FORM 2
THE PATENT ACT 1970
(39 of 1970)
&
The Patents Rules, 2003
COMPLETE SPECIFICATION
(See section 10 and rule 13)
1. TITLE OF THE INVENTION
A PHARMACEUTICAL FOR THE TREATMENT OF PAIN AND INFLAMMATION CONTAINING NIMESULIDE, MUSCLE RELAXANT AND METHIONINE
2. APPLICANT (S)
(a) NAME: LINCOLN PHARMACEUTICALS LIMITED
(b) NATIONALITY: an Indian Company
(c) ADDRESS: Nirav complex, Opp Navrang High School,
Naranpura, Ahmedabad-3 80014. Gujarat State, India.
3. PREMABLE TO THE DESCRIPTION

PROVISIONAL COMPLETE
The following specification describes The following specification particularly the invention. describes the invention and the manner
in which it is to be performed.

This application is a Patent of Addition of Indian Patent Application No. 591/MUM/2004 filed in India on May 24, 2004, all of which are hereby incorporated herein in their entirety by reference.
The present invention relates to a pharmaceutical composition for treatment of pain and inflammation.
More particularly, the present invention relates to a pharmaceutical composition containing nimesulide, muscular relaxant and methionine for treatment of pain and inflammation. Background of the invention
Painful Inflammatory Conditions of occurs in rheumatoid arthritis, osteo -arthritis, traumatic conditions, post-operative conditions, cervical spondylosis, low back pain, lambago and shoulder peri-arthritis.
A number of drug combinations for alleviating pain or treating other conditions associated with a pain component are known.
US 4,780,463 disclosed pharmaceutical composition of matter for treatment of musculoskeletal disorders in a mammalian organism, comprising an analgesically and anti-inflammatory effective amount of (i) at least one of the propionic acid NSAIDs, ibuprofen, naproxen, benoxaprofen, flurbiprofen, fenoprofen, fenbufen, ketoprofen, indoprofen, pirprofen, carprofen, oxaprozin, pranoprofen, moriprofen, ibuprofen aluminum, tioxaprofen, suprofen, alminoprofen, tiaprofenic acid, fluprofen, bucloxic acid, or pharmaceutically acceptable salt thereof, in combinatory immixture with a skeletal muscle relaxing

amount of (ii) at least one of the SMRs, analexin, baclofen, chlormezanone, cyclobenzaprine, orphenadrine, or pharmaceutically acceptable salt thereof.
US 4,923,898 described pharmaceutical composition of matter for use in the treatment of musculoskeletal disorders in a mammalian organism, comprising an analgesically and anti-inflammatory effective amount of (i) at least one of the propionic acid NSAIDs, ibuprofen, naproxen, benoxaprofen, flurbiprofen, fenoprofen, fenbufen, ketoprofen, indoprofen, pirprofen, carprofen, oxaprozin, pranoprofen, miroprofen, ibuprofen aluminum, tioxaprofen, suprofen, alminoprofen, tiaprofenic acid, fluprofen, bucloxic acid or pharmaceutically acceptable salt thereof, in combinatory immixture with a skeletal muscle relaxing amount of (ii) at least one of the SMRs, zoxazolamine, chlorzoxazone or pharmaceutically acceptable salt thereof.
US5260337 relates to pharmaceutical compositions for use in the treatment of pain and inflammation comprising, (i) an analgesically and anti-inflammatory effective amount of (S)-ibuprofen, or salt thereof, substantially free of (R)-ibuprofen and (ii) an amount effective in treatment of muscle spasm of at least one of the muscle relaxants, or a therapeutically active stereoisomer thereof, substantially free of its other stereoisomers.
So, all the treatments usually consist of an oral ingestion of an analgesic NSAIDs. But not a single invention is able to help to prevent side effect i.e. liver toxicity occurs due to that.
Object of Invention:

The main object of the present invention is to develop a pharmaceutical composition for the treatment of pain and inflammation containing nimesulide, muscle relaxant and methionine in single dosage form.
Another object of the invention is to provide pharmaceutical formulation that gives complete inflammatory Control.
Further object of the invention is to provide synergistic admixture showing improved properties of being administrable in single form and with reduced per diem dosage and not a mere aggregate of the properties of the individual ingredients.
An additional object of the invention is to provide pharmaceutical formulation that is 3 to 4 times more potent than indomethacin, having superior potency than Ibuprofen and better tolerance than Piroxicam and Diclofenac.
An additional object of the invention is to scavenges free oxygen radicals and prevent tissue damage.
An additional object of the invention is to provide pharmaceutical composition in the form of tablet, hard gelatin capsule or oral liquid suspension. Detailed description of the invention:
The present invention provides a novel pharmaceutical composition for the treatment of pain and inflammation containing nimesulide, a muscle relaxant and methionine in a single dose. The composition can be in the form of tablet, capsule or oral liquid suspension. The maximum dose per day of the dosage form is two.

The anti-inflammatory, analgesic and antipyretic activities of Nimesulide, a non-steroidal anti-inflammatory drug (NSAID) of the sulfonanilide class, have been demonstrated in a number of experimental models and in numerous clinical trials. Nimesulide appears to exert its therapeutic effects through a variety of mechanisms viz:
• Selective prostaglandin synthetase inhibition
• Inhibition of superoxide anions from stimulated polymorphs.
• Inhibition of platelet activating factory synthesis.
• Prevention of Bradykinin /Cytokine stimulation of nerves.
• Scavenging of hypochlorus acid.
• Blocking of histamine release
• Prevention of cartilage damage by inhibition of metalo protease synthesis.
Experimental evidences suggest that binding of nimesulde (NSAIDs) metabolites with sulphydryl groups with hepatocytes causes cell damage, increased concentration of the drugs in the hepatobiliary compartment, formation of reactive metabolites that covalently modify proteins and produce oxidative stress, and mitochonondrial injury.
In the present invention 100 to 200 mg of Nimesulide is used.
A muscle relaxant is a drug which decreases the tone of a muscle. This effect may be used to alleviate symptoms such as muscle spasm, pain, hyperreflexia, and gastrointestinal overactivity, such as in irritable bowel

syndrome. In the present invention muscle relaxants are selected from the group of baclofen, carisoprodol, chlorzoxazone, cyclobenzaprine, dantrolene, metaxalone, orphenadrine, pancuronium and tizanidine. In the present invention 250 to 500 mg of muscle relaxant is used. More preferably chlorzoxazone is used as muscle relaxant.
Chlorzoxazone is a centrally - acting agent for painful musculoskeletal conditions. Chlorzoxazone acts primarily at the level of the spinal cord and subcortical areas of the brain where it inhibits multisynapatic reflex arcs 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.
Methionine is metabolized in the liver and converted to S-adenosyl-1-methionine (SAMe). SAMe is a methyl group donor and is an enzyme activator in a number of biochemical reactions. In patients with liver diseases, these pathways are impaired because of the decreased contents of glutathione, the major abnormality being a reduction in SAMe synthetase activity. Exogenous SAMe may overcome the results of impaired SAMe synthetase activities. (Kaohsiung J. Med. Sci. 2001,Sep 17(9); 455-60).
Oral administration of SAMe resulted in its hepatic repletion with a corresponding attenuation of the ethanol-induced oxidative stress and liver injury, with significantly less GSH depletion, less increases in plasma aspartate aminotransferase (AST) levels, less leakage of mitochondrial glutamic

dehydrogenase into the plasma, and fewer megamitochondria. (Alcohol. 2002 Jul; 27(3); 173-7).
The methionine is selected from the L isomer, and D isomer or a racemic mixture thereof. Mehionine is taken in amount of 50 mg.
The invented pharmaceutical composition is prepared in the form of tablet, hard gelatin capsule or oral liquid suspension.
The invention is illustrated more in detail in the following examples. The
examples describe and demonstrate embodiments within the scope of the present
invention. These examples are given solely for the purpose of illustration and are
not to be construed as limitations of the present invention, as many variations
thereof are possible without departing from the spirit and scope.
Tablet:
Example 1:
No. Ingredient Quantity (mg/Tablet)
1 Nimesulide 100
2 Chlorzoxazone 250
3 Mehionine 50
4 Excipients q.s.
5 Colour & Flavor q.s.
6 Diluent q.s.
Example 2:
No. Ingredient Quantity (mg/Tablet)
1 Nimesulide 200 SR

2 Chlorzoxazone
3 Mehionine
4 Excipients
5 Colour & Flavor
6 Diluent

500 100 q.s. q.s. q.s.

Capsule

Example 3:
No. Ingredient Quantity (mg/Tablet)
1 Nimesulide 100
2 Chlorzoxazone 250
3 Mehionine 50
4 Excipients q.s.
5 Diluent q.s.
Example 4:
No. Ingredient Quantity (mg/Tablet)
1 Nimesulide 200 SR
2 Chlorzoxazone 500
3 Mehionine 100
4 Excipients q.s.
5 Diluent q.s.
Oral Liquid Suspension

Example 5: No. Ingredient Quantity (mg/Tablet)
1 Nimesulide 100

2 Chlorzoxazone 250
3 Mehionine 50
4 Excipients q.s.
5 Colour & Flavor q.s.
6 Diluent q.s.
Example 6:
No. Ingredient Quantity (mg/Tablet)
1 Nimesulide 200 SR
2 Chlorzoxazone 500
3 Mehionine 100
4 Excipients q.s.
5 Colour & Flavor q.s.
6 Diluent q.s.
Oral drug absorption is nearly complete and concomitant administration of food may decrease the rate, but not to the extent, of absorption of Nimesulide. The drug is extensively bound (99 per cent) to plasma proteins and has an estimated apparent volume of distribution of 0.19 to 0.33 L/Kg following oral administration. Nimesulide is extensively metabolised (1 to 3 per cent of a dose is excreted unchanged in the urine) to several metabolites which are excreted mainly in the urine. Blood levels of Chlorzoxazone can be detected in people during the first 30 minutes and peak levels reached in about 1 to 2 hours after oral administration of Chlorzoxazone. Chlorzoxazone is rapidly metabolized is excreted in the urine, primarily in a conjugated form as the glucuronidel Less than

one per cent of a dose of chlorzoxazone is excreted unchanged in the urine in 24 hours.
The present invention is strongly indicated in Cervical Spondylosis and Low back pain. Nimesulide is indicated in variety of painful inflammatory conditions, including those associated with Rheumatoid arthritis, other degenerative joint disorders, osteoarthritis, oncology, post operative trauma, sports injuries, bursitis, tendinitis, musculoskeletal disorders, low back pain, dysmencrrhoea, gynaecological conditions, thrombophlebitis, dental pain, and in ENT inflammations. Chlorzoxazone is indicated as an adjunct to rest, physical therapy, to treat injuries and other measures for the relief of discomfort associated with acute painful musculoskeletal conditions.

We Claim:
1. A pharmaceutical composition for the treatment of pain and inflammation comprising 100 mg to 200 mg nimesulide, 250 to 500 mg muscle relaxant, 50 mg methionine, one or more conventional additives and pharmaceutical acceptable excipients.
2. A pharmaceutical composition as claimed in claim 1 wherein muscle relaxants are selected from the group of baclofen, carisoprodol, chlorzoxazone, cyclobenzaprine, dantrolene, metaxalone, orphenadrine, pancuronium and tizanidine.
3. A pharmaceutical composition as claimed in claim 2 wherein muscle relaxant is chlorzoxazone.
4. A pharmaceutical composition as claimed in claim 1 wherein the methionine is selected from the L isomer, and D isomer or a racemic mixture thereof.
5. A pharmaceutical composition substantially as described herein before and with reference to the foregoing examples.

ABSTRACT
The present invention provides a novel pharmaceutical composition for the treatment of pain and inflammation containing nimesulide, a muscle relaxant methionine, one or more conventional additives and pharmaceutical acceptable excipients. The invention is to provide pharmaceutical formulation for treatment of pain and inflammation which does not show hepatotoxicity. A provided pharmaceutical composition is available in the form of tablet, hard gelatin capsule or oral liquid suspension.