Classifications

• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K9/00—Medicinal preparations characterised by special physical form
  • A61K9/20—Pills, tablets, discs, rods
  • A61K9/2072—Pills, tablets, discs, rods characterised by shape, structure or size; Tablets with holes, special break lines or identification marks; Partially coated tablets; Disintegrating flat shaped forms
  • A61K9/2086—Layered tablets, e.g. bilayer tablets; Tablets of the type inert core-active coat
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K31/00—Medicinal preparations containing organic active ingredients
  • A61K31/185—Acids; Anhydrides, halides or salts thereof, e.g. sulfur acids, imidic, hydrazonic or hydroximic acids
  • A61K31/19—Carboxylic acids, e.g. valproic acid
  • A61K31/192—Carboxylic acids, e.g. valproic acid having aromatic groups, e.g. sulindac, 2-aryl-propionic acids, ethacrynic acid 
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K31/00—Medicinal preparations containing organic active ingredients
  • A61K31/33—Heterocyclic compounds
  • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
  • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
  • A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
  • A61K31/4427—Non condensed pyridines; Hydrogenated derivatives thereof containing further heterocyclic ring systems
  • A61K31/4439—Non condensed pyridines; Hydrogenated derivatives thereof containing further heterocyclic ring systems containing a five-membered ring with nitrogen as a ring hetero atom, e.g. omeprazole
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K9/00—Medicinal preparations characterised by special physical form
  • A61K9/20—Pills, tablets, discs, rods
  • A61K9/2004—Excipients; Inactive ingredients
  • A61K9/2013—Organic compounds, e.g. phospholipids, fats
  • A61K9/2018—Sugars, or sugar alcohols, e.g. lactose, mannitol; Derivatives thereof, e.g. polysorbates
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K9/00—Medicinal preparations characterised by special physical form
  • A61K9/20—Pills, tablets, discs, rods
  • A61K9/2004—Excipients; Inactive ingredients
  • A61K9/2022—Organic macromolecular compounds
  • A61K9/2027—Organic macromolecular compounds obtained by reactions only involving carbon-to-carbon unsaturated bonds, e.g. polyvinyl pyrrolidone, poly(meth)acrylates
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K9/00—Medicinal preparations characterised by special physical form
  • A61K9/20—Pills, tablets, discs, rods
  • A61K9/2004—Excipients; Inactive ingredients
  • A61K9/2022—Organic macromolecular compounds
  • A61K9/205—Polysaccharides, e.g. alginate, gums; Cyclodextrin
  • A61K9/2054—Cellulose; Cellulose derivatives, e.g. hydroxypropyl methylcellulose

Definitions

• the present invention relates to a pharmaceutical composition in the form of bilayer tablet comprising a) first layer comprising granules or powder containing Naproxen and at least one pharmaceutically acceptable excipient, and b) second layer comprising dry granulated granules containing Esomeprazole and its pharmaceutically acceptable salt and at least one pharmaceutically acceptable excipient.
• the invention further relates to a process for the preparation of said pharmaceutical composition.
• Naproxen is a propionic acid derivative in the aryl acetic acid group of nonsteroidal anti-inflammatory drugs (NSAID).
• NSAID nonsteroidal anti-inflammatory drugs
• a chemical name for Naproxen is (S)-6-methoxy-a- methyl-2-naphthaleneacetic acid.
• Naproxen has been available on the market for many years and is used as either its free acid form or its sodium salt.
• Naproxen is chemically named 2-(6-Methoxy-2-naphthyl) propionic acid of formula (I),
• Naproxen has a molecular weight of 230.26 and a molecular formula C14H14O3. It is an odorless, white to off-white crystalline substance. It is lipid-soluble, practically insoluble in water at low pH and freely soluble in water at high pH.
• the octanol/water partition coefficient of Naproxen at pH 7.4 is 1.6 to 1.8.
• Esomeprazole is a proton pump inhibitor that reduces gastric acid secretion through inhibition of H/K+-ATPase enzyme in gastric parietal cells. It was developed and is marketed by AstraZeneca in products sold as N EXI UM® which is used in the treatment of dyspepsia, peptic ulcer disease, gastro-esophageal reflux disease and Zollinger- Ellison syndrome. Esomeprazole is the S-enantiomer of omeprazole (marketed as PRILOSECT®), having improved efficacy over the racemic mixture of omeprazole.
• NEXILIM® products are supplied in delayed-release capsules and in packets for a delayed-release oral suspension.
• Each delayed-release capsule contains 20 mg or 40 mg of Esomeprazole (as Esomeprazole magnesium trihydrate) in the form of enteric- coated granules.
• Each packet of NEXILIM® of Delayed-Release Oral Suspension contains 10 mg, 20 mg, or 40 mg of Esomeprazole, in the form of the same enteric- coated granules used in NEXILIM® Delayed-Release Capsules, and also inactive granules.
• the Esomeprazole granules and inactive granules are constituted with water to form a suspension and are given by oral, nasogastric, or gastric administration.
• NSAIDs including Naproxen
• NSAIDs are among the most commonly prescribed and used drugs world-wide.
• their use is frequently limited by an increased risk of gastrointestinal side-effects, mainly upper gastrointestinal side-effects like peptic ulceration and dyspeptic symptoms.
• Proton pump inhibitors such as omeprazole have been shown to be able to prevent gastric and duodenal erosions in healthy volunteers during treatment with NSAIDs.
• Clinical studies have shown that omeprazole heals gastric as well as duodenal ulcers as quickly and effectively in patients on continuous NSAID treatment as in non-NSAID users.
• EP 1411900 B2 discloses a monolithic tablet comprising a Naproxen core and Esomeprazole coated over it, which is commercially available under the trade name Vimovo® in the US and EU for the treatment of signs and symptoms of osteoarthritis, rheumatoid arthritis, and ankylosing spondylitis.
• Vimovo® manufacturing process of Vimovo® starts with producing a core tablet with Naproxen.
• This core tablet is manufactured by a conventional wet granulation process.
• the core tablet is coated with multi layers of film coating.
• An enteric coat and barrier coat are applied prior to the active coat.
• the fourth coat is the Esomeprazole magnesium trihydrate coat.
• the tablet manufacturing process involves multiple coating steps.
• the delayed release of Naproxen is achieved by the presence of an enteric coat.
• the marketed composition of Naproxen/Esomeprazole is manufactured multilayered tablet to achieve desired pharmacokinetic results and stable formulation.
• the first layer contains Naproxen sodium distributed throughout a matrix of pharmaceutically acceptable fillers, excipients, binding agents, disintegrants, and lubricants.
• the second layer is barrier layer which protects the first layer containing Naproxen sodium.
• the third layer is an enteric film coat. It does not dissolve in areas of the Gl tract where the pH is below 4 such as in an unprotected stomach but it dissolves only when the local pH is above 4. Therefore, the function of the third layer is to prevent the release of Naproxen sodium until the dosage form reaches an environment where the pH is above about 4.
• the tablets are formulated to release Esomeprazole immediately followed by the delayed release of Naproxen. Therefore, the tablets are developed as a combination of two distinct formulations, an inner enteric-coated component of Naproxen and an outer immediate release component of Esomeprazole.
• US 7,488,497 and US 6,365,184 discloses a tablet formulation comprising: (a) as a first component, an acid susceptible proton pump inhibitor, (b) as a separate second component, at least one NSAID, and (c) as an optional third component, one or more pharmaceutically acceptable excipients, wherein the first component is protected by an enteric coating layer, and wherein the second component is separated from the first component by the enteric coating layer protecting the first component.
• US 6,869,615 discloses solid oral dosage form comprising a) a population of substrates comprising a proton-pump inhibitor; b) an enteric coating layer coated over said substrates; and c) an NSAID coating layer coated over said enteric coated substrates.
• US 2005/0163847 and US 2007/0237820 discloses a solid oral dosage form comprising: a first portion comprising a therapeutically effective amount of an NSAID including Naproxen; and a coating comprising a therapeutically effective amount of an antiulcerative compound; said coating at least partially surrounding said first NSAID portion.
• US 2005/0249806 discloses a composition including (a) at least one acid labile proton pump inhibitor, (b) at least one buffering agent (c) a therapeutically effective amount of at least one nonsteroidal anti-inflammatory drug.
• US 2009/0022786 disclose an oral pharmaceutical dosage form comprising NSAID as granule combined with at least an acid inhibitor formulation, wherein the granule comprises at least an inner part and at least a NSAID drug part, the NSAID drug part surrounds the inner part, the dosage form further comprises at least a film coating containing no prostaglandin and being as outermost part of the dosage form wherein the said acid inhibitor is selected from a proton pump inhibitor including Esomeprazole.
• US 2009/0233970 discloses a pharmaceutical composition
• a pharmaceutical composition comprising: (a) at least one NSAID agent; and (b) at least one acid blocking agent, wherein a ratio of the NSAID to acid blocking agent in the composition is within a range that provides greater pain relief and reduction of inflammation with less gastrointestinal irritation than that obtainable by the administration of the NSAID or acid blocking agent alone.
• US 2010/0305163 discloses a pharmaceutical fixed unit dosage formulation for oral administration comprising a proton pump inhibitor and a non-steroidal antiinflammatory drug, wherein at least a portion of non-steroidal anti-inflammatory drug is released when the formulations are immersed into aqueous fluids having pH values below about 3.5.
• IN 2679/CHE/2009 discloses a pharmaceutical formulation in the form of a tablet comprising Naproxen and Esomeprazole and at least one pharmaceutically acceptable excipient, wherein said tablet is a bilayer tablet.
• the present invention provides a pharmaceutical composition comprising Naproxen and Esomeprazole, which is prepared in the form of bilayer tablet, to produce an improved formulation and thereby reducing the process time, increasing ease of manufacturing, and being cost effective.
• the main object of the present invention is to provide a solid pharmaceutical composition comprising Naproxen & Esomeprazole, which produce similar in-vitro and in-vivo profile as that of innovator composition i.e. Vimovo®.
• Another object of the present invention is to provide a stable solid pharmaceutical composition of Naproxen & Esomeprazole.
• Another object of the present invention is to provide a stable solid pharmaceutical composition of Naproxen & Esomeprazole in the form of a tablet, wherein said tablet is a bilayer tablet.
• Another object of the present invention is to provide a stable solid pharmaceutical composition of Naproxen & Esomeprazole, which overcomes the problems of the prior art.
• Yet another object of the invention is to provide a commercially scalable, cost effective, environment friendly and robust process for the preparation of Naproxen & Esomeprazole composition.
• the present invention discloses a pharmaceutical composition in the form of bilayer tablet comprising: a) first layer comprising granules or powder containing Naproxen and at least one pharmaceutically acceptable excipient, and b) second layer comprising dry granulated granules containing Esomeprazole and its pharmaceutically acceptable salt and at least one pharmaceutically acceptable excipient.
• the present invention discloses a pharmaceutical composition in the form of bilayer tablet comprising: a) first layer comprising granules or powder containing Naproxen, and at least one surfactant and at least one pharmaceutically acceptable excipient, and b) second layer comprising dry granulated granules Esomeprazole and its pharmaceutically acceptable salt and at least one pharmaceutically acceptable excipient.
• the present invention discloses a pharmaceutical composition in the form of bilayer tablet comprising: a) first layer comprising granules or powders containing Naproxen, at least one surfactant and at least one pharmaceutically acceptable excipient, and b) second layer comprising dry granulated granules containing Esomeprazole and its pharmaceutically acceptable salt and at least one pharmaceutically acceptable excipient, wherein both the layers are adjacent to each other.
• the present invention discloses a pharmaceutical composition in the form of bilayer tablet comprising: c) first layer comprising granules or powders containing Naproxen, at least one surfactant and at least one pharmaceutically acceptable excipient, and d) second layer comprising dry granulated granules containing Esomeprazole and its pharmaceutically acceptable salt and at least one pharmaceutically acceptable excipient, wherein both the layers are adjacent to each other & second layer is devoid of surfactant.
• the present invention discloses a pharmaceutical composition in the form of bilayer tablet comprising: a) first layer comprising granules or powders containing Naproxen, at least one surfactant wherein surfactant is selected from glycerol monostearate, Tween 80, Tween 40, Span 40, Labrafil M1944CS, polyoxyethylene-35-ricinoleate, brij 58, cremophor EL, lecithin, polysorbates, sorbitans, PEGs, sodium lauryl sulfate, and at least one pharmaceutically acceptable excipient, and b) second layer comprising dry granulated granules containing Esomeprazole and its pharmaceutically acceptable salt and at least one pharmaceutically acceptable excipient, wherein both the layers are adjacent to each other.
• surfactant is selected from glycerol monostearate, Tween 80, Tween 40, Span 40, Labrafil M1944CS, polyoxyethylene-35-ricinoleate
• the present invention discloses a pharmaceutical composition in the form of bilayer tablet comprising: a) first layer comprising granules or powders containing Naproxen, at least one surfactant and at least one pharmaceutically acceptable excipient, and b) second layer comprising dry granulated granules containing Esomeprazole and its pharmaceutically acceptable salt and at least one pharmaceutically acceptable excipient, wherein the granules of Esomeprazole are prepared by dry granulation, wherein both the layers are adjacent to each other.
• the present invention discloses a process for the preparation of pharmaceutical composition in the form of bilayer tablet comprising:
• the granules of Naproxen are prepared by wet granulation
• the granules of Esomeprazole are prepared by dry granulation.
• the present invention discloses a pharmaceutical composition in the form of bilayer tablet consisting of: a) first layer comprising granules or powder containing Naproxen, i. lactose, ii. croscarmellose sodium, iii. methacrylic acid-ethyl acrylate copolymer (1 :1 ), iv. polysorbate, v. glycerol monostearate, vi. triethyl stearate, b) second layer comprising dry granulated granules containing Esomeprazole or its pharmaceutically acceptable salt, i. microcrystalline cellulose, ii. croscarmellose sodium, iii. polyvinylpyrrolidone, iv. magnesium oxide.
• the present invention discloses a pharmaceutical composition in the form of bilayer tablet consisting of: a) first layer comprising granules or powder containing, i. 50% to 60% by wt of Naproxen, ii. 1 % to 5% by wt of actose, iii. 0% to 3% by wt of croscarmellose sodium, iv. 10% to 20% by wt of methacrylic acid-ethyl acrylate copolymer (1 :1 ), v. 0% to 1 % by wt of polysorbate, vi.
• second layer comprising dry granulated granules containing i. 2% to 5% by wt of Esomeprazole or its pharmaceutically acceptable salt, ii. 20% to %35 by wt of microcrystalline cellulose, iii. 0% to 1 .5% by wt of croscarmellose sodium, iv. 0% to 1 % by wt of polyvinylpyrrolidone, v. 2% to 3% magnesium oxide based on the total weight of the solid composition.
• the present invention discloses a stable pharmaceutical composition
• a stable pharmaceutical composition comprising Naproxen & Esomeprazole, wherein, the said composition remains stable when stored at about 40°C at about 75% relative humidity for at least 3 months, more preferably 6 months.
• the present invention discloses a stable, reproducible and bioequivalent pharmaceutical composition comprising Naproxen & Esomeprazole.
• the present invention discloses a process used to prepare said pharmaceutical composition is conventional process.
• the present invention includes methods of treating patients suffering from pain, inflammation, and/or other conditions using the said pharmaceutical composition.
• Figure 1 is a graph showing the in vivo results of Naproxen of example-1 vis-a-vis reference drug in fasting condition (Vimovo®).
• Figure 2 is a graph showing the in vivo results of Esomeprazole of example-1 vis-a- vis reference drug in fasting condition (Vimovo®).
• % used in this specification means the percentage by weight unless otherwise stipulated.
• composition as used in the present invention means solid pharmaceutical composition includes, without limitation, capsules, tablets, caplets, powders, pellets, granules, liquid dispersions, beads, etc.
• bilayer tablet means bilayer tablet includes, without limitation, Oros® push pull technology, DLIROS® technology, DUREDAS® technology.
• Naproxen ' as used in the present invention includes, but is not limited to, Naproxen per se, pharmaceutically acceptable salts, pharmaceutically acceptable solvates, pharmaceutically acceptable hydrates, pharmaceutically acceptable enantiomers, pharmaceutically acceptable derivatives, pharmaceutically acceptable polymorphs and pharmaceutically acceptable prodrugs thereof, and also its various crystalline and amorphous forms.
• Esomeprazole ' as used in the present invention includes, but is not limited to, Esomeprazole per se, pharmaceutically acceptable salts, pharmaceutically acceptable solvates, pharmaceutically acceptable hydrates, pharmaceutically acceptable enantiomers, pharmaceutically acceptable derivatives, pharmaceutically acceptable polymorphs and pharmaceutically acceptable prodrugs thereof, and also its various crystalline and amorphous forms.
• the present invention discloses a pharmaceutical composition in the form of bilayer tablet comprising: a) first layer comprising granules or powder containing Naproxen and at least one pharmaceutically acceptable excipient, and b) second layer comprising dry granulated granules containing Esomeprazole and its pharmaceutically acceptable salt and at least one pharmaceutically acceptable excipient.
• the present invention provides a bilayer tablet composition comprising Naproxen and Esomeprazole, wherein both Naproxen and Esomeprazole is present in an immediate release form.
• the present invention provides a bilayer tablet composition comprising Naproxen and Esomeprazole, wherein Naproxen is present in a modified release form while Esomeprazole is present in an immediate release form.
• the present invention provides a bilayer tablet composition comprising Naproxen and Esomeprazole, wherein Naproxen is present in an immediate release form while Esomeprazole is present in a modified release form.
• the present invention provides a bilayer tablet composition comprising Naproxen and Esomeprazole, wherein both Naproxen and Esomeprazole is present in a modified release form.
• a composition of the present invention comprises active ingredient Naproxen in the ranges from 50% to 60% by weight based on the total weight of the composition.
• a composition of the present invention comprises active ingredient Esomeprazole in the ranges from 2% to 5% by weight based on the total weight of the composition.
• the present invention discloses a pharmaceutical composition in the form of bilayer tablet comprising: a) first layer comprising granules or powders containing Naproxen, at least one surfactant and at least one pharmaceutically acceptable excipient, and b) second layer comprising dry granulated granules containing Esomeprazole and its pharmaceutically acceptable salt and at least one pharmaceutically acceptable excipient, wherein both the layers are adjacent to each other & second layer is devoid of surfactant.
• a composition of the present invention further comprises one or more pharmaceutically acceptable excipients.
• the excipients to be used in accordance with the present invention are well known and are those excipients which are conventionally used by the person skilled in the art.
• the pharmaceutical excipient can be selected from diluent, binder, disintegrant, plasticizing agent, basic agent, surfactant, glidant and lubricant.
• Diluent includes, but are not limited to, mannitol, lactose, microcrystalline cellulose, dibasic calcium phosphate, tribasic calcium phosphate, calcium carbonate, kaolin, magnesium carbonate, magnesium oxide, sugars such as sucrose; sugar alcohols such as sorbitol, erythritol; and mixtures thereof.
• the amount of diluent is preferably from 20% to 50%, more preferably from 30% to 40% by weight based on the total weight of the composition.
• Disintegrant includes, but are not limited to, croscarmellose sodium, sodium starch glycolate, pregelatinized starch, sodium carboxymethyl cellulose, microcrystalline cellulose, cross-linked polyvinylpyrrolidone, sodium alginate, low substituted hydroxypropyl cellulose and mixtures thereof.
• the amount of the disintegrant is preferably from 0.1 % to 10%, more preferably from 1 % to 8% by weight based on the total weight of the composition.
• Binder includes, but are not limited to, carrageenan, hydroxyethyl cellulose, hydroxypropyl cellulose, hydroxypropyl methylcellulose, carbomers, carboxymethylcellulose sodium, dextrin, ethyl cellulose, methylcellulose, shellac, zein, gelatin, polymethacrylates, polyvinyl pyrrolidone, sodium alginate, methacrylic acid- ethyl acrylate copolymers, gums, synthetic resins and the like.
• the amount of the binder is preferably from 0.1 % to 20%, more preferably from 2% to 20%, furthermore preferably from 2% to 15 % by weight based on the total weight of the solid composition. Without binding to any theory, it is observed that some specific excipient depends on their concentration could also have impact on the release profile of said active(s).
• Plasticizing includes, but are not limited to, polyhydric alcohols such as propylene glycol, glycerol, polyethylene glycol, acetate esters such as glyceryl triacetate, triethyl citrate, acetyl triethyl citrate, phthalate esters such as diethyl phthalate, glycerides such as acetylated monoglycerides, oils such as castor oil, mineral oil, and glycerol monostearate and mixtures thereof.
• polyhydric alcohols such as propylene glycol, glycerol, polyethylene glycol
• acetate esters such as glyceryl triacetate, triethyl citrate, acetyl triethyl citrate, phthalate esters such as diethyl phthalate
• glycerides such as acetylated monoglycerides
• oils such as castor oil, mineral oil, and glycerol monostearate and mixtures thereof
• the amount of the plasticizing is preferably from 0.15 to 10%, more preferably from 0.2 to 5% by weight based on the total weight of the composition.
• Basic agent includes, but are not limited to, magnesium oxide, sodium carbonate, sodium bicarbonate and mixtures thereof.
• the amount of the basic agent is preferably from 0.15 to 10%, more preferably from 0.2 to 5% by weight based on the total weight of the composition.
• Surfactant includes, but are not limited to, glycerol monostearate, Tween 80, Tween 40, Span 40, Labrafil M1944CS, polyoxyethylene-35-ricinoleate, brij 58, cremophor EL, lecithin, polysorbates, sorbitans, PEGs and mixtures thereof.
• the amount of the surfactant is preferably from 0% to 5%, more preferably from 0.5% to 1 .5% by weight based on the total weight of the composition.
• Glidant includes, but are not limited to, ascorbyl palmitate, calcium palmitate, magnesium stearate, fumed silica (colloidal silicon dioxide), starch and talc, cornstarch, silica derivatives, syloid, pyrogenic silica (0.25%), and hydrated sodium sulfoaluminate and mixtures thereof.
• the amount of the glidant is preferably from 0.15 to 10%, more preferably from 0.2 to 5% by weight based on the total weight of the composition.
• Lubricant includes, but are not limited to, metallic stearates such as magnesium stearate, calcium stearate, zinc stearate; stearic acid, hydrogenated vegetable oil, hydrogenated castor oil, glyceryl palmitostearate, glyceryl behenate, polyethylene glycols, com starch, sodium stearyl fumarate, sodium benzoate, mineral oil, talc, and mixtures thereof.
• the amount of the lubricant is preferably from 0.15 to 10%, more preferably from 0.2 to 5% by weight based on the total weight of the composition.
• the pharmaceutical composition in the form of bilayer tablet comprising a first layer comprising Naproxen granules prepared by wet granulation.
• Wet granulation methods include, but is not limited, low shear granulation, high shear mixture granulation, fluid bed granulation, reverse wet granulation, steam granulation, moisture-activated dry granulation or moist granulation, thermal adhesion granulation, melt granulation, freeze granulation, foamed binder or foam granulation.
• the pharmaceutical composition in the form of bilayer tablet comprising a second layer comprising Esomeprazole granules prepared by dry granulation.
• Dry granulation method includes, but is not limited, slugging, roller compaction or pneumatic dry granulation.
• Suitable solvents used for wet granulation are selected from the group comprising methyl alcohol, ethyl alcohol, isopropyl alcohol, n-butyl alcohol, acetone, acetonitrile, chloroform, methylene chloride, water, or mixtures thereof.
• composition of the present invention may further be coated with a film- forming polymer and one or more pharmaceutically acceptable excipients, using techniques well known in the art e.g., spray coating in a conventional coating pan, or a fluidized bed processor, or dip coating. Alternatively, coating can also be performed using a hot melt technique.
• the film coating may contain one or more film-forming polymers, and optionally one or more pharmaceutically acceptable excipients.
• a suitable film-forming polymer is selected from the group comprising hydroxypropyl methyl cellulose, ethyl cellulose, methyl cellulose, hydroxyethyl cellulose, hydroxypropyl cellulose, sodium carboxymethyl cellulose, cellulose acetate, hydroxypropyl methyl cellulose phthalate, cellulose acetate trimellitate, methacrylic acid copolymers e.g., Eudragit®, polyvinylpyrrolidone, polyvinyl alcohol, polyethylene glycol, or mixtures thereof.
• a preferred film- forming polymer is hydroxypropyl methyl cellulose.
• Other suitable filmforming polymers which are known in the art may also be used.
• the film coating may also contain opacifiers like titanium dioxide, flow aids like talc and pigment like iron oxide yellow.
• the composition in accordance with the present invention may be used as a medicament.
• the pharmaceutical composition typically may be used in the treatment of relief of signs and symptoms of osteoarthritis, rheumatoid arthritis, and ankylosing spondylitis and to decrease the risk of developing gastric ulcers in patients at risk of developing NSAID associated gastric ulcers.
• the solid composition of the present invention is very suitable for production on commercial scale making use of equipment and techniques commonly used in industry.
• Example-1 A bilayer tablet composition comprising Naproxen & Esomeprazole
• step 6 The dry mixture of step 5 was granulated by using binder solution of step 4.
• step 6 Obtained granules of step 6 was dried, sieved and transferred to container mixer.
• step-11 The powder blend of step-11 was pressed into solid compacts by using roller compactor.
• MCC PH 302, PVP K30 and Croscarmellose Sodium were sieved using an appropriate sieve, loaded to container mixer and mixed.
• Opadry 03B220096 Yellow was slowly added to purified water and mixing continuously until a homogenous coating solution was obtained. The coating solution was sprayed onto the compressed bilayer tablets. It is continued to coating process until weight required was gained.
• Comparative Example-2 A bilayer tablet composition comprising Naproxen & Esomeprazole
• Polysorbate 80, Triethyl Citrate and Glycerol Monostearate 40-55 were added into the heated water and was stirred well.
• step 3 The remaining amount of water of step-1 was added into the mixture of step 2 and it was mixed with stirring until reached at room temperature.
• step 6 The dry mixture of step 5 was granulated by using binder solution of step 4.
• step 6 Obtained granules of step 6 was dried, sieved and transferred to container mixer. 8. Lactose Monohydrate (SD) and Croscarmellose Sodium were sieved using an appropriate sieve and loaded to container mixer of step-7 and mixed.
• SD Lactose Monohydrate
• Croscarmellose Sodium were sieved using an appropriate sieve and loaded to container mixer of step-7 and mixed.
• Calcium stearate was sieved using an appropriate sieve, loaded to container mixer and mixed.
• Dissolution analyses of Naproxen layer was performed in media pH 6.8 phosphate buffer + %0.1 SLS in 1000 ml at 100 rpm in paddle.
• Dissolution analyses of Esomeprazole layer was performed in media pH 6.8 phosphate buffer in 900 ml at 75 rpm in paddle. Obtained dissolution profiles of the examples were compared to currently available reference product Vimovo® as depicted in below table-3 & table-4 respectively.
• Example-4 In-vivo analysis Naproxen and Esomeprazole were compared with the reference product Vimovo® in fasted conditions.
• Example - 1 The tablet prepared in Example - 1 was placed in a plastic bottle along with a desiccant and airtightly sealed for 6 months under conditions of 40°C/75% RH (accelerated test).
• Example-1 has similar stability profile with Vimovo® .

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