FORM 2
THE PATENT ACT 1970
(39 of 1970)
&
The Patents Rules, 2003
COMPLETE SPECIFICATION
(See section 10 and rule13)
1. TITLE OF THE INVENTION: COMBINATION DOSAGE FORM
2. APPLICANT (S)
(a) NAME: WOCKHARDT LTD.
(b) NATIONALITY: INDIAN
(c) ADDRESS: Wockhardt Towers, Bandra-Kurla Complex, Bandra
(East), Mumbai-400 051.
3. PREAMBLE TO THE DESCRIPTION
The present invention provides pharmaceutical composition in the form of fixed combination comprising of acetaminophen, propoxyphene or pharmaceutically acceptable salt thereof, diclofenac or pharmaceutically acceptable salt thereof and proton pump inhibitor or one of its single enantiomers or salt thereof along with pharmaceutically acceptable carriers. The following specification particularly describes the invention and the manner in which it is to be performed.
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4. DESCRIPTION
The present invention provides pharmaceutical compositions in the form of fixed combination comprising of acetaminophen, propoxyphene or pharmaceutically acceptable salt thereof, diclofenac or pharmaceutically acceptable salt thereof and proton pump inhibitor or one of its single enantiomers or salt thereof along with pharmaceutically acceptable carriers.
Paracetamol, also known as acetaminophen, 4'-hydroxyacetanilide, is a non-opiate, non-salicylate analgesic and antipyretic. It is known chemically as N-(4-hydroxyphenyl)ethanamide of formula 1. Acetaminophen provides temporary relief of minor aches and pains with heartburn or acid indigestion and upset stomach associated with these symptoms.

Narcotic analgesics are used to relieve pain. Some of these medicines are also used just before or during an operation to help the anesthetic work better. Narcotic analgesics act in the central nervous system (CNS) to relieve pain. Propoxyphene napsylate is a drug of narcotics analgesic class. Propoxyphene napsylate, chemically is, (aS,1R)-a-[2-(Dimethylamino)-1-methylethyl]-a-phenylphenethyl propionate compound with 2-naphthalenesulfonic acid (1:1) monohydrate, of formula 2. Propoxyphene napsylate differs from propoxyphene hydrochloride in that it allows more stable liquid dosage forms and tablet formulations. Propoxyphene napsylate is indicated for the relief of mild to moderate pain, either when pain is present alone or when it is accompanied by fever.
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Proton pump inhibitors (PPIs) are a class of acid-labile pharmaceutical compounds that block gastric acid secretion pathways. They suppress gastric acid secretion by the inhibition of the H+-K+-ATPase enzyme system at the secretory surface of the gastric parietal cell. Omeprazole is one such proton pump inhibitor. Omeprazole is a substituted benzimidazole, which chemically is 5-methoxy-2-[[(4-methoxy-3,5-dimethyl-2-pyridinyl)methyl]sulfinyl]-1H-benzimidazole of formula 3. It is a racemic mixture of two enantiomers that inhibits gastric acid secretion. Omeprazole is indicated for short-term treatment of active benign gastric ulcer, erosive esophagitis, treatment of Gastroesophageal Reflux Disease (GERD). It is also indicated for the reduction of risk of upper gastrointestinal bleeding in critically ill patients.

Nonsteroidal anti-inflammatory drugs ("NSAIDs") are among the most commonly prescribed drugs. The ability of NSAIDs to treat inflammatory disorders is attributed to their ability to inhibit cyclooxygenase, the enzyme responsible for biosyntheses of the prostaglandins and certain autocoid inhibitors, including inhibitors of lipoxygenase and cyclooxygenase (such as cyclooxygenase-l and
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cyclooxygenase-ll). Diclofenac sodium is a drug of NSAID class and chemically it is 2-[(2,6-dichlorophenyl)amino] benzeneacetic acid, monosodium salt of formula 4. It is indicated for the relief of signs and symptoms of osteoarthritis, rheumatoid arthritis and for acute or long-term use in the relief of signs and symptoms of ankylosing spondylitis. However, despite the therapeutic benefits of NSAIDs, their use is often limited by an increased risk of gastrointestinal side effects, in particular upper gastrointestinal side effects such as peptic ulceration and dyspeptic symptoms. It is also well known that NSAIDs have the potential to cause gastrointestinal (Gl) bleeding through a variety of mechanisms related to their topical and systemic effects. The Gl bleeding may depend on the length of the treatment and on the particular drug. This problem is important in cases where the therapy must be continued for a long period of time.

Therefore there exists a need in the art for a combination formulation, which includes an NSAID, analgesic-antipyretic with proton pump inhibitor to reduce the occurrence of gastro-intestinal side effects associated with analgesic treatment.
US Patent No. 6, 544,556 disclose solid oral dosage form comprising a diclofenac extended release tablet and an enterically coated proton-pump inhibitor without a separating layer between the proton pump inhibitor and the enteric coat; these proton pump inhibitor enteric coated beads and the diclofenac tablet are contained within a capsule.
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US Patent Application No. 20050163847 disclose solid oral dosage form comprising: a first potion comprising a therapeutically effective amount of an NSAID; and a coating comprising a therapeutically effective amount of an anti ulcerative compound; said coating at least partially surrounding said first NSAID portion.
US Patent No. 6,869,615 disclose solid oral dosage form comprising a population of substrates comprising a proton-pump inhibitor; an enteric coating layer coated over said substrates; and an NSAID coating layer coated over said enteric-coated substrates.
The present invention is now directed to a pharmaceutical composition that comprises a combination of acetaminophen, propoxyphene or pharmaceutically acceptable salt thereof, diclofenac or pharmaceutically acceptable salt thereof and proton pump inhibitor or one of its single enantiomers or salt thereof. These compositions reduce gastric side effects of long term administered antipyretic-analgesic and antiarthritic-antiinflammatory drugs. Also it enhances the compliance of patient by reducing the side effects of antipyretic-analgesic, antiarthritic-antiinflammatory drugs.
In one of the aspects of the present invention there is provided a pharmaceutical dosage form for oral administration comprising combination of acetaminophen, propoxyphene or pharmaceutically acceptable salt thereof, diclofenac or pharmaceutically acceptable salt thereof and proton pump inhibitor or one of its single enantiomers or salt thereof along with pharmaceutically acceptable carriers.
The therapeutically effective amount of diclofenac sodium, paracetamol, propoxyphene napsylate and proton pump inhibitor such as omeprazole magnesium is included in this combination. The dosage form can be selected
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from tablet, layered tablet, tablet in tablet, tablet in capsule, granules, caplet and microtablet.
The combination can be employed in admixture with pharmaceutically acceptable excipients. Pharmaceutically acceptable excipients can be diluent, filler, binder, lubricant, sweetener, coloring and flavoring agent, glidant and the like. The binders may be one or more of starch, sugars, gums, low molecular weight hydroxypropylmethyl cellulose, polyvinyl pyrrolidone and hydroxypropyl cellulose. The lubricants may be one or more talc, magnesium stearate, polyethylene glycol, hydrogenated vegetable oils, stearic acid, sodium stearyl fumarate and sodium benzoate. The glidant may be one or both of colloidal silicon dioxide and talc or magnesium stearate. Suitable coloring and flavoring agents include those approved for use by the United States Food and Drug Administration (FDA) and are well known to those skilled in the art.
In another aspect of the present invention there is provided a pharmaceutical dosage form for oral administration comprising combination of:
a) acetaminophen, propoxyphene or pharmaceutically acceptable salt thereof, diclofenac or pharmaceutically acceptable salt thereof along with pharmaceutically acceptable carriers in an immediate release form, and
b) omeprazole or pharmaceutically acceptable salt thereof along with pharmaceutically acceptable carriers, in an delayed release form
wherein the said immediate release form and said delayed release form are present with or without an intermediate layer in between the two active layers.
The acetaminophen, propoxyphene napsylate and diclofenac sodium is present in an immediate release form so that it is released immediately upon ingestion. Omeprazole is present in an extended release form so that it is released in a sustained fashion over a period of time.
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In yet another aspect of the present invention there is provided a tablet in tablet dosage form for oral administration comprising
a) an inner tablet comprising of omeprazole or pharmaceutically acceptable salt thereof along with pharmaceutically acceptable carriers, an inert intermediate layer surrounding the core followed by enteric coating over the said intermediate layer and
b) outer tablet comprising of granules comprising of acetaminophen, propoxyphene or pharmaceutically acceptable salt thereof, diclofenac or pharmaceutically acceptable salt thereof along with pharmaceutically acceptable carriers.
The intermediate layer also can be called as seal coat is formed from an inert water-soluble or water insoluble film former. The pharmaceutically acceptable seal coat forming polymers can be selected from a group comprising of one or more of suitable cellulose ethers include one or more of hydroxypropyl methylcellulose, hydroxypropyl cellulose and other suitable cellulose ethers. The film former has been applied from a solution. The intermediate layer is surrounded by outer enteric coat. The pharmaceutically acceptable enteric coating forming polymers can be selected from methacrylic acid copolymers such as Eudragit L, methyl methacrylate copolymers, ethoxy ethyl methacrylates or cellulose derivatives such as carboxymethyl cellulose, cellulose acetate phthalate, hydroxypropylmethyl cellulose phthalate, shellac and other suitable polymers.
In yet another aspect of the present invention there is provided a solid dosage
form for oral administration comprising:
a) an inner tablet comprising of omeprazole or pharmaceutically acceptable salt thereof along with pharmaceutically acceptable carriers, an inert intermediate layer surrounding the core followed by enteric coating over the said intermediate layer and
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b) granules comprising of acetaminophen, propoxyphene or pharmaceutical^ acceptable salt thereof, diclofenac or pharmaceutical^ acceptable salt thereof along with pharmaceutical^ acceptable carriers
wherein the said enteric-coated tablet and said granules are contained within a
hard gelatin capsule.
In yet another aspect of the present invention there is provided a solid dosage form for oral administration comprising:
a) granules comprising of acetaminophen, propoxyphene or pharmaceutical^ acceptable salt thereof, diclofenac or pharmaceutically acceptable salt thereof along with pharmaceutical^ acceptable carriers in an extended release form;
b) pellets comprising of omeprazole or pharmaceutical^ acceptable salt thereof along with pharmaceutical^ acceptable carriers in a delayed release form.
wherein the said delayed release pellets and said immediate release granules are further compressed into bilayer tablets or filled into capsules.
The extended release can be achieved by matrix formation or by enteric coating. The enteric coating that is designed to prevent the absorption of the diclofenac in the stomach, and thus reduce the risk of stomach irritation. This also provides more prolonged pain relief.
The enteric-coated tablets disclosed in the present invention may be prepared by direct compression, dry granulation or by wet granulation. The omeprazole magnesium enteric-coated tablet may be prepared by direct compression. Omeprazole magnesium, magnesium oxide light, anhydrous sodium carbonate and pearlitol SD 200 were weighed, sifted through a suitable sieve and mixed properly using double cone blender. Hydroxy propyl cellulose, sodium metabisulphite and crospovidone, magnesium stearate and glyceryl behenate were weighed, sifted through a suitable sieve, added to above mix and mixed
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properly using double cone blender. This blend was compressed into tablets using rotary tablet compression machine. These tablets were further coated with seal coat followed by enteric coating.
The granules of paracetamol, propoxyphene napsylate and diclofenac sodium may be prepared by dry granulation or by wet granulation. The blend of all these ingredients may also be filled directly into the capsule.
While the present invention has been described in terms of its specific embodiments, certain modifications and equivalents will be apparent to those skilled in the art and are intended to be included within the scope of the present invention.
EXAMPLES- The composition of batches is provided in table 1. Table 1 - Composition of batches

Sr. No. Ingredients Quantity (mg)
Acetaminophen, Propoxyphene napsylate and Diclofenac sodium Granules
1 Paracetamol 250.00
2 Propoxyphene napsylate 50.00
3 Diclofenac sodium 50.00
4 Siliconised Talc 50.00
5 Lactose monohydrate 42.50
6 Colloidal silicon dioxide (Aerosil 200) 2.50
7 Magnesium stearate 10.00
8 Maize stearate 5.00
Total 460.00
Omeprazole Tablets
1 Omeprazole magnesium 11.30
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2 Anhydrous sodium carbonate 2.00
3 Magnesium oxide light 2.50
4 Mannitol (Pearlitol SD 200) 37.70
5 Hydroxy propyl cellulose-LH 11 4.00
6 Glyceryl behenate 0.50
7 Sodium meta bi sulphate 1.00
8 Crospovidone 5.00
9 Magnesium stearate 2.00
Total 66.00
Coating composition
1 Instacoat SO 1(seal coating) 2.00
2 Instacoat EN-11 (enteric coating) 10.12
3 Isopropyl alcohol q. s.
4 Methylene chloride q. s.
5 Acetone q. s.
Total 75.00
Process for the preparation of Omeprazole magnesium enteric coated tablets-A) Tablet Compression-
1) Omeprazole magnesium, magnesium oxide light, anhydrous sodium carbonate and pearlitol SD 200 were weighed, sifted through a suitable sieve and mixed properly using double cone blender.
2) Hydroxy propyl cellulose, sodium metabisulphite and crospovidone were weighed, sifted through a suitable sieve, added to above mix and mixed properly using double cone blender.
3) Magnesium stearate and glyceryl behenate were weighed, sifted through a suitable sieve, added to above mix and mixed properly using double cone blender.
4) The above blend was compressed into tablets using rotary tablet compression machine.
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B) Seal Coating-
1) Instacoat SO 1 was weighed accurately and dissolved in mixture of isopropyl alcohol and methylene chloride, stirred for few minutes and filtered.
2) The above tablets were seal coated until weight gain reaches to 2.5-3.0%.
C) Enteric coating-
1) Instacoat EN-11 was weighed accurately and dispersed in a mixture of isopropyl alcohol and acetone, stirred for few minutes and filtered.
2) Seal coated tablets were further enteric coated with this coating solution until weight gain reaches to 10-12%.
Process for the preparation of Acetaminophen, Propoxyphene napsylate and Diclofenac sodium Blend-
1) Paracetamol, Propoxyphene napsylate and Diclofenac sodium were weighed, sifted through a suitable sieve and mixed properly.
2) Lactose monohydrate, colloidal silicon dioxide, maize starch and Siliconised starch were weighed, sifted through a suitable sieve and blended properly with above mix.
3) Magnesium stearate was added as a lubricant and mixed properly.
4) This blend was further filled into empty gelatin capsules along with omeprazole enteric coated tablet or further granules were prepared and compressed into tablets.
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WE CLAIM:
1. A pharmaceutical dosage form for oral administration comprising combination of acetaminophen, propoxyphene or pharmaceutically acceptable salt thereof, diclofenac or pharmaceutically acceptable salt thereof and proton pump inhibitor or one of its single enantiomers or salt thereof along with pharmaceutically acceptable carriers.
2. A dosage form according to claim 1, wherein the propoxyphene is present in the form of propoxyphene napsylate.
3. A dosage form according to claim 1, wherein the diclofenac is present in the form of diclofenac sodium.
4. A dosage form according to claim 1, wherein the omeprazole is present in the form of omeprazole magnesium.
5. A pharmaceutical dosage form for oral administration comprising combination of:

a) acetaminophen, propoxyphene or pharmaceutically acceptable salt thereof, diclofenac or pharmaceutically acceptable salt thereof along with pharmaceutically acceptable carriers in an immediate release form, and
b) omeprazole or pharmaceutically acceptable salt thereof along with pharmaceutically acceptable carriers in a delayed release form
wherein the said immediate release form and said delayed release form are present with or without an intermediate layer in between the two active layers.
6. A tablet in tablet dosage form for oral administration comprising
a) an inner tablet comprising of omeprazole or pharmaceutically acceptable salt thereof along with pharmaceutically acceptable carriers, an inert
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intermediate layer surrounding the core followed by enteric coating over the said intermediate layer and b) outer tablet comprising of granules comprising of acetaminophen, propoxyphene or pharmaceutically acceptable salt thereof, diclofenac or pharmaceutically acceptable salt thereof along with pharmaceutically acceptable carriers.
7. A solid dosage form for oral administration comprising:
a) an inner tablet comprising of omeprazole or pharmaceutically acceptable salt thereof along with pharmaceutically acceptable carriers an inert intermediate layer surrounding the core followed by enteric coating over the said intermediate layer and
b) granules comprising of acetaminophen, propoxyphene or pharmaceutically acceptable salt thereof, diclofenac or pharmaceutically acceptable salt thereof along with pharmaceutically acceptable carriers
wherein the said enteric-coated tablet and said granules are contained within a hard gelatin capsule.
8. A solid dosage form for oral administration comprising:
a) granules comprising of acetaminophen, propoxyphene or pharmaceutically acceptable salt thereof, diclofenac or pharmaceutically acceptable salt thereof along with pharmaceutically acceptable carriers in an immediate release form;
b) pellets comprising of omeprazole or pharmaceutically acceptable salt thereof along with pharmaceutically acceptable carriers in a delayed release form
wherein the said delayed release pellets and said immediate release granules are further compressed into bilayer tablets or filled into capsules.
9. A solid dosage form according to claims 5, 6, 7 and 8, wherein enteric coating
forming polymer is selected from methacrylic acid copolymers such as Eudragit
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L, methyl methacrylate copolymers, ethoxy ethyl methacrylates or cellulose derivatives such as carboxymethyl cellulose, cellulose acetate phthalate, hydroxypropylmethyl cellulose phthalate, shellac and other suitable polymers.
10. A solid dosage form according to claims 5, 6, 7 and 8, wherein intermediate layer forming polymer is selected from a group comprising of one or more of suitable cellulose ethers include one or more of hydroxypropyl methylcellulose, hydroxypropyl cellulose and other suitable cellulose ethers.

Dated this 28th day of June,2006

For Wockhardt Limited

(Mandaw Codgule) Authorized Signatory
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