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:
USE OF ACETAMINOPHEN, CODEINE AND CHLORZOXAZONE IN MODERATE TO SEVERE PAIN ASSOCIATED WITH MUSCULOSKELETAL CONDITIONS.
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 method of treating moderate to severe pain associated with musculoskeletal conditions, wherein the method comprise of administering to a patient in need thereof, a therapeutically effective amount of acetaminophen, codeine and chlorzoxazone in a triple combination.
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 method of treating moderate to severe pain associated with acute painful musculoskeletal conditions, wherein the method comprise of administering to a patient in need thereof, a therapeutically effective amount of acetaminophen, codeine and chlorzoxazone in a triple combination.
Acetaminophen or 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.

Codeine is a centrally active analgesic. It is chemically (5a, 6a)-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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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

adjunct to rest, physical therapy, and other measures for the relief of discomfort associated with acute painful musculoskeletal conditions. 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 250 mg-1.4 gm of acetaminophen and 10-100 mg of codeine is combined with 250-500 mg of chlorzoxazone along with pharmaceutically acceptable excipients 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 method of treating discomfort and mild to severe pain wherein the method comprise of administering to a patient in need thereof, a pharmaceutical composition comprising a combination of acetaminophen or a pharmaceutically acceptable salt or derivative thereof and codeine or a pharmaceutically acceptable salt or derivative thereof, and chlorzoxazone or a pharmaceutically acceptable salt or derivative thereof, as active ingredients and pharmaceutically acceptable excipients.
Acetaminophen or a pharmaceutically acceptable salt or derivative thereof can be present from 250 to 1000 mg. The codeine or a pharmaceutically acceptable salt or derivative thereof can be present from 10 to 100 mg. Chlorzoxazone or a pharmaceutically acceptable salt or derivative thereof is chlorzoxazone and is present from 250 to 500 mg.
The pharmaceutical composition comprises of acetaminophen, codeine and chlorzoxazone, which may be formulated in parts or together as immediate release, delayed release, sustained release, controlled release or extended release.
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The pharmaceutical composition may be formulated as a matrix or a polymer coated composition. The matrix may comprise of granules, beads, pellets, tablet having the active ingredients and pharmaceutically acceptable excipients.
The granulation may be carried out by dry granulation or wet granulation using pharmaceutically acceptable excipients wherein the pharmaceutically acceptable excipient may comprise of binders, fillers, rate controlling polymer, lubricants, glidants and disintegrants. The granules of acetaminophen, codeine and chlorzoxazone are mixed with extra-granular 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.
The coated composition may be prepared by coating the core tablets, pellets, granules, beads or minitablet comprising active ingredients with a suitable coating material wherein the coating material comprise of polymer and pharmaceutically acceptable excipients. The coated granules, tablet, pellets, beads or minitablets of acetaminophen, dextropropoxyphene and chlorzoxazone may be formulated as capsule, suspension, sachet, 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.
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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. 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, 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,
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methyl methacrylate copolymers, poly(methyl methacrylate) copolymer, polyacrylamide, aminoalkyl 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 combination of acetaminophen, codeine and chlorzoxazone is useful in better pain management of acute painful musculoskeletal conditions. Elimination half-life of all the active ingredients of the triple combination i.e. acetaminophen, codeine and chlorzoxazone is about 1 to 4 hours after oral administration. Thus, the proposed combination of these drugs provides immediate relief in moderate to sever acute painful conditions associated with musculoskeletal system.
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.
Example 1

SN Ingredients mg/tab
Intragranular
1 Chlorzoxazone 250
2 Acetaminophen 300
3 Codeine Phosphate 10
4 Lactose Monohydrate 115
5 Starch 35
6 Sodium Starch Glycolate 10
7 Povidone - K 30 15
Extragranular
8 Sodium Starch Glycolate 5
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9 Microcrystalline cellulose 50
10 Talc 10
11 Colloidal Silicon Dioxide 8
12 Magnesium stearate 10
Procedure: Chlorzoxazone, acetaminophen and codeine phosphate along with intragranular excipients i.e lactose, starch and sodium starch glycolate are sifted and mixed in rapid mixer granulator (RMG). Povidone K-30 is dissolved in purified water and added to the RMG to prepare the granules. The granules are dried and then lubricated by adding the sifted extragranular material i.e. sodium starch glycolate, microcrystalline cellulose, talc, colloidal silicon dioxide and magnesium stearate. The lubricated granules are compressed to tablets. The tablets are then coated with aqueous dispersion of Opadry.
Example 2

SN Ingredients mg/tab
PART1
Intragranular
1 Chlorzoxazone 250
2 Acetaminophen 300
3 Lactose Monohydrate 115
4 Starch 35
5 Sodium Starch Glycolate 10
6 Povidone - K 30 15
Extragranular
7 Sodium Starch Glycolate 5
8 Microcrystalline cellulose 50
9 Talc 10
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10 Collodial Silicon Dioxide 8
11 Magnesium stearate 10
PART 2
12 Codeine Phosphate 60
13 Lactose Monohydrate (Pharmatose DCL 11) 50
14 Avicel PH 102 40
15 Methocel K 100 LVCR 70
16 Talc 3
17 Magnesium stearate 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 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 method of treating discomfort and mild to severe pain wherein the method comprise of administering to a patient in need thereof, a pharmaceutical composition comprising a combination of acetaminophen or a pharmaceutically acceptable salt or derivative thereof and codeine or a pharmaceutically acceptable salt or derivative thereof, and chlorzoxazone or a pharmaceutically acceptable salt or derivative thereof, as active ingredients and pharmaceutically acceptable excipients.
2. The pharmaceutically acceptable excipient as per claim 1 and 2 may comprise of binders, fillers, lubricants, glidants and disintegrants.
3. As per claim 1, acetaminophen or a pharmaceutically acceptable salt or derivative thereof is acetaminophen.
4. As per claim 2, acetaminophen is present from 250 mg to 1.4 g.
5. As per claim 1, codeine or a pharmaceutically acceptable salt or derivative thereof is codeine sulphate.
6. As per claim 1, codeine or a pharmaceutically acceptable salt or derivative thereof is codeine phosphate.
7. As per claim 4, codeine or a pharmaceutically acceptable salt or derivative thereof is present from 10 mg to 100 mg.
8. As per claim 1, chlorzoxazone or a pharmaceutically acceptable salt or derivative thereof is chlorzoxazone.
9. As per claim 6, chlorzoxazone is present from 250 mg to 500 mg.
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10.As per claim 1 the pharmaceutical composition is capsule, suspension, sachet, powder, tablet wherein the tablet can be a plain tablet, minitablets, tablet in tablet, bilayer tablet or multilayer tablet.

Dated this28th June, 2006

For Wockhardt Limited
tULV
(Manda^Kodgule) Authorized Signatory
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