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 A COMBINATION OF ACETAMINOPHEN, CODEINE AND CHLORZOXAZONE
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 comprising a triple combination of acetaminophen, codeine and chlorzoxazone for providing relief in moderate to sever pain in musculoskeletal 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 pharmaceutical composition comprising a triple combination of acetaminophen, codeine and chlorzoxazone for providing relief in moderate to sever pain in musculoskeletal 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 N-(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.

Codeine is a centrally active analgesic. It is chemically (5α, 6α)-7,8-Didehydro-4,5-epoxy-3-methoxy-17-methylmorphinan-6-ol (Formula II). Codeine is available in two salt forms; one is codeine sulfate and other is codeine phosphate. It is indicated for the relief of mild to moderate pain. Both the salts of codeine are commercially available and are indicated for the relief of mild to moderate pain.
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Chlorzoxazone is a centrally acting agent for painful musculoskeletal conditions. It acts primarily at the level of the spinal cord and subcortical areas of the brain where it inhibits multisynaptic reflex a.c. involved in producing and maintaining skeletal muscle spasm of varied etiology. The clinical result is a reduction of the skeletal muscle spasm with relief of pain and increased mobility of the involved muscles. Chemically, it is 5-Chloro-2(3H)-benzoxazolone represented by Formula III. It is commercially available under the trade name of PARAFLEX®. Chlorzoxazone is indicated as an adjunct to rest, physical therapy, and other measures for the relief of discomfort associated with acute painful musculoskeletal conditions.

Acetaminophen and Codeine is a well-known combination used for relief in mild to moderate pain. This combination is commercially available as CODRIX®. Chlorzoxazone is commercially available as PARAFLEX® and is indicated as an
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adjunct to rest, physical therapy, and other measures for the relief of discomfort
associated with acute painful musculoskeletal conditions.
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 300 mg of acetaminophen and 250 mg of chlorzoxazone is combined
with 30 mg of codeine phosphate
wherein codeine phosphate is present as extended release component.
This triple combination offers a high efficacy pain relief and can be used for
treating moderate to severe pain associated with musculoskeletal conditions.
In one of the aspect of present invention, a pharmaceutical composition comprises a combination of 300 mg of acetaminophen, 250 mg of chlorzoxazone and 30 mg of codeine phosphate,
wherein codeine phosphate is present as extended release component along with suitable pharmaceutically acceptable excipient.
In yet another aspect of present invention, a pharmaceutical composition comprises a combination of 300 mg of acetaminophen, 250 mg of chlorzoxazone and 60 mg of codeine phosphate,
wherein codeine phosphate is present as extended release component along with suitable pharmaceutically acceptable excipient.
The pharmaceutical composition comprises of acetaminophen, chlorzoxazone and codeine phosphate wherein acetaminophen and chlorzoxazone may be formulated in parts or together as immediate release, extended release, delayed release, controlled release or sustained release component.
Extended release codeine phosphate may be formulated as a matrix or a polymer coated composition.
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The matrix may comprise of granules having codeine phosphate 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, chlorzoxazone and extended release codeine phosphate 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.
Extended release codeine phosphate 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.
Codeine phosphate core tablet may be prepared by compressing the granules comprising codeine phosphate 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 codeine phosphate core tablets. These core tablets are then coated with a suitable rate-controlling coating material.
The coated codeine phosphate tablets and the granules of acetaminophen and chlorzoxazone 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.
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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.
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 pharmaceutically acceptable polymers to achieve delayed release,
sustained release, controlled release or extended release can be hydrophilic or
hydrophobic polymers or a combination thereof. 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
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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, Carnauba 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, aminoalkyi methacrylate copolymer, poly(methacrylic acid anhydride), and glycidyl methacrylate copolymers.
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 300 mg of acetaminophen, 250 mg chlorzoxazone and 30 mg codeine phosphate as extended release, is useful for the relief of discomfort and moderate to severe pain associated with painful musculoskeletal conditions.
The pharmaceutical composition comprising 300 mg of acetaminophen, 250 mg chlorzoxazone and 60 mg codeine phosphate in extended release form, is useful for the relief of discomfort and moderate to severe pain associated with painful musculoskeletal conditions.
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

SN Ingredients Example 1 mg/tab Example 2 mg/tab
PART1
Intragranular
1 Chlorzoxazone 250 250
2 Acetaminophen 300 300
3 Lactose Monohydrate 115 115
4 Starch 35 35
5 Sodium Starch Glycolate 10 10
6 Povidone - K 30 15 15
Extragranular
7 Sodium Starch Glycolate 5 5
8 Microcrystalline cellulose 50 50
9 Talc 10 10
10 Colloidal Silicon Dioxide 8 8
11 Magnesium stearate 10 10
PART 2
12 Codeine Phosphate 30 60
13 Lactose Monohydrate (Pharmatose DCL11) 25 50
14 Avicel PH 102 20 40
15 Methocel K 1OO LVCR 35 70
16 Talc 1.5 3
17 Magnesium stearate 1 2
Procedure: The pharmaceutical composition is prepared in two parts. In the first part, acetaminophen and chlorzoxazone along with intragranular excipients i.e lactose, starch and sodium starch glycolate is sifted and mixed in rapid mixer granulator (RMG). Povidone K-30 is dissolved in purified water and added to the
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RMG containing acetaminophen and chlorzoxazone to prepare the granules. The granules are dried and 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, codeine phosphate along with intragranular material i.e Lactose monohydrate, Avicel and Methocel is sifted and mixed in non-shear blender. Talc and magnesium stearate are sifted and added to the blender. This blend and lubricated granules of acetaminophen and chlorzoxazone are compressed to bi-layered 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 300 mg of
acetaminophen, 250 mg of chlorzoxazone and 30 mg of codeine
phosphate,
wherein codeine phosphate is present as extended release component along with suitable pharmaceutically acceptable excipient.
2. A pharmaceutical composition comprises a combination of 300 mg of
acetaminophen, 250 mg of chlorzoxazone and 60 mg of codeine
phosphate,
wherein codeine phosphate is present as extended release component along with suitable pharmaceutically acceptable excipient.
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, acetaminophen and chlorzoxazone is formulated as immediate release, delayed release, sustained release, controlled release or extended release.
5. A pharmaceutical composition as per claim 1 and 2, extended release codeine phosphate is formulated as matrix or a coated component.
6. A pharmaceutical composition as per claim 1 and 2, wherein the extended release codeine phosphate is granules, pellets, minitablets, beads comprising codeine phosphate and a rate controlling polymer.
7. A pharmaceutical composition as per claim 1 and 2, wherein the extended release codeine phosphate is rate controlling polymer coated granules, pellets, minitablets, and beads of codeine phosphate.
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8. A pharmaceutical composition as per claim 1 and 2, wherein extended release codeine phosphate is formulated with acetaminophen, chlorzoxazone and pharmaceutical^ acceptable excipients into tablet, capsule, suspension, sachet, beads, granules, powder, wherein the tablet can be a plain tablet, effervescent tablet, minitablets, tablet in tablet, bilayer tablet or multilayer tablet.
9. The pharmaceutical composition as per claims 1 and 2 for treatment of moderate to severe pain.
Dated this 28TH day of June, 2006
For Wockhardt Limited

(Mandar Kodgule) Authorized Signatory

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