WO2023129069A2

WO2023129069A2 - A pharmaceutical composition comprising naproxen and esomeprazole

Info

Publication number: WO2023129069A2
Application number: PCT/TR2022/051640
Authority: WO
Inventors: Udaya Kumar DUDE; Nurcin YILMAZ
Original assignee: Abdi Ibrahim Ilac Sanayi Ve Ticaret Anonim Sirketi
Priority date: 2021-12-29
Filing date: 2022-12-28
Publication date: 2023-07-06
Also published as: WO2023129069A3

Abstract

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.

Description

A PHARMACEUTICAL COMPOSITION COMPRISING NAPROXEN AND ESOMEPRAZOLE

FIELD OF THE INVENTION

BACKGROUND OF THE INVENTION

Naproxen is a propionic acid derivative in the aryl acetic acid group of nonsteroidal anti-inflammatory drugs (NSAID). 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),

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. It has a molecular formula C17H18N3O3S and is chemically named 5-methoxy-2-[(4- methoxy-3,5-dimetil-2-pyridyl) methylsulfinyl]benzimidazole of formula (II),

Formula II.

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, are among the most commonly prescribed and used drugs world-wide. Despite the therapeutic benefits of NSAIDs, their use is frequently limited by an increased risk of gastrointestinal side-effects, mainly upper gastrointestinal side-effects like peptic ulceration and dyspeptic symptoms. It appears that a major factor contributing to the development of these lesions is the presence of acid in the stomach and upper small intestine of patients. 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.

According to Public Assessment Report of the Medicines Evaluation Board in Netherlands, 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.

According to Australian Public Assessment Report for Naproxen/Esomeprazole, the tablet manufacturing process involves multiple coating steps. The delayed release of Naproxen is achieved by the presence of an enteric coat.

As mentioned, Public Assessment Report of the Medicines Evaluation Board in Netherlands and Australian Public Assessment Report, 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.

According to Public Assessment Report of the Medicines Evaluation Board in Netherlands, formal compatibility studies between Naproxen and Esomeprazole magnesium trihydrate were not required, as a film-coat barrier is present. 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.

There are various strategies disclosed in the art for combining the two types of active agents for therapeutic purposes, other than by concomitant administration due to the potential benefits of proton pump inhibitors for the prevention of NSAID-induced gastroduodenal damage.

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 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.

Above mentioned one or more prior art suffers from various drawbacks for example the technology used in the manufacture of marketed composition of Vimovo® is complicated and time consuming at larger scale. And also, the method contains so much in-process control test and parameters to produce finished dosage form of Naproxen and Esomeprazole.

Thus, there remains a need for alternative pharmaceutical composition comprising Naproxen and Esomeprazole, which overcomes the problems associated with prior art.

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. OBJECT OF THE INVENTION

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.

SUMMARY OF THE INVENTION

In one aspect, 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.

In another aspect, 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.

In another aspect, 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.

In another aspect, 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.

In another aspect, 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.

In another aspect, 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.

In another aspect, the present invention discloses a process for the preparation of pharmaceutical composition in the form of bilayer tablet comprising:

- first layer comprising granules containing Naproxen and at least one pharmaceutically acceptable excipient, and

- second layer comprising granules of Esomeprazole and its pharmaceutically acceptable salt and at least one pharmaceutically acceptable excipient, characterized in that,

- the granules of Naproxen are prepared by wet granulation, and

- the granules of Esomeprazole are prepared by dry granulation.

In another aspect, 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.

In another aspect, 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. 0% to 1 % by wt of glycerol monostearate and/or triethyl stearate based on the total weight of the solid composition, b) 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.

In another aspect, the present invention discloses 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.

In another aspect, the present invention discloses a stable, reproducible and bioequivalent pharmaceutical composition comprising Naproxen & Esomeprazole. In another aspect, the present invention discloses a process used to prepare said pharmaceutical composition is conventional process.

In another aspect, the present invention includes methods of treating patients suffering from pain, inflammation, and/or other conditions using the said pharmaceutical composition.

The details of one or more embodiments of the present invention are set forth in the description below. Other features, objects and advantages of the invention will be apparent from the description.

BRIEF DESCRIPTION OF THE DRAWINGS

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®).

DETAILED DESCRIPTION OF THE PRESENT INVENTION

The present invention will now be more specifically illustrated as hereunder.

The term % used in this specification means the percentage by weight unless otherwise stipulated.

The term "about" can indicate a difference of 10 percent of the value specified. Numerical ranges as used herein are meant to include every number and subset of numbers enclosed within that range, whether particularly disclosed or not. Further, these numerical ranges should be construed as providing support for a claim directed to any number or subset of numbers in that range. The term “pharmaceutical composition” as used in the present invention means solid pharmaceutical composition includes, without limitation, capsules, tablets, caplets, powders, pellets, granules, liquid dispersions, beads, etc.

The term “bilayer tablet” as used in the present invention means bilayer tablet includes, without limitation, Oros® push pull technology, DLIROS® technology, DUREDAS® technology.

The term ' 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.

The term ' 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.

In general embodiment, 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.

Manufacturing method for the preparation of pharmaceutical composition of Naproxen and Esomeprazole of the present invention is simplified. In one embodiment, the present invention provides a bilayer tablet composition comprising Naproxen and Esomeprazole, wherein both Naproxen and Esomeprazole is present in an immediate release form.

In one embodiment, 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.

In one embodiment, 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.

In one embodiment, the present invention provides a bilayer tablet composition comprising Naproxen and Esomeprazole, wherein both Naproxen and Esomeprazole is present in a modified release form.

In one embodiment, 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.

In one embodiment, 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.

In another aspect, 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. In one embodiment, 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. Depending on the dosage form chosen for the pharmaceutical composition, the person skilled in the art will be able to select suitable pharmaceutically acceptable excipients. 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.

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.

The 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.

Moreover, 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.

The following examples are intended to illustrate the scope of the present invention but not to limit it thereto.

Examples:

Example-1 : A bilayer tablet composition comprising Naproxen & Esomeprazole

Table-1

*Eudragit L30 D-55 coating solution contains 47.39 mg solid substance for each tablet.

Process For The Preparation: Naproxen Layer Preparation

1. Raw materials were weighed in conformity with above table. Purified water was separated to 2 parts and one part was heated. The remaining part was waited at room temperature.

2. Polysorbate 80, Triethyl Citrate and Glycerol Monostearate 40-55 were added into the heated water and was stirred well. 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.

4. Eudragit L30 D-55 solution was added to the mixture of step-3 and it was mixed for a while and transferred to granulator.

5. Naproxen and Colloidal Silicone Dioxide were added into granulator by passing through the sieve.

6. The dry mixture of step 5 was granulated by using binder solution of step 4.

7. 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.

9. Sodium Stearyl Fumarate was transferred to the above container mixer of step-8 and mixed.

Esomeprazole Layer Preparation

10. Raw materials were weighed in conformity with above table.

11 . Esomeprazole mg trihydrate, MCC PH 112, Magnesium oxide light and half of calcium stearate were sieved using an appropriate sieve, loaded to container mixer and mixed.

12. The powder blend of step-11 was pressed into solid compacts by using roller compactor.

13. Solid compacts at step-12 were sieved using an appropriate sieve to obtain the desired granules. Sieved granules were transferred to container mixer.

14. MCC PH 302, PVP K30 and Croscarmellose Sodium were sieved using an appropriate sieve, loaded to container mixer and mixed.

15. The remain part of Calcium stearate was sieved using an appropriate sieve, loaded to container mixer and mixed. Tablet Compression

16. Final blend of Naproxen layer of step-9 and final blend of Esomeprazole layer of step- 15 were load to tablet compressing machine and the tablets were compressed as bilayer tablet at the defined specifications.

Film Coating

17. 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

Table-2

Process For The Preparation:

Naproxen Layer Preparation

2. Polysorbate 80, Triethyl Citrate and Glycerol Monostearate 40-55 were added into the heated water and was stirred well.

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.

6. The dry mixture of step 5 was granulated by using binder solution of step 4.

7. 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.

Esomeprazole Layer Preparation

10. Raw materials were weighed in conformity with above table.

11 . Esomeprazole mg trihydrate, MCC PH 102, Sodium carbonate anhydrous, Magnesium oxide light were sieved using an appropriate sieve, loaded to container mixer and mixed.

12. Povidon K90 and Croscarmellose Sodium were sieved using an appropriate sieve and transferred to container at Step-11 and mixed.

13. Calcium stearate was sieved using an appropriate sieve, loaded to container mixer and mixed.

Tablet Compression

14. Final blend of Naproxen layer of step-9 and final blend of Esomeprazole layer of step- 13 were load to tablet compressing machine but when compression process was started it had been observed that flow of Esomeprazole blend was so poor and material sticking to the tablet forming surface of the punch.

Conclusion: Without bind to any theory, it has been observed when final blend of Esomeprazole layer obtained by direct compression (as per comparative example-2) it didn’t provide proper flow of material, created material sticking to the tablet forming surface of the punch and assay of active part was also not obtained within the defined criteria. The similar problems have not been encountered while preparing the tablet as per example-1.

Example-3: Dissolution Profile Analysis

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.

Table-3: Naproxen’s In-vitro analysis of Reference product and Example-1 product at pH: 6.8 phosphate buffer + 0.1% SLS medium

Table-4: Esomeprazole’s In-Vitro analysis of Reference product and Example-1 product at pH 6.8 phosphate buffer

Example-4: In-vivo analysis Naproxen and Esomeprazole were compared with the reference product Vimovo® in fasted conditions.

Table-5: In Vivo analysis of Naproxen Layer of Example-1 and Reference

Product in fasting condition

Table-6: In Vivo analysis of Esomeprazole Layer of Example-1 and Reference Product in fasting condition

Example-5: Stability Testing

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).

6 months stability results are presented at the below table-7.

Table-7: Stability Test

It can be seen from Table-7, Example-1 has similar stability profile with Vimovo® .

Claims

Claims:

1 . A pharmaceutical composition in the form of bilayer tablet comprising:

- first layer comprising granules or powder containing Naproxen and at least one pharmaceutically acceptable excipient, and

- second layer comprising dry granulated granules containing Esomeprazole and its pharmaceutically acceptable salt and at least one pharmaceutically acceptable excipient.

2. A pharmaceutical composition according to claim 1 , wherein both the layers are adjacent to each other.

3. A pharmaceutical composition according to claim 1 and claim 2, further comprises at least one pharmaceutically acceptable excipient is selected from the group consisting of binders, diluents, disintegrants, lubricants, glidants, plasticizing, basic agents.

4. A pharmaceutical composition according to claim 3, wherein the binder selected from hydroxyethyl cellulose, hydroxypropyl cellulose, hydroxypropyl methylcellulose, carbomers, carboxymethylcellulose sodium, dextrin, ethyl cellulose, methylcellulose, shellac, zein, gelatin, polymethacrylates, polyvinyl pyrrolidone, sodium alginate, gums, methacryclic acid-ethyl acrylate copolymer (1 :1 ) dispersion.

5. A pharmaceutical composition according to claim 4, wherein the binder is methacrylic acid-ethyl acrylate copolymer (1 :1 ) dispersion or polyvinyl pyrrolidone.

6. A pharmaceutical composition in the form of bilayer tablet according to claim 1 , wherein first layer comprising granules or powder containing Naproxen, surfactant and at least one pharmaceutically acceptable excipient.

7. A pharmaceutical composition according to claim 6, wherein the surfactant is selected from glycerol monostearate, Tween 80, Tween 40, Span 40, Labrafil

25 M1944CS, polyoxyethylene-35-ricinoleate, brij 58, cremophor EL, lecithin, polysorbates, sorbitans, PEGs. A pharmaceutical composition according to claim 6, wherein surfactant is present in amount from 0.5% to 1 .5% by weight based on the total weight of the composition. A pharmaceutical composition according to claim 7, wherein surfactant is polysorbate 80. A pharmaceutical composition in the form of bilayer tablet according to claim 1 , wherein second layer comprising dry granulated granules containing Esomeprazole and its pharmaceutically acceptable salt is devoid of any surfactant. A process for the preparation of pharmaceutical composition in the form of bilayer tablet comprising:

- the granules of Naproxen are prepared by wet granulation, and

- the granules of Esomeprazole are prepared by dry granulation. A process for preparing a pharmaceutical composition according to claim 11 , wherein dry granulation is carried out by using either slugging or roller compaction. A process for preparing a pharmaceutical composition according to Claim 11 , wherein dry granulation is carried out by using roller compaction. The bilayer tablet according to claim 1 and 11 , which is useful for treating 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. 1