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:
MODIFIED RELEASE PHARMACEUTICAL 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 modified release pharmaceutical compositions in the form of fixed combination comprising of at least one non-steroidal antiinflammatory 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 modified release pharmaceutical compositions in the form of fixed combination comprising of at least one non-steroidal antiinflammatory 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(

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-pyridinyl]-methyl]sulfinyl]-1H-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).
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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.
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FORMULA 3
)##
US Patent No. 6,132,768 disclose an oral pharmaceutical reversible-proton-pump-inhibitor composition in which at least part of the reversible-proton-pump inhibitor is in slow-release form and the composition including an effective amount of polymer to control release of at least part of the reversible-proton-pump inhibitor.
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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.
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.
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US Patent No. 6,599,529 disclose an oral pharmaceutical modified release multiple-units composition in unit dosage form for administration of a therapeutically and/or prophylactically effective amount of a non-steroid antiinflammatory drug substance in which first NSAID-containing fraction of multiple-units is for quick release form and second NSAID-containing fraction of multiple-units is for delayed release form.
The present invention is now directed to a modified release pharmaceutical compositions that comprises triple combination of at least one non-steroidal antiinflammatory drug (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.
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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. The term proton pump inhibitors as used herein, includes but not limited to, omeprazole, lansoprazole, rabeprazole, pantoprazole and leminoprazole, including isomers, enantiomers and tautomers thereof, and alkaline salts thereof.
Non-steroidal anti-inflammatory drugs (NSAID) are used to treat inflammatory conditions. The term non-steroidal anti-inflammatory drugs as used herein, includes but not limited to, the group consisting of salicylates, indomethacin, flurbiprofen, diclofenac, ketorolac, naproxen, piroxicam, tebufelone, ibuprofen, etodolac, nabumetone, acedofenac, aminopyrine, phenylbutazone, oxyphenbutazone, fenoprofen, flufenamic acid, ketoprofen, mefenamic acid, phenacetin, sulindac, including isomers, enantiomers and tautomers thereof, and alkaline salts thereof.
Analgesic-antipyretic agents are the drugs that are used to alleviate pain and to reduce fever. The term Analgesic-antipyretic agents as used herein, includes but not limited to, aspirin, acetaminophen, ibuprofen and the like.
In one of the aspects of the present invention there is provided a pharmaceutical
composition comprising of triple combination of rabeprazole sodium, acedofenac
and paracetamol wherein release of rabeprazole from the said composition is
independent of the release of acedofenac and paracetamol characterized by the
fact that,
at least 50% of rabeprazole is released within 15 minutes, or
at least 70% of rabeprazole is released within 30 minutes or
at least 80% of rabeprazole is released within 45 minutes.
when measured using USP type II apparatus and 6.8-pH phosphate buffer as
dissolution medium at 37°C±2°C.
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The dissolution test may be carried out using USP type II apparatus. For determining the release rate of enteric coated rabeprazole 0.1N HCI may be used as dissolution medium for first two hours and further dissolution test is carried out with 6.8-pH phosphate buffer replacing 0.1 N HCI at 37°C±2°C.
In another aspect of the present invention there is provided a pharmaceutical
composition comprising of triple combination of rabeprazole sodium, aceclofenac
and paracetamol wherein release of aceclofenac from the said composition is
independent of the release of rabeprazole and paracetamol characterized by the
fact that,
at least 50% of aceclofenac is released within first 15 minutes, or
at least 70% of aceclofenac is released within first 30 minutes or
at least 80% of aceclofenac is released within first 45 minutes.
when measured using USP type II apparatus and 6.8-pH phosphate buffer as
dissolution medium at 37°C±2°C.
The dissolution test may be carried out using USP type II apparatus and 6.8-pH phosphate buffer as dissolution medium at 370C±2°C.
In yet another aspect of the present invention there is provided a pharmaceutical
composition comprising of triple combination of rabeprazole sodium, aceclofenac
and paracetamol wherein release of aceclofenac from the said composition is
independent of the release of rabeprazole and paracetamol characterized by the
fact that,
at least 50% of paracetamol is released within first 15 minutes, or
at least 70% of paracetamol is released within first 30 minutes or
at least 80% of paracetamol is released within first 45 minutes.
when measured using USP type II apparatus and 6.8-pH phosphate buffer as
dissolution medium at 37°C±2°C.
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The dissolution test may be carried out using USP type II apparatus and 6.8-pH phosphate buffer as dissolution medium at 37°C±2°C. The release rate of aceclofenac is independent of the release of paracetamol.
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.
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EXAMPLES - The composition of batches is provided in table 1.
Example 1- Pharmaceutical composition comprising rabeprazole, aceclofenac
and paracetamol.
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
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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.
The enteric-coated rabeprazole tablets along with aceclofenac-paracetamol lubricated granules were compressed using tablet in tablet machine.
Table 2 and 3 provides the dissolution data for the triple combination dosage form prepared as per the Formula given in Table 1. For determination of drug release rate of aceclofenac and paracetamol, USP Type 2 Apparatus was used wherein 6.8 pH phosphate buffer was used as a dissolution medium and for determination of drug release rate of rabeprazole, USP Type 2 Apparatus was used wherein 0.1 N hydrochloric acid was used as a medium (2 hrs), followed by 1000ml of 6.8 pH phosphate buffer (1 hr).
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Table 2 -Dissolution data of aceclofenac-paracetamol as per the present invention

Time (minutes) % Released of aceclofenac % Released of paracetamol
0 0 0
5 63.72 62.19
10 78.90 72.58
15 88.32 81.46
30 91.13 90.33
45 98.72 97.29
Table 3-Dissolution data of rabeprazole as per the present invention

Time (minutes) % Released of rabeprazole
0.1 N HCI (2 hrs) 0.0
6.8 pH phosphate buffer
0 0.00
5 63.02
10 73.57
15 81.64
30 89.42
45 95.38
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WE CLAIM:
1. A pharmaceutical composition comprising of triple combination of rabeprazole
sodium, aceclofenac and paracetamol wherein release of rabeprazole from the
said composition is independent of the release of aceclofenac and paracetamol
characterized by the fact that,
at least 50% of rabeprazole is released within 15 minutes, or
at least 70% of rabeprazole is released within 30 minutes or
at least 80% of rabeprazole is released within 45 minutes.
when measured using USP type II apparatus and 6.8-pH phosphate buffer as
dissolution medium at 37°C±2°C.
2. A pharmaceutical composition according to claim 1, wherein rabeprazole sodium is in enteric coated form.
3. A pharmaceutical composition according to claim 1, wherein release of enteric coated rabeprazole sodium is less than 5% when measured using USP type II apparatus in 0.1 N HCI for first two hours.

5. A pharmaceutical composition according to claim 1, wherein about 81% of rabeprazole is released within first 15 minutes.
6. A pharmaceutical composition comprising of triple combination of rabeprazole sodium, aceclofenac and paracetamol wherein release of aceclofenac from the said composition is independent of the release of rabeprazole and paracetamol characterized by the fact that,
at least 50% of aceclofenac is released within first 15 minutes, or
at least 70% of aceclofenac is released within first 30 minutes or
at least 80% of aceclofenac is released within first 45 minutes.
when measured using USP type II apparatus and 6.8-pH phosphate buffer as
dissolution medium at 37°C±2°C.
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7. A pharmaceutical composition comprising of triple combination of rabeprazole
sodium, aceclofenac and paracetamol wherein release of aceclofenac from the
said composition is independent of the release of rabeprazole and paracetamol
characterized by the fact that,
at least 50% of paracetamol is released within first 15 minutes, or
at least 70% of paracetamol is released within first 30 minutes or
at least 80% of paracetamol is released within first 45 minutes.
when measured using USP type II apparatus and 6.8-pH phosphate buffer as
dissolution medium at 37°C±2°C.
8. A pharmaceutical composition according to claims 1, 6 and 7 further
comprising pharmaceutically acceptable excipients.
«
9. A pharmaceutical composition according to claim 8, in form of tablet, capsule,
pellet or powder for oral administration.


Dated this28TH.day of April, 2006
For Wockhardt Limited

(Yatendra Kumar) Authorized Signatory

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