FIELD OF INVENTION

The invention relates to a pharmaceutical formulation in the form of a tablet comprising an anti-inflammatory agent and a proton pump inhibitor.

The invention also relates to a process for the preparation of a pharmaceutical formulation in the form of a tablet comprising an anti-inflammatory agent and a proton pump inhibitor.

BACKGROUND OF THE INVENTION AND RELATED PRIOR ART

Non steroidal anti-inflammatory drugs (NSAIDs) are used as an effective analgesic in acute and chronic pain. However, their administrations are associated with a number of adverse effects which include effect on the kidney and exacerbating asthma in some people, but the most important adverse effect of NSAIDs is that on the gastrointestinal tract, which can lead to ulcers and erosions in susceptible individuals. The major factor contributing to the development of these lesions is the presence of acid in the stomach and upper small intestine of patients.

To overcome the above disadvantages, many acid inhibitors are used in combination/ coordination with NSAIDs. In general, when a short acting acid inhibitor and NSAIDs are administered simultaneously, NSAID-related mucosal damage occurs before the pH of the gastrointestinal tract can be raised and after the acid inhibiting effect of the short acting acid inhibitor dissipates. However, it is seen that more potent and longer lasting acid inhibitors, i.e. Proton pump inhibitors are more protective during chronic administration of NSAIDs than shorter acting agents as it raises the pH of the gastrointestinal tract and maintains it before the release of NSAIDs.

So to reduce the disadvantages of NSAIDs and at the same time to enhance the utility, a patient need to take two separate dosage forms. Further to enhance the patient compatibility, a single composition comprising a NSAID along with a long acting proton pump inhibitor has been developed.

A monolithic tablet comprising a naproxen core and esomeprazole coated over it is commercially available under the trade name Vimovo® in the US for the treatment of signs and symptoms of osteoarthritis, rheumatoid arthritis and ankylosing spondylitis.

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 6,926,907, US 2005/0249811 and US 2010/0172983 discloses a composition in unit dose form suitable for oral administration comprising (a) an acid inhibitor present in an amount effective to raise the gastric pH of said patient to at least 3.5 upon the administration of one or more of said unit dosage forms; (b) a NSAID drug in an amount effective to reduce or eliminate pain or inflammation in said patient upon administration of one or more of said unit dosage forms. It further discloses a bilayer tablet comprising naproxen pellets coated with enteric coating with an aqueous dispersion of methacrylic acid copolymer, which optionally compressed into a core and film coated with an acid inhibitor.

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 disclose a composition including (a) at least one acid labile proton pump inhibitor, (b) at least one buffering agent and (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 disclose 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.

The present inventors hereby disclose a formulation comprising NSAID and esomeprazole magnesium which is prepared in the form of either a bilayer tablet or an inlay tablet, to produce an improved formulation and thereby reducing the process time, increasing ease of manufacturing and being cost effective.

SUMMARY AND OBJECTIVE OF THE INVENTION

The invention relates to a pharmaceutical formulation in the form of a tablet comprising a combination of NSAID and proton pump inhibitor and process for its preparation.

More particularly, the invention relates to 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.

More particularly, the invention relates to a pharmaceutical formulation in the form of a tablet comprising naproxen and esomeprazole and at least one pharmaceutically acceptable excipient, wherein said tablet is an inlay tablet.

The invention also relates to a process for preparing 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 invention also relates to a process for preparing a pharmaceutical formulation in the form of a tablet comprising naproxen and esomeprazole and at least one pharmaceutically acceptable excipient, wherein said tablet is an inlay tablet.

DETAILED DESCRIPTION OF THE EMBODIMENTS OF THE INVENTION

The invention relates to pharmaceutical formulation in the form of a tablet comprising NSAID and proton pump inhibitor, wherein said tablet is either a bilayer tablet or an inlay tablet.

NSAID of the invention includes diclofenac sodium, diclofenac potassium, ibuprofen, fulbuprofen, etodolac, naproxen, aspirin or their pharmaceutically acceptable salts and combinations thereof.

Proton pump inhibitors may be selected from the group comprising esomeprazole, omeprazole, lansoprazole, dexlansoprazole, pantoprazole, pariprazole, rabeprazole, tenatoprazole or their pharmaceutically acceptable salts and combinations thereof.

More particularly, the invention relates to a tablet formulation comprising naproxen and esomeprazole.

In an embodiment of the invention, pharmaceutical formulation in the form of a tablet comprising naproxen and esomeprazole in the form of an inlay tablet or bilayer tablet, wherein the naproxen is present as an internal layer and esomeprazole is present as an external layer.

As per the invention, the two layers are placed usually "adjacent" to each other which implies that the two layers are present side by side.

In another embodiment of the invention, there is provided a tablet formulation comprising naproxen and esomeprazole, wherein both naproxen and esomeprazole is present in an immediate release form.

In another embodiment of the invention, there is provided a tablet formulation comprising naproxen and esomeprazole, wherein naproxen is present in a modified release form while esomeprazole is present in an immediate release form.

In an another embodiment of the invention, there is provided a tablet formulation comprising naproxen and esomeprazole, wherein naproxen is present in an immediate release form while esomeprazole is present in an modified release form.

In another embodiment of the invention, there is provided a tablet formulation comprising naproxen and esomeprazole, wherein both naproxen and esomeprazole are present in a modified release form.

The formulation may further contain fillers, binders, disintegrants, plasticizers, glidants and lubricants as excipients.

Fillers according to the invention are selected from the group comprising lactose, cellulose, mannitol, microcrystalline cellulose, dextrose, calcium phosphate, fructose, maltose and the like or combinations thereof.

Disintegrants according to the invention are selected from the group comprising starch and derivatives, sodium starch glycolate, calcium carboxymethlycellulose, croscarmellose sodium, polacrillin potassium, alginic acid, crospovidone, low-substituted hydroxypropyl cellulose and the like or combinations thereof.

Binders according to the invention are selected from the group comprising povidone, copovidone, hyroxypropyl methylcellulose, hyroxypropyl cellulose, polyvinyl alcohol, sodium alginate, sodium carboxymethyl cellulose, polydextrose, methacrylic acid copolymers (Eudragit™), Hydroxypropyl methylcellulose phthalate, polyvinyl alcohol phthalate, cellulose acetate phthalate and the like or combinations thereof.

Glidants according to the invention are selected from the group comprising colloidal silicon dioxide, talc and the like or combinations thereof Lubricants according to the invention are selected from the group comprising magnesium stearate, sodium stearyl fumarate, stearic acid, hydrogenated vegetable oil and the like or combinations thereof.

In an embodiment, the formulation may contain an alkalizing agent selected from the group of compound comprising sodium chloride, sodium carbonate, sodium hydroxide, sodium bicarbonate, potassium bicarbonate, magnesium carbonate, magnesium oxide and the like or combinations thereof. The presence of alkalizing agent in the formulation is favorable since it prevents degradation of proton pump inhibitors, which is unstable in acidic medium.

In a preferred embodiment, the bilayer tablet comprises a first layer comprising naproxen and one or more pharmaceutically acceptable excipients and a second layer comprising esomeprazole magnesium, one or more alkalizing agent and one or more pharmaceutically acceptable excipients.

In a preferred embodiment, the inlay tablet comprises a core tablet comprising naproxen and one or more pharmaceutically acceptable excipients and an overcoat partially covering the said core tablet, comprising esomeprazole magnesium, one or more alkalizing agent and one or more pharmaceutically acceptable excipients.

In an another preferred embodiment, there is provided a pharmaceutical formulation in the form of a tablet having:

a) a first layer comprising naproxen and one or more pharmaceutically acceptable excipient(s); and

b) a second layer comprising esomeprazole magnesium, alkalizing agent and one or more pharmaceutically acceptable excipient(s);

wherein said two layers are positioned adjacent to each other to form a bilayer tablet.

In further embodiment, there is provided a process for preparing both the inlay and bilayer tablets wherein the tablets are prepared either by wet granulation, dry granulation or direct compression.

The bilayer tablet comprising naproxen and esomeprazole is prepared involving the steps of:

(a) Granulating naproxen with a binder in a granulator to form granules;

(b) Drying, milling and lubricating said granules to form lubricated blend;

(c) Compressing said lubricated blend to form the first layer;

(d) Mixing esomeprazole magnesium, alkalizing agent and one or more pharmaceutically acceptable excipient to get dry blend;

(e) Compressing said dry blend with the first layer of step (c) in a bilayer tablet compression machine to form the bilayer tablet.

The inlay tablet comprising naproxen and esomeprazole is prepared involving the steps of:

(a) Granulating naproxen with a binder in a granulator to form granules;

(b) Drying, milling and lubricating said granules to form lubricated blend;

(c) Compressing said lubricated blend to form the core tablet;

(d) Mixing esomeprazole magnesium, alkalizing agent and one or more pharmaceutically acceptable excipient to get dry blend,

(e) Compressing said dry blend with the core tablet of step (c) in a compression coating machine to form the inlay tablet.

The following examples further exemplify the invention and are not intended to limit the scope of the invention. It is obvious to those skilled in the art to find out the composition for other dosage forms and substitute the equivalent excipients as described in this specification or with the one known to the industry.

Example 1

a) Naproxen layer
S. No. Ingredient mg /unit
1 Naproxen 500.00
2 Mannitol 130.00
3 Colloidal Silicone Dioxide 15.00
4 Crospovidone 40.00
5 Eudragit L30 D-55 (solid laquer) 50.00 (Neutralized to pH 5.5 with sodium hydroxide)
6 Sodium stearyl fumarate 15.00
Naproxen layer Weight 750.00
b) Esomeprazole layer

S. No. Ingredient mg /unit
1 Esomeprazole Magnesium 44.50
2 Mannitol 188.00
4 Sodium bicarbonate 100.00
4 Crospovidone 40.00
5 Copovidone 20.00
6 Sodium stearyl fumarate 7.50
Esomeprazole layer Weight 400.00

Brief manufacturing process: Naproxen layer:

1. Naproxen was blended with mannitol, colloidal silicon dioxide and crospovidone;

2. The blend mass of step 1 was granulated using top spray granulator with Eudragit™ which was previously neutralized to pH 5.5;

3. The granules of step 2 were dried and milled to get desired granules;

4. Lubricated the granules of step 3 with sodium stearyl fumarate for about 5 minutes in a blender;

5. Compressed the lubricated blend of step 4 to form the naproxen layer;

Esomeprazole layer:

6. Esomeprazole magnesium, sodium bicarbonate, mannitol, crospovidone, copovidone and sodium stearyl fumarate were blended together for about 30 minutes in a blender;

7. Compressed the blend of step 6 over the pre-compressed layer of step 5, using bilayer compression machine to get the bilayer tablet.

Example 2

a) Naproxen layer

S. No. Ingredient mg /unit
1 Naproxen 500.00
2 Mannitol 130.00
3 Colloidal Silicone Dioxide 15.00
4 Crospovidone 40.00
5 Eudragit™ L30 D-55 (solid laquer) 50.00 (Neutralized to pH 5.5 with sodium hydroxide)
6 Sodium stearyl fumarate 15.00
Naproxen layer Weight 750.00

b) Esomeprazole layer

S. No. Ingredient mg /unit
1 Esomeprazole Magnesium 22.30
2 Mannitol 94.00
4 Sodium bicarbonate 50.00
4 Crospovidone 20.00
5 Copovidone 10.00
6 Sodium stearyl fumarate 3.70
Esomeprazole layer Weight 400.00

The formulation given in Example 2 was prepared using similar procedure as described in Example 1.

Example 3

a) Naproxen layer
S. No. Ingredient mg /unit
1 Naproxen 500.00
2 Mannitol 130.00
3 Colloidal Silicone Dioxide 15.00
4 Crospovidone 40.00
5 Eudragit1M L30 D-55 (solid laquer) 50.00 (Neutralized to pH 5.5 with sodium hydroxide)
6 Sodium stearyl fumarate 15.00
Naproxen layer Weight 750.00

b) Esomeprazole layer

S. No. Ingredient mg /unit
1 Esomeprazole Magnesium 22.30
2 Mannitol 210.3
4 Sodium bicarbonate 100.0
4 Crospovidone 40.00
5 Copovidone 20.00
6 Sodium stearyl fumarate 7.40
Esomeprazole layer Weight 400.00

Brief manufacturing process: Naproxen layer:

1. Naproxen was blended with mannitol, colloidal silicon dioxide and crospovidone;

2. The blend mass of step 1 was granulated using top spray granulator with Eudragit™ which was previously neutralized to pH 5.5;

3. The granules of step 2 were dried and milled to get desired granules;

4. Lubricated the granules of step 3 with sodium stearyl fumarate for about 5 minutes in a blender;

5. Compressed the lubricated blend of step 4 to form naproxen core.

Esomeprazole layer:

6. Esomeprazole magnesium, sodium bicarbonate, mannitol, crospovidone, copovidone and sodium stearyl fumarate were blended together for about 30 minutes in a blender;

7. Compressed the blend of step 6 over the pre-compressed core of step 5 in a compression coating machine to form an inlay tablet.

Example 4

a) Naproxen layer
S. No. Ingredient mg /unit
1 Naproxen 500.00
2 Mannitol 130.00
3 Colloidal Silicone Dioxide 15.00
4 Crospovidone 40.00
5 Eudragit L30 D-55 (solid laquer) 50.00 ( Neutralized to pH 5.5 with sodium hydroxide)
6 Sodium stearyl fumarate 15.00
Naproxen layer Weight 750.00

b) Esomeprazole layer

S. No. Ingredient mg /unit
1 Esomeprazole Magnesium 44.6
2 Mannitol 188.0
4 Sodium bicarbonate 100.0
4 Crospovidone 40.0
5 Copovidone 20.0
6 Sodium stearyl fumarate 7.40 Esomeprazole layer Weight 400.00

The formulation given in Example 4 was prepared using similar procedure as described in Example 3.
Dissolution Study:

Drug release profile of the tablet prepared according to Example (2) was carried out under following dissolution conditions:

Acid Release:

Media: 0. IN HC1, Volume: 1000ml,
Apparatus: USP Dissolution Apparatus Type II, Rotational Speed: 50 rpm, Time: 1 hr

Buffer Release:
Media: pH 6.8 phosphate buffer,
Volume: 1000ml,
Apparatus: USP Dissolution Apparatus Type II,
Rotational Speed: 100 rpm,
Time: 1 hr

The samples of the media were periodically withdrawn and analyzed for naproxen and esomeprazole content. The dissolution profile is given in Table 1.

Table-1
Naproxen Esomeprazole
Example 0.1N HC1, 1000ml, 50RPM, Paddle pH 6.8 phosphate buffer, 1000ml,
(2) (II) Followed by pH 6.8 phosphate 100RPM, Paddle (II).
buffer, 1000ml, 50RPM, Paddle (II).
Time 2 hr I 10 I 20 I 30 I 45 I 60 10 I 15 I 20 I 30 I 45 I 60
(min) Acid
release
Reference Nil 6.9 55 88.3 95.6 97.6 40.3 56.8 66.8 77.7 80.4 82.1
(Vimovo®)
Test 1 Nil 1 2 1 30 1 84 1 98 | 100 | 53 | 61 [ 65 | 71 | 78 | 82

WE CLAIM:

1. 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.

2. A pharmaceutical formulation in the form of a tablet comprising naproxen and esomeprazole and at least one pharmaceutically acceptable excipient, wherein said tablet is an inlay tablet.

3. A pharmaceutical formulation in the form of a tablet having:

(a) a first layer comprising naproxen and one or more pharmaceutically acceptable excipient; and

(b) a second layer comprising esomeprazole and one or more pharmaceutically acceptable excipient;

wherein said two layers are positioned adjacent to each other to form a bilayer
tablet.

4. A process for preparing a bilayer tablet comprising naproxen and esomeprazole, involving steps of:

(a) Granulating naproxen with a binder in a granulator to form granules;

(b) Drying and lubricating said granules to form lubricated blend;

(c) Compressing said lubricated blend to form the first layer;

(d) Mixing esomeprazole magnesium, alkalizing agent and one or more pharmaceutically acceptable excipient to get dry blend;

(e) Compressing said dry blend with the first layer of step (c) in a bilayer tablet compression machine to form said bilayer tablet.

5. A process for preparing an inlay tablet comprising naproxen and esomeprazole, involving steps of:

(a) Granulating naproxen with a binder in a granulator to form granules;

(b) Drying and lubricating said granules to form lubricated blend;

(c) Compressing said lubricated blend to form the core tablet;

(d) Mixing esomeprazole magnesium, alkalizing agent and one or more pharmaceutically acceptable excipient to get dry blend,

(e) Compressing said dry blend with the core tablet of step (c) in a compression coating machine to form said inlay tablet.

6. The excipient according to any of the preceding claims are selected from the group comprising fillers, binders, disintegrants, alkalizing agent, lubricants, glidants or combinations thereof.

7. The filler according to claim 6, is selected from a group comprising lactose, cellulose, mannitol, microcrystalline cellulose, dextrose, calcium phosphate, fructose, maltose or combinations thereof.

8. The binder according to claim 6, is selected from a group comprising povidone, copovidone, hyroxypropyl methylcellulose, hyroxypropyl cellulose, polyvinyl alcohol, sodium alginate, sodium carboxymethyl cellulose, polydextrose, Eudragit™, hydroxypropyl methylcellulose phthalate, polyvinyl alcohol phthalate, cellulose acetate phthalate or combinations thereof.

9. The disintegrant according to claim 6, is selected from a group comprising sodium starch glycolate, calcium carboxymethly cellulose, croscarmellose sodium, polacrillin potassium, alginic acid, crospovidone, low-substituted hydroxypropyl cellulose or combinations thereof.

10. The alkalizing agent according to claim 6, is selected from a group comprising sodium chloride, sodium carbonate, sodium hydroxide, sodium bicarbonate, potassium bicarbonate, magnesium carbonate, magnesium oxide or combinations thereof.