 0.82% w / w, a second buffering agent is a combination of sodium hydrogen carbonate present in 6.93% w / w, and potassium hydrogen carbonate present in 26.93% w / w; e) 5.38% w / w of sodium alginate; f) a combination of sodium benzoate present in 0.97% w / w, and sodium methyl parahydroxy benzoate present in 0.45% w / w; g) 0.39% w / w of sucralose; and h) 0.19% w / w of mint spray dried flavour.

27. The powder composition for oral suspension of Proton Pump Inhibitors according to claim 1, wherein the powder composition comprising: a) 1.16% w / w of Lansoprazole or pharmaceutically acceptable salts thereof; b) mannitol present in 4.47% w / w and xylitol present in 53.13% w / w; c) 0.01% w / w of xanthan gum; d) a first buffering agent is sodium hydrogen carbonate present in 0.82% w / w, a second buffering agent is a combination of sodium carbonate anhydrous present in 6.93% w / w and potassium hydrogen carbonate present in 26.93% w / w; e) 5.38% w / w of sodium alginate; f) a combination of sodium benzoate present in 0.35 %w / w and sodium methyl para hydroxy benzoate present in 0.23% w / w; g) 0.39% w / w of sucralose; and h) 0.19% w / w of natural mint flavour.

28. The powder composition for oral suspension of Proton Pump Inhibitors according to claim 1, wherein a method for assessing therapeutic equivalence and Bioequivalence of Proton Pump Inhibitor comprising the steps of: a) administering a predetermined dose of the reference product (R) or test product (T) to a number of human subjects; b) collecting gastric juice samples from the human subjects by inserting the tube through the subject’s nose; c) measuring the pH of the collected gastric juice samples and storing collected gastric juice samples at -70 +15 °C for 6 months; d) collecting blood samples from the human subjects; e) determining the concentration of drug in the blood samples, preferably by High Performance-Electrospray- Liquid Chromatography-Mass Spectrometry / Mass Spectrometry (HPLC-ESI-MS / MS); and f) comparing the pharmacokinetic parameters of test product formulation with a reference formulation but not limited to Cmax (ng / mL), AUCO-t (hr*ng / mL), AUCO-inf (hr*ng / mL), Tmax (hr), Kel (1 / hr), t’A (hr), AUC ratio, residual area (%)29. The method for assessing therapeutic equivalence and bioequivalence of proton pump Inhibitor as claimed in claim 28, wherein administering a predetermined dose of the reference product (R) or test product (T) to 52 human subjects for the omeprazole and 41 subjects for the lansoprazole Bio-therapeutics and Bioequivalence study; wherein test product is omeprazole 4 mg / ml, powder for oral suspension, and Lansoprazole 30mg / 5mL powder for oral suspension and their reference product is Losec® 20 mg capsules duras gastro resistances (Hard gastro-resistant capsules) and OGAST ORO 30 mg, comprime orodispersible (orodispersible tablet) respectively30. The method for assessing therapeutic equivalence and bioequivalence of proton pump Inhibitor as claimed in claim 28, wherein collecting gastric juice samples of Omeprazole and Lansoprazole from the human subjects by inserting the tube through the subject’s nose: i) from 25.00 hrs pre-dose and up to 24.00 hrs post-dose for omeprazole, as follows:Day 0 (Housing day): After nasogastric tube insertion [(-25.00) ± of scheduled time], -23.00, - 22.00, -21.00, -20.00, -18.00, -16.00, -14.00, -12.00, -10.00, -07.00, -05.00, - 03.00, -1.00 hrs pre-dose (± 15 minutes of scheduled time), and Day 1 (Dosing day): Pre-dose (collected within45 minutes prior to dosing) (0.00), 01.00, 02.00, 03.00, 04.00, 05.00, 07.00, 09.00, 11.00, 13.00, 15.00, 18.00, 20.00, 22.00, 23.00 hrs post dose (± 15 minutes of scheduled time); ii) from -24.00 hrs pre-dose and up to 23.00 hrs post-dose for lansoprazole, as follows:Day 0 (Housing day): After nasogastric tube insertion -24.00, -23.00, -22.00, -21.00, -20.00, - 19.00, -17.00, -15.00, -13.00, -11.00, -09.00, -06.00, -04.00, -02.00, -01.00 hrs pre-dose (± 15minute o scheduled times), and Day 1 (Dosing day): Pre-dose (collected within ± 45 minutes prior to dosing) (00.00), 01.00, 02.00, 03.00, 04.00, 05.00, 07.00, 09.00, 11.00, 13.00, 15.00, 18.00, 20.00, 22.00, 23.00 hrs post-dose (±15 minutes of scheduled time).

31. The therapeutic equivalence method of proton pump inhibitor of Omeprazole as claimed in any one of claims 28 to 30, wherein pH value for Day 0 is 2 to 6 (Median>3), preferably 3.58 ± 0.11(Median>3); the pH value for Day 1 is 2 to 6 (Median>3), preferably 3.67 ± 0.28(Median>3); the pH value for Day 0 is 2 to 6 (Median>4), preferably 4.76 ± 0.47 (Median>4); the pH value for Day 1 is 2 to 6 (Median>4), preferably 4.65 ± 0.46 (Median>4); the AUC of pH data for Day 0 is 50 to 60, preferably 53.48±19.50; and the AUC of pH data for Day 1 is 50 to 60, preferably 52.39±16.6432. The therapeutic equivalence method of proton pump inhibitor of Lansoprazole as claimed in any one of claims 28 to 30, wherein pH value for Day 0 is 2 to 6 (Median>3), preferably 3.90±0.14(Median>3); the pH value for Day 1 is 2 to 6 (Median>3), preferably 3.74 ± 0.28 (Median>3); the pH value for Day 0 is 3 to 6 (Median>4), preferably 4.98 ± 0.22 (Median>4), the pH value for Day 1 is 3 to 6 (Median>4), preferably 4.52 ± 0.47 (Median>4); the AUC of pH data for Day 0 is 60 to 70, preferably 64.338±23.807, and the AUC of pH data for Day 1 is 80 to 90, preferably 85.328 ±19.72533. The bioequivalence method of proton pump inhibitor of Omeprazole as claimed in any one of claims 28 to 30, wherein the AUCO-t is 2100 to 2900 (hr*ng / mL), preferably 2500.358 ± 2194.657 (hr*ng / mL); AUCO-inf is 2100 to 2900 (hr*ng / mL), preferably 2528.279 ± 2223.897(hr*ng / mL); the maximum plasma concentration (Cmax) is 700 to 1200 (ng / mL), preferably 1006.336 ± 451.539 (ng / mL); the time to reach maximum concentration (Tmax) is 0.25 to 1 hours, preferably 0.50 hour; the elimination rate constant (Kel) is 0.20 to 0.90 (1 / hr), preferably 0.55 ± 0.27 (1 / hr); and the t’A is 0.5 to 3 (hr), preferably 1.75 ± 1.17 (hr).

34. The bioequivalence method of proton pump inhibitor of Lansoprazole as claimed in any one of claims 28 to 30, wherein the AUCO-t is 3000 to 4000 (hr*ng / mL), preferably 3464.891 ± 2521.249 (hr*ng / mL); the AUCO-inf is 3000 to 4000 (hr*ng / mL), preferably 3576.389 ± 2668.482 (hr*ng / mL); the maximum plasma concentration (Cmax) is 200 to 1000 (ng / ml), preferably 590.078 ± 229.778 (ng / mL); the time to reach maximum concentration (Tmax) is 0.1 to 2.50 hours, preferably 0.75 hours; the elimination rate constant (Kel) is 0.1 to 1 (1 / hr), preferably 0.25± 0.11 (1 / hr); and the t’A is 1 to 10 hr, preferably 3.32 ± 1.45 (hr).

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