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:
PHARMACEUTICAL COMPOSITION COMPRISING ACETAMINOPHEN, DEXTROPROPOXYPHENE AND DICLOFENAC
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 a pharmaceutical composition comprising a therapeutically effective amount of acetaminophen, dextropropoxyphene napsylate and diclofenac potassium in a triple combination for the relief or treating moderate to severe painful conditions.
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 a pharmaceutical composition comprising a therapeutically effective amount of acetaminophen, dextropropoxyphene napsylate and diclofenac potassium in a combination for the relief or treating moderate to severe painful conditions.
Acetaminophen, 4'-hydroxyacetanilide, is a non-opiate, non-salicylate analgesic and antipyretic drug. It is a peripherally acting analgesic and is well absorbed orally. It produces analgesia by elevation of the pain threshold and antipyresis through action on the hypothalamic heat-regulating center. Acetaminophen is chemically A/-(4-Hydroxyphenyl)acetamide represented by Formula I. It is commercially available under the trade name of TYLENOL®. Acetaminophen provides temporary relief of minor aches and pains with heartburn or acid indigestion and upset stomach associated with these symptoms.

FORMULA I

Dextropropoxyphene is a centrally acting narcotic analgesic agent. It is a mild narcotic analgesic available as hydrochloride and napsylate salts. Chemically, it is (2S,3R)-(+)-4-(Dimethylamino)-3-methyl-1,2-diphenyl-2-butanol propionate (ester) hydrochloride represented by Formula II. Dextropropoxyphene hydrochloride is commercially available under the trade name of DARVON® and dextropropoxyphene napsylate is DARVON-N. Dextropropoxyphene is indicated for the relief of mild to moderate pain.
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.HCI

FORMULA II
Diclofenac is a nonsteroidal anti-inflammatory drug (NSAID), benzene-acetic acid derivative It exhibits anti-inflammatory, analgesic, and antipyretic but its mechanism of action is not completely understood but may be related to prostaglandin synthetase inhibition. The chemical name of diclofenac is 2-[(2,6-dichlorophenyl)amino] benzeneacetic acid, monosodium salt represented by Formula III. It is commercially available under the trade name of VOLTAREN®. Diclofenac is indicated for relief of signs and symptoms of osteoarthritis, rheumatoid arthritis and ankylosing spondylitis.
COOH

FORMULA III
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Acetaminophen and dextropropoxyphene is a well-known combination used for relief in mild to moderate pain. This combination is commercially available as COPROXOMAL®. Diclofenac is commercially available as VOLTAREN® and is indicated for relief of signs and symptoms of osteoarthritis, rheumatoid arthritis and ankylosing spondylitis. As there is a continuing need for analgesic medications that provide high efficacy pain relief and also reducing the possibility of undesirable effects. The present inventors while working on the analgesic combinations have surprisingly found that when 650 gm of acetaminophen and 100 mg of dextropropoxyphene napsylate is combined with 25 to 100 mg of diclofenac potassium along with pharmaceutical^ acceptable excipients wherein diclofenac potassium may be present as immediate release or extended release component, offers a high efficacy pain relief and can be used for treating moderate to severe pain.
In one of the aspect of present invention, a pharmaceutical composition comprises a combination of 325 mg of acetaminophen and 50 mg of dextropropoxyphene napsylate and 50 mg diclofenac potassium, as active ingredients and pharmaceutically acceptable excipients, wherein the diclofenac potassium is present as immediate release component.
In yet another aspect of present invention, a pharmaceutical composition comprises a combination of 325 mg of acetaminophen and 50 mg of dextropropoxyphene napsylate and 100 mg diclofenac potassium as active ingredients and pharmaceutically acceptable excipients, wherein the diclofenac potassium is present as extended release component.
The pharmaceutical composition comprises of acetaminophen, dextropropoxyphene napsylate and diclofenac potassium wherein acetaminophen and dextropropoxyphene napsylate may be formulated individually or together as immediate release, delayed release, sustained release, controlled release or extended release.
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The pharmaceutical composition comprises of diclofenac potassium formulated as immediate release component. Diclofenac potassium may be granulated along with suitable pharmaceutical^ acceptable intragranular excipients. The granulation may be done by dry granulation or wet granulation. The intragranular pharmaceutical^ acceptable excipient may comprise of binders, fillers, lubricants, glidants and disintegrants. The granules are then mixed with extragranular material like binders, fillers, lubricants, glidants and disintegrants.
The granules of all the three active ingredients are mixed with extragranular material like lubricants, glidants, disintegrants and fillers and then may be formulated as capsule, suspension, sachet, beads, granules, powder, tablet wherein the tablet can be a single tablet, minitablets, tablet in tablet, bilayer tablet or multilayer tablet.
The pharmaceutical composition comprises acetaminophen,
dextropropoxyphene napsylate and diclofenac potassium as extended release wherein extended release diclofenac potassium may be formulated as a matrix or a polymer coated composition.
The matrix may comprise of granules having diclofenac potassium and a rate-controlling polymer prepared by dry granulation or wet granulation using pharmaceutically acceptable excipients. The pharmaceutically acceptable excipient may comprise of binders, fillers, rate controlling polymer, lubricants, glidants and disintegrants.
The granules of acetaminophen, dextropropoxyphene napsylate and extended release diclofenac potassium are mixed with extragranular material like lubricants, glidants, disintegrants and fillers and then formulated as capsule, suspension, sachet, beads, granules, powder, tablet wherein the tablet can be a plain tablet, minitablets, tablet in tablet, bilayer tablet or multilayer tablet.
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Extended release diclofenac potassium may be prepared by coating the core tablet with a rate controlling polymer coating. The core tablet may optionally be given an intermittent seal coat. The seal coat may comprise a binder, solvent, opacifying agent, film-forming polymer, and coloring agent.
The rate-controlling polymer coating material may comprise of a binder, opacifying agent, rate-controlling polymer, and coloring agent.
Diclofenac potassium core tablet may be prepared by compressing the granules comprising Diclofenac potassium and suitable intragranular material like binders, fillers, lubricants, glidants and disintegrants. The granulation may be carried out as dry granulation or wet granulation. The granules are mixed with extragranular material and then compressed to Diclofenac potassium core tablets. These core tablets are then coated with a suitable rate-controlling coating material.
The coated diclofenac potassium tablets and the granules of acetaminophen and dextropropoxyphene napsylate may be formulated as capsule, suspension, sachet, beads, granules, powder, tablet wherein the tablet can be a plain tablet, minitablets, tablet in tablet, bilayer tablet or multilayer tablet.
Suitable binders may be one or more of starch, sugars, gums, low molecular weight hydroxypropylmethyl cellulose, polyvinyl pyrrolidone and hydroxypropyl cellulose and the like.
Suitable fillers may be one or more of lactose, dicalcium phosphate, microcrystalline cellulose, mannitol and the like.
Suitable lubricants may be one or more talc, magnesium stearate, polyethylene glycol, hydrogenated vegetable oils, stearic acid, sodium stearyl fumarate and sodium benzoate and the like.
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Suitable glidants may be one or both of colloidal silicon dioxide and talc or magnesium stearate and the like.
Suitable disintegrant may be one or more of starch, croscarmellose sodium, crospovidone, sodium starch glycolate and the like.
Suitable pharmaceutical^ acceptable polymers to achieve delayed release, sustained release, controlled release or extended release can be hydrophilic or hydrophobic polymers. Hydrophilic polymers can be selected from a group comprising of one or more of cellulose ethers, carbohydrate gum, polyuronic acid salts and mixtures, thereof. Suitable carbohydrate gums include one or more of xanthan gum, tragacanth gum, gum karaya, guar gum, acacia, gellan, locust bean gum and other carbohydrate gums having similar properties. Suitable polyuronic acid salts include one or more of alkali metal salts of alginic acid or pectic acid and mixtures thereof. Suitable cellulose ethers include one or more of methylhydroxypropylcelluloses, hydroxyethylcelluloses, hydroxypropylcelluloses, methylcelluloses, ethylcelluloses, and carboxymethylcelluloses and most particularly selected from the group consisting of methylhydroxypropylcelluloses, hydroxyethylcelluloses, and hydroxypropylcelluloses.
Hydrophobic polymers can be selected from a group comprising of one or more of cellulose ethers, acrylic acid polymers, aliphatic alcohols and natural or synthetic wax or oil. Suitable natural or synthetic wax or oil can be selected from a group comprising of hydrogenated vegetable oil, hydrogenated castor oil, microcrystalline wax, Beeswax, Camauba wax or glyceryl monostearate. Suitable aliphatic alcohols can be selected from a group comprising of stearyl alcohol, cetostearyl alcohol, lauryl alcohol, myristyl alcohol and mixtures, thereof. Suitable acrylic acid polymers include any suitable acrylic acid and methacrylic acid copolymers, methyl methacrylate copolymers, poly(methyl methacrylate) copolymer, polyacrylamide, aminoalkyl methacrylate copolymer, poly(methacrylic acid anhydride), and glycidyl methacrylate copolymers.
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The pharmaceutical composition may be a tablet, capsule, suspension, sachet, beads, granules, powder, wherein the tablet can be a plain tablet, minitablets, tablet in tablet, bilayer tablet or multilayer tablet.
The pharmaceutical composition comprising 325 mg of acetaminophen, 50 mg of dextropropoxyphene napsylate and 50 mg diclofenac potassium wherein diclofenac potassium is immediate release, is provided to achieve better pain management. The triple combination is useful in providing relief for moderate to sever pain related to osteoarthritis, rheumatoid arthritis and ankylosing spondylitis.
The pharmaceutical composition comprising 325 mg of acetaminophen, 50 mg of dextropropoxyphene and 100 mg diclofenac potassium wherein diclofenac potassium is extended release, is provided to achieve better pain management. The triple combination is useful in providing relief for moderate to sever pain related to osteoarthritis, rheumatoid arthritis and ankylosing spondylitis.
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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Example 1

SN Ingredients mg/tab
PART1
Intragranular
1 Propoxyphene Napsylate 50
2 Acetaminophen 325
3 Starch 17.5
4 Sodium Starch Glycolate 5
5 Povidone - K 30 7.5
6 Sodium Lauryl Sulfate 5
Extragranular
7 Sodium Starch Glycolate 2.5
8 Microcrystalline cellulose 11
9 Talc 5
10 Colloidal Silicon Dioxide 4
11 Magnesium stearate 5
PART 2
Intragranular
12 Diclofenac potassium 50
13 Lactose monohydrate 40
14 Dibasis Calcium Phosphate 50
15 Microcrystalline cellulose 84
16 Sodium starch glycolate 7.5
17 Povidone K 30 5
Extragranular
18 Sodium starch glycolate 7.5
19 Magnesium stearate 2
20 Talc 4
Wt. of core tablets 687.5
21 Opadry 13.5
Total wt of coated tablet 701
Procedure: The pharmaceutical composition is prepared in two parts. In the first part, acetaminophen, propoxyphene napsylate along with intragranular excipients i.e starch and sodium starch glycolate is sifted and mixed in rapid mixer
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granulator (RMG). Povidone K-30 and sodium lauryl sulphate are dissolved in purified water and added to the RMG containing acetaminophen and dextropropoxyphene to prepare the granules. The granules are lubricated by adding the sifted extragranular material having sodium starch glycolate, microcrystalline cellulose, talc, colloidal silicon dioxide and magnesium stearate. In the second part of the formulation, diclofenac potassium along with intragranular material i.e Lactose monohydrate, dibasis Calcium Phosphate, microcrystalline cellulose and sodium starch glycolate is sifted and mixed in RMG. Povidone K-30 is dissolved in purified water and added to the RMG containing diclofenac potassium and intragranular material to prepare the granules. The granules are lubricated by adding the sifted extragranular material having Sodium starch glycolate, talc and magnesium stearate.
The lubricated granules of acetaminophen and dextropropoxyphene napsylate and diclofenac potassium are compressed to tablets. The tablets are then coated with aqueous dispersion of Opadry.
Example 2

SN Ingredients mg/tab
PART1
Intragranular
1 Propoxyphene Napsylate 50
2 Acetaminophen 325
3 Starch 17.5
4 Sodium Starch Glycolate 5
5 Povidone - K 30 7.5
6 Sodium Lauryl Sulfate 5
Extragranular
7 Sodium Starch Glycolate 2.5
8 Microcrystalline cellulose 11
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9 Talc 5
10 Colloidal Silicon Dioxide 4
11 Magnesium stearate 5
PART 2
Intragranular
12 Diclofenac Potassium 100
13 Lactose monohydrate 60
14 Microcrystalline cellulose 30
15 Hypromellose [Methocel K 100 LV Premum CR] 75
16 Povidone K 30 4
Extragranular
17 Talc 5
18 Magnesium stearate 1
Procedure: The pharmaceutical composition is prepared in two parts. In the first part, acetaminophen, propoxyphene napsylate along with intragranular excipients i.e starch and sodium starch glycolate is sifted and mixed in rapid mixer granulator (RMG). Povidone K-30 and sodium lauryl sulphate are dissolved in purified water and added to the RMG containing acetaminophen and dextropropoxyphene to prepare the granules. The granules are lubricated by adding the sifted extragranular material having sodium starch glycolate, microcrystalline cellulose, talc, colloidal silicon dioxide and magnesium stearate.
In the second part of the formulation, diclofenac potassium along with intragranular material i.e Lactose, microcrystalline cellulose and hypromellose is sifted and mixed in RMG. Povidone K-30 is dissolved in purified water and added to the RMG containing diclofenac potassium and intragranular material to prepare the granules. The granules are lubricated by adding the sifted extragranular material i.e. talc and magnesium stearate.
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The lubricated granules of acetaminophen and dextropropoxyphene napsylate and diclofenac potassium are compressed to bi-layer tablets. The tablets are then coated with aqueous dispersion of Opadry.
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WE CLAIM:
1. A pharmaceutical composition comprises a combination of 325 mg of acetaminophen and 50 mg of dextropropoxyphene napsylate and 50 mg diclofenac potassium, as active ingredients and pharmaceutically acceptable excipients, wherein the diclofenac potassium is present as immediate release form.
2. A pharmaceutical composition comprises a combination of 325 mg of acetaminophen and 50 mg of dextropropoxyphene napsylate and 100 mg diclofenac potassium as active ingredients and pharmaceutically acceptable excipients, wherein the diclofenac potassium is present as extended release form.
3. The pharmaceutically acceptable excipient as per claim 1 and 2 may comprise of binders, fillers, lubricants, glidants and disintegrants.
4. A pharmaceutical composition as per claim 1 and 2, wherein acetaminophen and dextropropoxyphene napsylate are formulated individually or together as immediate release, delayed release, sustained release, controlled release or extended release.
5. A pharmaceutical composition as per claim 2, wherein diclofenac potassium, extended release is a matrix or rate-controlling polymer coated.
6. The pharmaceutical composition as per claim 1 and 2 wherein diclofenac potassium, acetaminophen and dextropropoxyphene napsylate components are formulated as capsule, suspension, sachet, powder,
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tablet wherein the tablet can be a plain tablet, minitablets, tablet in tablet, bilayer tablet or multilayer tablet.
7. The pharmaceutical composition as per claim 1 and 2 is useful for the relief of moderate to severe pain.

Dated this 23th day of June, 2006

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For Wockhardt Limited
(Mandar Kodgule) Authorized Signatory