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
NOVEL FORMULATION OF NIMESULIDE
2. APPLICANT'S)
(a) NAME; LINCOLN PHARMACEUTICALS LIMITED
(b) NATIONALITY: an Indian Company
(c) ADDRESS: Nirav complex, Opp Navrang High School,
Naranpura, Ahmedabad-380014. Gujarat State, India.
3. PREMABLE TO THE DESCRIPTION
COMPLETE
The following specification particularly describes the invention and the manner in which it is to be performed.

NOVEL FORMULATION OF NIMESULIDE TO PROTECT ITS HEPATOTOXIC NATURE
FILED OF INVENTION:
The present invention relates to a novel formulation of nimesulide in order to protect against its hepatotoxic nature. More particularly, the present invention relates to novel formulation of nimesulide and its dosage forms to protect the liver from the hepatotoxic effect of Nimesulide by using amino acid. BACKGROUND OF INVENTION:
Nimesulide is a Non-steroidal Anti-inflammatory Drug (NSAUD) with Anti-inflammatory, Analgesic and Anti-pyretic actions indicated for osteoarthritis, rheumatoid -arthritis, psoriatic arthritis (US patent 2002016369), chronic inflammatory states of the superior respiratory tract, inflammation of the otolaryngologycal sphere, soft tissues, genital-urinary tract, dysmenorrhea, thrombophlebitis, phlebitis, odontalgial. Nimesulide is administered in various oral dosage forms and also formulated as cream, gels, etc. for topical application,
NSAIDs have been known for there idiosyncratic hepatotoxicity in susceptible patients, though the exact molecular mechanisms underline this toxicity have not yet been fully elucidated. However, experimental evidences suggest that binding of their metabolites with sulphydryl groups with hepatocyts 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 mitochondrial injury.
In case of Nimesulide, a selective cyclo-oxygenase-2 inhibitor is widely used for the treatment of inflammatory and pain conditions, which has been recently associated with rare but serious and unpredictable adverse reactions in the liver (increase in serum aminotransferase activities, hepatocellular necrosis, and/or intrahepatic cholestasis). Similar to other drugs causing idiosyncratic hepatotoxicity, both the molecule and the patient contribute to the hazard. Here, the weakly acidic sulfonanilide drug undergoes bioreductive metabolism of the nitroarene group to reactive intermediates that have been implicated in oxidative stress, covalent binding, and mitochondrial injury (Ref: Drug Saf: 2002;25(9):633-48).
One study of Nimesulide induced hepatitis showed hepatocellular injury with median peak serum alanine aminotransferase 15 times the upper limit of normal (range 4-35), reversing to normal in 2-4 months after discontinuation of the drug. Continuation of the drug

In one patient led to acute hepatic failure with encephalopathy and hepatorenal syndrome (Ref.Isr Med Assoc J.1999 Oct; 1(2):89-91).
Paracetamol is a well known drug used as NSAIDs and its hepatotoxic effects are also proved. In case of potential liver damage, amino acid (methionine) is administered orally for recovery of the liver function (Ref: Martindale Extra Pharmacoepoia, 32nd ed. Page 72).
Methionine is an amino acid, which enhances the synthesis glutathione and prevents hypatic damage. It has been used to protect the hepatotoxic effect of paracetamol (Ref: Martindale Extra Pharmacoepoia, 32nd ed. Page 984).
Oral administration of methionine significantly prevents the rise in tansaminases levels produced by hepatotoxic doses of paracetamol. (Ref: Indian J Exp Biol.2000 No; 38(ll):1138-42)
The administration of a combination of nicotinamide and methionine results in complete protection from acetaminophen induced release of GOT and GPT (Ref: Gen Pharmacol. 1997 Feb; 28(2):257-63).
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 disease, 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 activity. (Ref: 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 increase in plasma aspartate aminotransferase (AST) levels, less leakage of mitochondrial glutamic dehyderogenase into the plasma, and fewer megamitochondria. (Ref: Alcohol. 2002 Jul; 27(3); 173-7).
European Patent No. EP0935964 and JP8143562 disclose novel compositions of NSAIDs like Nimesulide or the derivatives with piperiene for enhancing the bioavailability ofNSAIDs.
Chinese Patent CN1253776 and European EP1005865 presents an invention for composite formed from Nimesulide and its salt with cetirizine. Said composite possesses the actions of resisting leukotrienes, resisting histamine, resisting allergic reaction and resisting inflammation.

European Patent EP1147767 indicates a controlled release formulation in the form of oral dosage for treating inflammatory and pain disorders by administering Nimesulide in combination with hyprohillic matrix forming polymer.
CZ289746, US5756546, EP0714386 and BE1008307 explain water soluble Nimesulide salt and its preparations by combining with L-lysine and L-arginine with cyclodextrin.
US Patent No. US2002156091 explains the analgesic combination of Oxycodone and Nimesulide.
Canadian Patent No. CA2279277, US Patent No. 2002119997, European Patent No. EP0971708 and Brazilian Patent No. BR9807729 disclose the preparation of Nimesulide gel systems comprising of a carboxyvinyle polymer as a gel forming agent or polyacrylamideisoparafiin.
PCT publication No. WO 01/22917 explains the effervescent formulation of Nimesulide with one or more acids and one or more carbonate source. OBJECTS OF INVENTION
Nimesulide is very commonly used NSAID in various clinical disorders and also used in supportive therapy. Hepatotoxic effects of Nimesulide are well known and documented.
It is therefore, a principal object of the present invention to provide a formulation of Nimesulide to prevent its hepatotoxic effect. SUMMARY OF THE INVENTION
The present invention provides a pharmaceutical composition comprising of nimesulide and methionine in a ratio of 1:1 to 4:1 all ratios being in terms of weight respectively, and the balance if any comprising one or more conventional additives.
In one embodiment of the invention, the nimesulide is used as such or in a polymeric form thereof and wherein the methionine is selected from the L isomer, the D isomer or a racemic mixture thereof.
In another embodiment of the invention, the composition is in the form of a tablet, an oral liquid suspension or a capsule.
In another embodiment of the invention, the conventional ingredients are selected from the group consisting of diluents, disintegrants, colorants, flavoring agents, suspending agents, and other conventional additives.
In another embodiment of the invention, the oral liquid suspension form comprises of nimesulide in an amount of 50 mg to 200 mg and methionine in an amount of 25 mg to 100 mg per 5 ml of the dosage.

The present invention also relates to a method for the preparation of a pharmaceutical composition comprising of nimesulide and methionine in a ratio of 1:1 to 4:1 all ratios being in terms of weight respectively, and the balance if any comprising one or more conventional additives, said method comprising subjecting said nimesulide to conventional method of tableting, capsule formation or suspension. These conventional methods comprise several steps for manufacturing tablet, capsule and suspension. These methods are explained in detail description.
Detailed Description of Invention:
Various compounds were studied for their role in preventing hepatotoxic effect of Nimesulide and a novel composition has been invented for preventing the hepatotoxic effect of Nimesulide.
1. Formulation contains Nimesulide with Methionine (L isomer, D isomer or racemic mixture {Racemethionine}) as a hepatoprotector and hepato-revitalizer.
2. Formulation is developed in the form of tablets, capsules and oral liquid suspension.
3. Quality of Racemethionine in the different formulations ranges from 25 mg to 100 mg.
4. Quality of Nimesulide in the different formulations ranges from 50 mg to 200 mg.
Various formulations were prepared of nimesulide along with methionine in the form of tablets, capsules and oral liquid suspensions by conventional methods. Clinical trials were conducted with the formulations and compared to administration of only nimesulide. The trials show that patients treated with the combination of nimesulide and methionine show no changes in levels of SGPT and SGOT or they were within specified limits. However, a rise in SGPT and SGOT levels were observed in patients treated only with nimesulide. In addition, surprisingly, it was observed that patients on a therapy of only nimesulide showed decrease in the levels of SGPT and SGOT when the therapy was shifted to the combination of nimesulide and methionine duet to the revitalizing of the liver by the combination. It is observed that the administration of methionine in

combination with nimesulide actually mitigates the hepatotoxic effect of nimesulide.
Details of the formulations developed are indicated by the following examples:
Tablet:
Example 1:
Sr, No. Ingredient Quantity (nig/Tablef)
01 Nimesulide 100
2 Methionine 50
3 Excipients q.s.
4 Colour & Flavor q.s.
5 Diluent q.s.

Example 2:
Sr. No. Ingredient Quantity fmg/Tablet)
1 Nimesulide 100
2 Methionine 75
3 Excipients qs
4 Color & Flavor qs
5 Diluent qs Example 3:
Sr. No. Ingredient Quantity Cma/Tablet)
1 Nimesulide 200
2 Methionine 50
3 Excipients qs
4 Color & Flavor qs
5 Diluent qs Example 4:
Sr. No.Ingredient Quantity (ma/Tablet)
1 Nimesulide 200
2 Methionine 75
3 Excipients qs
4 Color & Flavor qs
5 Diluent qs Example 5:
Sr. No. Ingredient Quantity (ma/Tablet)
1 Nimesulide 50
2 Methionine 25
3 Excipients qs
4 Color & Flavor qs
5 Diluent qs Example 6:
Sr. No. Ingredient Quantity fmg/Tableri
1 Nimesulide 50
2 Methionine 50
3 Excipients qs
4 Color & Flavor qs

05 Diluent qs
Example 7:
Sr. No. Ingredient Quantity (mg/Tablet)
1 Nimesulide 100
2 Methionine 25
3 Excipients qs
4 Color & Flavor qs
5 Diluent qs Capsule
Example 1:
Sr. No. Ingredient Quantity (mg/Capsule)
1 Nimesulide 100
2 Methionine 50
3 Excipients qs
4 Diluent qs Example 2:
Sr. No. Ingredient Quantity (mg/Capsule)
1 Nimesulide 100
2 Methionine 75
3 Excipients qs
4 Diluent qs Example 3:
SrJVa Ingredient Quantity (mg/Capsule)
1 Nimesulide 200
2 Methionine 50
3 Excipients qs
4 Diluent qs Example 4:
Sr. No. Ingredient Quantity (mg/Capsulel
1 Nimesulide 200
2 Methionine 75
3 Excipients qs 04 Diluent qs

Example 5:
Sr. No. Ingredient Quantity fmg/Capsule)
1 Nimesulide 50
2 Methionine 25
3 Excipients qs
4 Diluent qs Example 6:
Sr. No. Ingredient Quantity fmg/Capsule)
1 Nimesulide 50
2 Methionine 50
3 Excipients qs
4 Diluent qs Example 7:
Sr. No. Ingredient Quantity (mg/Capsule)
1 Nimesulide 100
2 Methionine 25
3 Excipients qs
4 Diluent qs Oral Liquid Suspension
Example 1:
Sr. No. Ingredient Quantity (me/5ml)
1 Nimesulide 100
2 Methionine 50
3 Excipients qs
4 Color & Flavor qs
5 Diluent qs Example 2:
Sr. No. Ingredient Quantity fmg/5ml)
1 Nimesulide 100
2 Methionine 75
3 Excipients qs
4 Color & Flavor qs
5 Diluent qs

Example 3:
Sr. No. Ingredient Quantity (mg/5ml)
1 Nimesulide 200
2 Methionine 50
3 Excipients qs
4 Color & Flavor qs
5 Diluent qs Example 4:
Sr. No. Ingredient Quantity (mg/5ml)
1 Nimesulide 200
2 Methionine 75
3 Excipients qs
4 Color & Flavor qs
5 Diluent qs Example 5:
Sr. No. Ingredient Quantity (mg/5ml)
1 Nimesulide 50
2 Methionine 25
3 Excipients qs
4 Color & Flavor qs
5 Diluent qs Example 6:
Sr. No. Ingredient Quantity (me/5ml)
1 Nimesulide 50
2 Methionine 50
3 Excipients qs
4 Color & Flavor qs
5 Diluent qs Example 7:
Sr. No. Ingredient Quantity (mg/5ml)
1 Nimesulide 100
2 Methionine 25
3 Excipients qs
4 Color & Flavor qs

05 Dilunt qs
It must be understood that what is described hereinbefore is illustrative of the invention and is not intended to limit the scope of the invention in any manner. Variations and modification are possible without departing from the scope and spirit of the invention.
Capsule
Example 8:

No. Item Name Qty Per Capsule
1 Nimesulide( Micronize) 100 mg
2 B etacy clodextri ne 50 mg
3 Racemethionine 50 mg
4 Aerosil 2mg
5 Magnesium Stearate 3mg
6 Imdisole 5mg
Manufacturing Procedure:
1. Pass Ingredients 1 to 6 through 40# sieve and mix for 20 minutes.
2.Fill capsule on capsules filling machine.
Tablet
Example 9:

No. Item Name Qty Per Tablet
1 Nimesulide (Micronize) 100.000 mg
2 Betacyclodextrine 100.000 mg
3 Starch 67.000 mg
4 Gelatin 4.200 mg
5 Starch Paste 17.000 mg
6 Racemethionine 50.000 mg
7 Sod. Methyl Hydroxy Benzoate 0.800 mg

8 Sod. Propyl Hydroxy Benzoate 0.200 mg
9 Isopropyl Alcohol 10.000 mg
10 Polyvinylpyrrolidone(K-3 0) 0.250 mg
11 Aerosil 4.200 mg
12 Magnesium Stearate 4.200 mg
13 Color: Tartrazine Supra 0.642 mg
14 Sodium Starch Glycolate 4.200 mg
15 Microcrystalline cellulose powder 60.000 mg
16 Aspartame 4.200 mg
17 Croscarmellose Sodium 4.200 mg
Manufacturing Procedure:
1. Mix Nimesulide, Betacyclodextrine, Starch and bind with Starch paste, Gelatine, Sodium Methyl, Hydroxy Benzoate and Sodium Propyl Hydroxy Benzoate, dry the granules;
2. Mix Racemethionine, Colour Tartrazine supra, Microcrystalline cellulose powder and Bind with Iso Propyl Alcohol, and Polyvinylpyrrolidone(K-30), Dry granules;
3. Mix Step-1 and Step-2 with magnesium stearate, Aerosil, Sodium Starch Glycolate, Aspartame and Croscarmellose Sodium.
Suspension
Example 10

No. Item Name Qty Per Tablet
1 Nimesulide (Micronize) 50.000 mg
2 Racemethionine 50.000 mg
3 Sodium Methyl Paraben 10.000 mg
4 Sodium Propyl Paraben 2.000 mg
5 Sodium Citrate 2.000 mg

6 Citric Acid (Monohydrate) 1.000 mg
7 Sucrose 3500.000 mg
8 Sorbitol 70% 250.000 mg
9 Glycerin 150.000 mg
10 Aspertame 5.000 mg
11 Aerosil 10.000 mg
12 Tween-80 5.000 mg
13 Color: Tartrazine Supra 0.200 mg
14 Sodium carboxy methyl cellulose 5.000 mg
15 ESS: Orange Liquid 30.000 mg
16 ESS: Vanilla 10.000 mg
Manufacturing Procedure:
1. Take minimum quantity of water, add Tween-80 and heat up to 60 degree C and add Nimesulide, Racemethionine and stirring well till completely dissolve;
2. Take minimum quantity of water and heat up to 80 degree C and add Sucrose, Sorbitol 70%, Glycerin and Citric acid, Maintain temperature 80 degree C with continues stirring till all ingredients are completely dissolved;
3, Lower the temperature to 60 degree C than add Sodium Methyl Paraben, Sodium Propyl Paraben, Sodium Citrate and Sodium carboxy methyl cellulose, stir well;
4. Add slowly step (3) into step (1) with continues stirring, cool down temperature, add aerosol, color and flavour into solution.

We claim:
1. A pharmaceutical composition comprising of nimesulide 50-200 mg and methionine 25-100 mg in a ratio of 1:1 to 4:1 being in terms of weight respectively, and the balance if any comprising one or more conventional additives.
2. A composition as claimed in claim 1 wherein the nimesulide or polymeric form thereof is used and wherein the methionine is selected form the L isomer, the D isomer or a racemic mixture thereof.
3. A composition as claimed in claim 1 wherein the composition is in the form of a tablet, an oral liquid suspension or a capsule.
4. A composition as claimed in any preceding claim wherein the conventional ingredients are selected from the group of consisting of diluents, disintegrants, colorants, flavoring agents, suspending agents and other conventional additives.
5. A composition as claimed in claim 3 wherein the oral liquid suspension form comprises of nimesulide in an amount of 50 mg to 200 mg and methionine in an amount of 25 mg to 100 mg per 5 ml of dosage.
6. A method for preparation of a pharmaceutical capsule composition comprising
(i) passing Nimesulide, Betacyclodextrine, racemethionine, Aerosil, Magnesium Stearate and Imdisole through 40# sieve and mix for 20 minutes;
(ii) filling capsules on capsule filling machine.

7. A method for preparation of a pharmaceutical Tablet composition comprising
(i) mixing Nimesulide, Betacyclodextrine, Starch and bind with Starch paste, Gelatine, Sodium Methyl Hydroxy Benzoate and Sodium Propyl Hydroxy Benzoate, drying the granules;
(ii) mixing Racemethionine, colour tartrazine supra, Microcrystalline cellulose powder and binding with Iso Propyl Alcohol and Polyvinylpyrrolidone(K-30), drying the granules;
(iii) mixing Step (i) and step (ii) with magnesium stearate, Aerosil, Sodium Starch Glycolate., Aspartame and Croscarmellose sodium.
8. A method for preparation of a pharmaceutical Suspension composition comprising (i) taking minimum quantity of water then adding Tween-80 and heating up to 60 degree C, then adding Nimesulide, Racemethionine and stirring well till completely suspended;
(ii) taking minimum quantity of water and heating up to 80 degree C and adding Sucrose, Sorbitol 70%, Glycerin and Citric acid, then maintaining temperature 80 degree C with continues stirring till all ingredients are completely dissolved, lowering the temperature to 60 degree C then adding Sodium Methyl Paraben, Sodium Propyl Paraben, Sodium Citrate and Sodium carboxy methyl cellulose, stirring well;
(iii) adding slowly step (ii) into (i) with continues stirring, cooling down temperature then adding aerosol, colour and flavour into solution.

10. A method for the preparation of a pharmaceutical composition substantially as described herein before and with reference to the foregoing examples.