FORM 2THE PATENT ACT 1970(39 of 1970)&The Patents Rules, 2003 COMPLETE SPECIFICATION(See section 10 and rule 13)
1. TITLE OF THE INVENTIONA FORMULATION OF DICLOFENAC TO PROTECT ITS HEPATOTOXIC NATURE
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
PROVISIONALThe following specification describes the invention. 0 COMPLETEThe following specification particularly describes the invention and the manner in which it is to be performed.

The present invention relates to a novel formulation of diclofenac in order to protect against its hepatotoxic nature. More particularly, the present invention relates to a novel formulation of diclofenac and its dosage forms to protect the liver from hepatotoxic effect of diclofenac by using amino acid.
Background of the Invention:
Diclofenac is an anti-inflammatory agent approved for several uses in the United States. It has analgesic, antipyretic and anti-inflammatory activities. It is an inhibitor of cyclooxygenase, and its potency is substantially greater than that of indomethacin, naproxen, or several other agents. In addition, diclofenac appears to reduce intracellular concentrations of free arachidonate in leukocytes, perhaps by altering the release or uptake of the fatty acid.
Diclofenac produces side effects in about 20% of patients, and approximately 2% of patients discontinue therapy as a result. Gestrointestinal effects are the most common; bleeding and ulceration or perforation of the intestinal wall have been observed.
EP0236855 disclosed the novel pharmaceutical preparation is in form of a lyophilisate containing sodium diclofenac and is characterized in that it contains a physiologically acceptable amino acid, a matrix-forming substance and such an amount of a physiologically acceptable base that together with water it gives a solution of a pH of 8 to 10.
W09735568 disclosed an oral drug preparation containing the g-cyclodextrin complex of diclofenac (or pharmaceutically acceptable salts thereof,
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especially sodium salt) prepared by known methods and by which the gastrointestinal irritancy of diclofenac - at the same or improved bioavailability - can be considerably decreased.
In JP56127338 the reaction of Diclofenac with a basis amino acid, e.g. lysine, arginine, histidine etc., in water-containing methanol gives e.g. Diclofenac 1-lysine salt. The distinctive character of this compound is that the side effects such as gastroenteric disorder of the Diclofenac Na salt for oral administration are improved by converting to a suppository preparation.
All above stated patents had disclosed complex process of preparation of diclofenac composition.
Objects of Invention
It is therefore, a principle object of the present invention to provide a formulation of Diclofenac to prevent its hepatotoxic effect.
Other object of the present invention is to provide simple composition to eliminate hepatotoxic effect of diclofenac.
Summary of the Invention
The present invention provides a pharmaceutical composition comprises of diclofenac and methionine in a ratio of 1:1 being in terms of weight respectively, and the balance it any comprising one or more conventional additives.
In one embodiment of the invention, the diclofenac is used as such or in a polymeric form thereof and wherein the methionine is selected from the L isomer, and D isomer or a racerhic mixture thereof.
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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 diclofenac in an amount of 50 to 100 mg and methionine in an amount of 50 mg to 100 mg per 5 ml of the dosage.
The present invention also relates to method for the preparation of a pharmaceutical composition comprising of diclofenac and methionine in a ratio of 1:1 being in terms of weight respectively and the balance if any comprising one or more conventional additives, said method comprising subjecting said declofenac to conventiorial method of tableting, capsule formation or suspension. Detailed Description of Invention:
Various compounds were studied for their role in preventing hepatotoxic effect of Diclofenac and a novel composition has been invented for preventing the hepatotoxic effect of Diclofenac.
1. Formualtion contiains Diclofenac with Methionine (L isomer, D isomer or racemic mixture {Racemethionine}) as hepatoprotector and hepato-revitalizer.
2. Formulation is developed in the form of tablets, capsules and oral liquid suspension.
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3. Quality of Racemethionine in the different formulations ranges from 50 mg to 100 mg.
4. Quality of Diclofenac in the different formulations ranges from 50 mg to 100 mg.
Various formulations were prepared of diclofenac along with mehionine 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 diclofenac. The trials show that patients treated with the combination of diclofenac 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 diclofenac. In addition, surprisingly, it was observed that patients on a therapy of only diclofenac showed decrease in the levels of SGPT and SGOT when the therapy was shifted to the combination of diclofenac and methionine duet to the revitalizing of the liver by the combination. It is observed that the administration of mehionine in combination with diclofenac actually mitigates the hepatotoxic effect of diclofenac.
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.
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Tablet:

Example 1:
No. Ingredient Quantity (mg/Tablet)
1 Diclofenac 100 SR
2. Mehionine 100
3 Excipients q.s.
4 Colour & Flavor q.s.
5 Diluent q.s.

Example 2:
No. Ingredient Quantity (mg/Tablet)
1 Diclofenac 50
2. Mehionine 50
3 Excipients q.s.
4 Colour & Flavor q.s.
5 Diluent q.s.

Example 3:
No. Ingredient Quantity (mg/Tablet)
1 Diclofenac 50 SR
2. Mehionine 50
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3 Excipients q.s.
4 Colour & Flavor q.s.
5 Diluent q.s.

Example 4:
No. Ingredient Quantity (mg/Tablet)
1 Diclofenac 75 SR
2. Mehionine 75
3 Excipients q.s.
4 Colour & Flavor q.s.
5 Diluent q.s.
Capsule

Example 5:
No.. Ingredient Quantity (mg/Tablet)
1 Diclofenac 100 SR
2. Mehionine 100
3 Excipients q.s.
4 Diluent q.s.
Example 6:
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No. Ingredient Quantity (mg/Tablet)
1 Diclofenac 50
2. Mehionine 50
3 Excipients q.s.
4 Diluent q.s.

Example 7:
No. Ingredient n,,ontity (mg/Tablet)
1 Diclofenac 50 SR
2. Mehionine 50
3 Excipients q.s.
4 Diluent q.s.

Example 8:
No. Ingredient Quantity (mg/Tablet)
1 Diclofenac 75 SR
2. Mehionine 75
3 Excipients q.s.
4 Diluent q.s.
Oral Liquid Suspension
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Example 9:
No. Ingredient Quantity (mg/Tablet)
1 Diclofenac 100 SR
2. Mehionine 100
3 Excipients q.s.
4 Colour & Flavor q.s.
5 Diluent q.s.

Example 10:
No. Ingredient Quantity (mg/Tablet)
1 Diclofenac 50
2. Mehionine 50
3 Excipients q.s.
4 Colour & Flavor q.s.
5 Diluent q.s.

Example 11:
No. Ingredient Quantity (mg/Tablet)
1 Diclofenac 50 SR
2. Mehionine 50
3 Excipients q.s..
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4 Colour & Flavor q.s.
5 Diluent q.s.

Example 12:
No. Ingredient Quantity (mg/Tablet)
1 Diclofenac 75 SR
2. Mehionine 75
3 Excipients q.s.
4 Colour & Flavor q.s.
5 Diluent q.s.
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claim:
1. A pharmaceutical composition comprising of diclofenac and methionine in a ratio of 1:1 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 diclofenac is used as such or in a polymeric form thereof and wherein the mehtionine is selected form the L isomer, the D isomer or a racemic mixture thereof.
3. A compostition as claimed in claim 1 wherein the composition is in the form of a tablet, an oral 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 diclofenac in an mount of 50 mg to 100 mg and mehtionine in an amount of 50 mg to 100 mg per 5 ml of dosage.
6. A method for the preparation of a pharmaceutical composition comprising of nimesulide and methionine in a ratio of 1:1 being in terms of weight respectively, and the balance if any comprising one or more conventional additives, said method comprising subjecting said diclofenac to conventional methods of tableting, capsule formation or suspension.
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7. A pharmaceutical composition substantially as described herein before and with reference to the foregoing examples.
8. A method for the preparation of a pharmaceutical composition substantially as described herein before and with reference to the forgoing examples.


Dated this 16l" day of March 2007.

Dr. Rajeshkumar H. Acharya
Advocate & Patent Agent
For & on behalf of the Applicant.

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ABSTRACT
The present invention relates to formulation containing Diclofenac and methionine in which methionine (its isomers and/or racemic mixture) prevents the hepatototic effects of Diclofenac. Methionine also revitalizes the liver in case of hepatotoxicity of Diclofenac. The oral dosage forms containing Methionine and Diclofenac together in various concentrations are developed as tablets, capsules and suspension.