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:
TRIPLE COMBINATION COMPOSITIONS COMPRISING NON-STEROIDAL ANTIINFLAMMATORY DRUG, ANTIPYRETIC-ANALGESIC DRUG AND PROTON PUMP INHIBITOR
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 compositions in the form of fixed combination comprising of at least one non-steroidal anti-inflammatory drug (NSAID) or one of its single enantiomers or salt thereof, one antipyretic-analgesic drug and one proton pump inhibitor or one of its single enantiomers or salt thereof.
The following specification particularly describes the invention and the manner in which it is to be performed.
The present invention provides pharmaceutical compositions in the form of fixed combination comprising of at least one non-steroidal anti-inflammatory drug (NSAID) or one of its single enantiomers or salt thereof, one antipyretic-analgesic drug and one proton pump inhibitor or one of its single enantiomers or salt thereof.
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
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biosyntheses of the prostaglandins and certain autocoid inhibitors, including inhibitors of lipoxygenase and cyclooxygenase (such as cyclooxygenase-l and cyclooxygenase-ll). Aceclofenac belongs to a group of non-steroidal antiinflammatory drugs (NSAIDs). Aceclofenac is known chemically as 2-[(2,6-dichlorophenyl)amino]benzeneacetic acid, carboxymethyl ester of formula 1. Aceclofenac is used to relieve pain and inflammation in arthritic conditions. It is also indicated for the treatment of a form of arthritis called as ankylosing spondylitis, Inflammatory disease of the joints and Osteoarthritis. 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.
##STR(

FORMULA 1
)##
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. Rabeprazole sodium is one such proton pump inhibitor. Rabeprazole sodium, a substituted benzimidazole inhibits gastric acid secretion. It is known chemically as 2-[[[4-(3-methoxypropoxy)-3-
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methyl-2-pyndinyl]-methyl]sulfinyl]-1W-benzimidazole sodium salt of formula 2. It is indicated for the treatment of Symptomatic Gastroesophageal Reflux Disease (GERD), Pathological Hypersecretory Conditions, including Zollinger-Ellison Syndrome and Maintenance of Healing of Erosive or Ulcerative Gastroesophageal Reflux Disease (GERD).
##STR(

FORMULA 2
)##
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 3. Acetaminophen provides temporary relief of minor aches and pains with heartburn or acid indigestion and upset stomach associated with these symptoms.
##STR(

FORMULA 3
)##
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 NSAID treatment.
US Patent No. 6, 544,556 disclose solid oral dosage form comprising a diclofenac extended release tablet and an enterically coated proton-pump
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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.
US Patent No. 6,926,907 disclose pharmaceutical composition in unit dose form for oral administration comprising an acid inhibitor present in an amount effective to raise the gastric pH to at least 3.5 upon the administration of one or more of said unit dosage forms; and a non-steroidal anti-inflammatory drug (NSAID) in an amount effective to reduce or eliminate pain or inflammation upon administration of one or more of said unit dosage forms.
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.
US Patent Application No. 20050249806 disclose pharmaceutical composition comprising a therapeutically effective amount of at least one acid labile proton pump inhibitor; at least one buffering agent in an amount sufficient to increase gastric fluid pH to a pH that prevents acid degradation of at least some of the proton pump inhibitor in the gastric fluid; and a therapeutically effective amount of at least one nonsteroidal anti-inflammatory drug.
The present invention is now directed to a pharmaceutical compositions that comprises triple combination of at least one non-steroidal anti-inflammatory drug
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(NSAID) or one of its single enantiomers or salt thereof, one antipyretic-analgesic drug, one proton pump inhibitor or one of its single enantiomers or salt thereof, in a single oral pharmaceutical dosage form. 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.
The anti-ulcer drugs of benzimidazole derivatives are very sensitive to light, temperature, moisture and gastric acid secretion hence it has to be delivered in the delayed release form i. e. as enteric-coated tablet. The present invention delivers a very stable benzimidazole derivative.
Proton pump inhibitors are potent inhibitors of gastric acid secretion, inhibiting H+-K+-ATPase, the enzyme involved in the final step of hydrogen ion production in the parietal cells.
Non-steroidal anti-inflammatory drugs (NSAID) are used to treat inflammatory conditions.
Analgesic-antipyretic agents are the drugs that are used to alleviate pain and to reduce fever.
In one of the aspects of the present invention there is provided a tablet in tablet dosage form for oral administration comprising:
a) an inner tablet comprising of inert intermediate layer surrounding the core comprising of therapeutically effective amount of rabeprazole sodium and the inert intermediate layer is further coated with enteric coating and
b) outer core comprising of granules comprising of aceclofenac and paracetamol in a therapeutically effective amount.
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The pharmaceutical compositions containing the rabeprazole sodium, aceclofenac and paracetamol disclosed herein are administered orally. 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.
The dosage form can be prepared by direct compression, dry granulation or by wet granulation. The inner core may be prepared by dry granulation. Rabeprazole sodium, Pearlitol SD 200, light Magnesium oxide, sodium carbonate (anhydrous), L-Hydroxy propyl cellulose (LH-11), crospovidone INF and other ingredients were sifted through mesh no. 40, mixed well and compressed into tablets. The core tablets of rabeprazole were coated with hydroxy propyl cellulose. The coated tablets were then enteric coated with organic dispersion of methacrylic acid copolymer, talc, dimethyl phthalate, titanium dioxide and iron oxide red.
In another aspect of the present invention there is provided a solid dosage form for oral administration comprising:
a) pellets comprising of rabeprazole sodium with an inert intermediate layer surrounding the core followed by enteric coating over the said intermediate layer and
b) granules comprising of aceclofenac and paracetamol in a therapeutically effective amount;
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wherein the said enteric-coated pellets and said granules are further compressed into bilayer tablets.
The enteric-coated tablets may be prepared by direct compression, dry granulation or by wet granulation. Rabeprazole sodium, Pearlitol SD 200, light Magnesium oxide, sodium carbonate (anhydrous), L-Hydroxy propyl cellulose (LH-11), crospovidone INF and other ingredients were sifted through mesh, mixed well and compressed into tablets. The core tablets of rabeprazole were coated with coating solution. These coated tablets were then enteric coated with organic dispersion of methacrylic acid copolymer.
The enteric-coated pellets may be prepared by mixing rabeprazole sodium, colloidal silicon dioxide, and magnesium oxide along with other suitable ingredients, mixed well and compressed to get desired size pellets. These pellets were further coated with coating solution and then enteric coated with organic dispersion of methacrylic acid copolymer.
The granules of aceclofenac and paracetamol may be prepared by dry granulation or by wet granulation. Aceclofenac, paracetamol pre-gelatinized starches were mixed and granulated with suitable binder. These granules were further lubricated.
The tablet in tablet dosage form may be prepared by first compressing the enteric coated granules followed by aceclofenac and paracetamol granules compression.
The layered tablet may be prepared by forming first layer of enteric coated granules followed by layers containing NSAIDs and analgesic-antipyretics.
While the present invention has been described in terms of its specific embodiments, certain modifications and equivalents will be apparent to those
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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. Example 1- Triple combination tablet in tablet
Table 1 - Composition of batches

INGREDIENTS Example (mg/tab)
INNER TABLET
Rabeprazole sodium 100.0
Pearlitol SD 200 39.0
Light Magnesium oxide 2.5
Sodium carbonate (anhydrous) 2.0
L-Hydroxy propyl cellulose (LH-11) 3.0
Glyceryl behenate 0.5
Crospovidone INF 105.0
Sodium metabisulphite 1.0
252.0
SEAL COAT
Organic dispersion of Hydroxy propyl cellulose Till weight gain reaches to 2.5%
ENTERIC COAT
Methacrylic acid copolymer Till weight gain reaches to 10.0%
Talc
Dimethyl phthalate
Titanium dioxide
Iron oxide red
OUTER TABLET
Aceclofenac 100.0
Paracetamol 500.0
Pre-gelatinized starch 20.0
Povidone (PVPK-30) 20.0
Maize Starch 20.0
Sodium starch glycolate 20.0
Microcrystalline cellulose 255.0
Talc 10.0
Magnesium stearate 5.0
950.0

Process for the manufacture of enteric coated Rabeprazole tablet-All the above ingredients listed for inner tablet were sifted through ASTM mesh # 40, mixed well and compressed into tablets. The core tablets of rabeprazole were seal coated with organic dispersion of hydroxy propyl cellulose till weight gain reaches to 2.5%. The seal coated tablets then enteric coated with organic dispersion of methacrylic acid copolymer, talc, dimethyl phthalate, titanium dioxide and iron oxide red till weight gain reaches to 10.0%.
Process for the manufacture of aceclofenac and paracetamol granules-Aceclofenac, paracetamol, pre-gelatinized starch were mixed and granulated with povidone-starch paste. Wet granules were passed through sieve 12 and dried in fluidized bed dryer at 45-50°C for 20 minutes. The dried granules were passed through sieve 20 and mixed with sodium starch glycolate, microcrystalline cellulose, talc and magnesium stearate.
Process for the manufacture of Tablet in tablet -
The enteric-coated rabeprazole tablets along with aceclofenac-paracetamol
lubricated granules were compressed using tablet in tablet machine.
Example 2- Triple combination bilayer tablets.
Procedure for preparation of enteric-coated rabeprazole sodium pellets -The bend of rabeprazole sodium, light magnesium oxide, colloidal silicon dioxide was prepared, sifted through sieve 40 and mixed well to give uniform drug blend. Povidone was dissolved in isopropyl alcohol to give clear binder solution; this binder solution was sprayed on the blend until blend gets sufficient moisture, pellets were prepared and dried. The pellets of rabeprazole sodium were seal coated with solution of hydroxypropylmethyl cellulose (5CPS), magnesium carbonate and triethyl citrate in isopropyl alcohol and methylene chloride (40:60) The seal coated pellets then enteric coated with aqueous dispersion of Eudragit L30D 55, sodium hydroxide, triethyl citrate, talc and titanium dioxide and dried.
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Procedure for preparation of aceclofenac and paracetamol granules-The aceclofenac and paracetamol granules were prepared as described in example 1. The bilayer tablet was compressed in which inner layer was made up of rabeprazole sodium. This bilayer tablet was further coated with organic dispersion of hydroxypropylmethyl cellulose.
The bilayer tablet was compressed in which inner layer was made up of rabeprazole sodium. This bilayer tablet was further coated with organic dispersion of hydroxypropylmethyl cellulose
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WE CLAIM:
1. A tablet in tablet dosage form for oral administration comprising:
a) an inner tablet comprising of inert intermediate layer surrounding the core comprising of therapeutically effective amount of rabeprazole sodium and the inert intermediate layer is further coated with enteric coating and
b) outer core comprising of granules comprising of therapeutically effective amount of aceclofenac and paracetamol.
2. A solid dosage form for oral administration comprising:
a) enteric coated pellets comprising of rabeprazole sodium with an inert intermediate layer surrounding the core followed by enteric coating over the said intermediate layer and
b) granules comprising of aceclofenac and paracetamol in a therapeutically effective amount;
wherein the said enteric-coated pellets and said granules are further compressed into bilayer tablets.
3. A solid dosage form according to claims 1 and 2, 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.
4. A solid dosage form according to claims 1 and 2, wherein enteric coating forming polymer is selected from methacrylic acid/methyl methacrylate copolymers such as Eudragit L or cellulose derivatives such as carboxymethyl cellulose, cellulose acetate phthalate, hydroxypropyl methyl cellulose phthalate and other suitable polymers.
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5. A solid dosage form according to claims 1 and 2, wherein the enteric-coated
rabeprazole is present in the core.
6. A solid dosage form according to claims 1 and 2, the enteric-coated
rabeprazole is present in the therapeutically effective amount to reduce the side
effects associated with aceclofenac and paracetamol.

Dated this28 TH day of April, 2006

For Wockhardt Limited

(Yatendra Kumar) Authorized Signatory

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