FORM 2
THE PATENTS ACT, 1970
(39 of 1970)
&
PATENTS RULES, 2003
(COMPLETE SPECIFICATION)
TITLE OF INVENTION - "High concentration Diclofenac sodium composition for the treatment of pain/'
NAME OF APPLICANT - LINCOLN PHARMACEUTICALS LIMITED
ADDRESS OF APPLICANT -
LINCOLN PHARMACEUTICALS LIMITED
B/h. Satyam Complex, Lincoln House,
Science City Road, Sola,
Ahmedabad - 380062, Gujarat, India.
PREAMBLE OF INVENTION - The following specification particularly describes the nature of the invention and the manner in which it is to be performed.

FIELD OF THE INVENTION
The present invention generally relates to pharmaceutical compositions comprising high concentration of Diclofenac sodium as an active ingredient with other pharmaceutical ingredients for the treatment of pain.
BACKGROUND OF THE INVENTION
Diclofenac is a non-steroidal anti-inflammatory drug (NSAID) taken to reduce inflammation and as an analgesic reducing pain in certain conditions. The name is derived from its chemical name: 2-(2,6-dichloranilino) phenylacetic acid. Normally it is supplied as either sodium or potassium salt.

Diclofenac Sodium is soluble in water and freely soluble in methanol, sparingly soluble in water, soluble in alcohol, slightly soluble in acetone. Water solubility of Diclofenac is 50mg/mL( Sodium salt).
The exact mechanism of action is not entirely known, but it is thought that the primary mechanism responsible for its anti-inflammatory, antipyretic, and analgesic action is inhibition of prostaglandin synthesis by inhibition of cyclooxygenase (COX). It also appears to exhibit bacteriostatic activity by inhibiting bacterial DNA synthesis.
Diclofenac for systemic use is available as tablets (25/50/100 mg), capsule (100 mg), eye drop (0.1% w/v), transdarmal gel, and injectable solution (25 and 75 mg/ml). Diclofenac Injection available in market contains in each ml Diclofenac sodium 25/75 mg.

Some existing inventions are following-
In US 2008/0153914 disclosed that Injectable preparations of viscosity ranging from about 1.50 to 4.7 CPS and pH of ~8-9, containing 75 mg/ml of diclofenac sodium or its therapeutically equivalent amounts of water-soluble salts of diclofenac, comprising, cosolvents /solubilisers such as a monohydric alcohol 4% to 25% % v/v, or a polyhydric alcohol ~27% to 45% v/v, or tetrahydrofurfuryl alcohol propylene glycol ether (glycofurol) "18% to 35% v/v, in combination with water,
In CN101244278 wherein The invention provides an injection formulation of diclofenac sodium for intravenous injection and the preparation method, which is characterized in that the diclofenac sodium is included successfully with the inclusion material of propyl-Betacyclodextrin. The injection formulation has the advantages of improving the solubility of diclofenac sodium in the solution and reducing the adverse reaction in intravenous injection. The injection formulation exists in the form of injection, frozen powder, sterile powder and large-capacity infusion. The invention also describes the main technical parameters of adopting propyl- Beta -cyclodextrin to include the diclofenac sodium, such as inclusion method, the concentration of propyl- Beta-cyclodextrin, solution temperature in inclusion and inclusion time.
In United States Patent Application 20080153914 wherein The present invention provides injectable formulations of water-soluble salts of diclofenac in single doses of less than 2 ml, which cause significantly less pain at the site of injection and can be administered by intradeltoid route, in addition to intragluteal and slow intravenous route. More specifically the injectable preparations contain 75 mg to 100 mg of water-soluble salts of diclofenac, in about 1 ml injection solution without significantly raising the viscosity of the injection solution without the use surfactants. The formulations are adjusted to pH 6 to 10 containing up to 100 mg of diclofenac salt in a medium comprising of water, along with one or more co-solvent(s)/solubiliser(s), antioxidants, preservatives, buffers, alkali and stabilizers.
IN2011DE00295 wherein Diclofenac is a non-steroidal anti inflammatory drug (NSAED) taken to reduce inflammation and as an analgesic reducing pain in conditions such as arthritis or acute injury. It is a phenylacetic acid derivative. The name is derived from its chemical name: 2- (2,6-dichloranilino)phenyl acetic acid.

Disclosed is a formulation of injectable dosage form of diclofenac sodium in a low volume and without any irritating substance which may cause pain during administration. The major advantages are (a) presenting the diclofenac sodium injection in small volume i.e. 1 ml and without any irritating substance, thus it is very convenient for practitioners to administer the injection to the patient with reduced pain due to low volume and absence of irritating substance, (b) Since the formulation is in small volume and it can be administered in deltoid muscle besides gluteal muscle, and (c) viscosity of the formulation is comparatively very low. Preservatives are used to preserve the preparation. The other excipients are chelating agent and antioxidant agent. The active ingredient is diclofenac sodium salt which is well accepted and is a phenyl acetic acid derivative. The solubilizers used in the formulation are mixture of polyethylene glycol (300 or 400) and benzyl alcohol. The preservative used in the formulation is benzyl alcohol. EP15 74221A1 wherein This invention relates to a stable parenteral aqueous solutions comprising either (a) diclofenac or a pharmaceutically acceptable diclofenac salt and a cyclodextrin, or (b) an inclusion complex of diclofenac or a pharmaceutically acceptable diclofenac salt and a cyclodextrin, or a mixture of (a) and (b), which are suitable for intramuscular and intravenous administration. The solutions contain diclofenac or diclofenac salt, cyclodextrin, and an antioxidant selected from monothioglycerol, or a combination of ethylene diamine tetra-acetic acid and N- acetyl-cysteine.
However there is no pharmaceutical composition that causes less pain to the patient, is less viscous, and reduces the side effects at the site of administration yet providing high concentration of the drug which contributes to the ease of administration.
SUMMARY OF THE INVENTION
In accordance with the object of the invention, the present invention discloses a pharmaceutical formulation which is less viscous (0.5 cps to 4.0 cps) contains high concentration of Diclofenac sodium (75mg per 1 ml) in less volume of solvent, cause less pain to the patient, useful for effective treatment of bacterial infections.
The pharmaceutical formulation of the instant invention further comprises pharmaceutically acceptable excipients such as Solubilizing agent, stabilizing agent as well as buffering agent, anti microbial agent and pH adjusting agents.

In an aspect, the pharmaceutical formulation of the invention can be in a form of medication selected from intravenous injectable forms or sprays; preferably I.V. injection.
The formulation of the present invention contains the therapeutically active amount of sodium salt of Diclofenac.
The pharmaceutical composition is useful for the treatment of pain.
In another aspect, the present invention provides a method for the preparation of said pharmaceutical formulation.

DETAILED DESCRIPTION OF THE INVENTION
The foregoing and other aspects of the present invention will now be described in more detail with respect to the description and methodologies provided herein. It should be appreciated that the invention can be embodied in different forms and should not be construed as limited to the embodiments set forth herein. Rather, these embodiments are provided so that this disclosure will be thorough and complete, and will fully convey the scope of the invention to those skilled in the art.
All patents, patent applications and publications referred to herein are incorporated by reference in their entirety. In case of a conflict in terminology, the present specification is controlling.
The invention is described in various embodiments below. The described embodiments of the invention and the disclosed examples are given for the purpose of illustration rather than limitation of the invention.
The present invention relates to a novel pharmaceutical formulation which is less viscous, contains high concentration of Diclofenac sodium in less volume of solvent, cause less pain to the patient, useful for effective treatment of bacterial infections.
In an embodiment, the pharmaceutical formulation of the invention can be in a form of medication is selected from intravenous injectable forms i.e preferably I.V. injection which leads to direct availability of drug to systemic circulation which provides faster onset of action compared to other forms of known administration such as tablets, syrups, capsules or suspensions.
The lower viscosity of the composition of present invention helps in faster diffusion of the drug from the site of action and also contributes to ease of administration resulting in lesser pain at the site of administration. Moreover, high concentration of the drug in less volume of solvent reduces the time of administration and enhances the effectiveness of the drug for the treatment of pain.

The pharmaceutically acceptable excipients are selected from Solubilizing agent, stabilizing agent, anti microbial agent, antioxidant and pH adjusting agents.
According to proffered embodiment, contains Solubilizing agent wherein it is selected from cyclodextrin, beta-cyclodextrin, alpha-cyclodextrin and like in amount of 10.0 % w/v to 50.00 %
w/v.
According to proffered embodiment, contains stabilizing agent wherein it is selected from alpha-amino acid, beta-amino acid, gama- amino acid like Arginine, Aspartic acid, Glutamine, Glycin and Lysine in the concentration of 0.001 % w/v 1.0 % w/v.
According to proffered embodiment, contains antimicrobial agent is selected from sodium sulfite, benzyl alcohol, methy paraben, propyl paraben in the concentration of 0.01 % w/v 1.0 %
w/v.
According to proffered embodiment, contains antioxidant is selected from sodium sulfite, ascorbic acid, butyletd hydroxytoluene in the concentration of 0.01 % w/v 1.0 % w/v.
According to proffered embodiment, contains pH adjusters include hydrochloric acid, glacial acetic acid, and amino acid in the concentration of 0.001 % w/v 1.0 % w/v to and it was adjusted between 2.0 to 8.0.
It is a less viscous solution and maintained at a viscosity in the range of 0.5 cps to 5.0 cps
The pharmaceutical composition is useful for the treatment of pain.
The maximum dose of 75 mg per 1 ml use in children and adults is 150 mg per day.
In another embodiment, the present invention provides a method for preparation of said pharmaceutical formulation. Accordingly, the process of preparation comprises;
1. Dissolving Solubilizing agent in 0.5 ml of water for injection;
2. Adding antimicrobial agent and antioxidant to step (1) solution under continuous stirring and dissolving using a mechanical sifter;
3. Adding Diclofenac sodium in to step (2) solution under continuous stirring and dissolving Diclofenac sodium using a mechanical sifter;

4. Adding stabilizing agent in to step (3) solution continuous stirring and dissolving using a mechanical sifter;
5. Maintaining the pH using buffering agent; checking the clarity and
6. Making the final volume by adding water for injection followed by filtering.
The present investigation is more specifically explained by following examples. However, it will be evident to those skilled in the art that the invention is not limited to the details of the foregoing illustrative examples and that the present may be embodied in other specific forms without departing from the essential attributes thereof, and it is thereof desired that the present embodiments and examples be considered in all respects as illustrative and not restrictive, reference being made to the appended claims rather than to the foregoing description, and all charges which come within the meaning and range of equivalency of the claims are therefore intended to be embraced therein.
The following examples are for the purpose of illustration of the invention only and are not intended in any way to limit the scope of the invention.
Examples Example 1:

SR.NO INGREDIENTS LABEL CLAIM
(Quantity/ml)
1 Diclofenac sodium 75 mg
2 Hydroxypropyl betacyclodextrine 300 mg
3 Sodium sulfite 3mg
4 Glycin lmg
5 Water for injection Q.S. to 1 ml

Example 2:

SR.NO INGREDIENTS LABEL CLAIM (Quantity/ mi)
1 Diclofenac sodium 75 mg
2 Hydroxypropyl betacyclodextrine 500 mg
3 Methyl paraben 3mg
4 Butyletd hydroxy toluene 4mg
5 Lysine 5mg
6 Hydrochloric acid (35% v/v) 3 ml
7 Water for injection Q.S. to 1 ml
Example 3:

SR.NO INGREDIENTS LABEL CLAIM
(Quantity/50 ml)
1 Diclofenac sodium 75 mg
2 Hydroxypropyl betacyclodextrine 600 mg
3 Methyl paraben 3mg
4 Butyletd hydroxy toluene 4mg
5 Hydrochloric acid (35% v/v) 10 ml
6 Water for injection Q.S. to 1 ml

The pharmaceutical formulation of the present invention consisting of higher concentration of Diclofenac sodium as active ingredient while being useful for the effective treatment of pain relief also has the following advantages;
1. Being less viscous reduces phlebitis, swelling, erythema at site of injection and causes less pain;
2. Reduces the time of administration; and
3. I.V infusion leads to direct availability of the drug to systemic circulation thereby providing faster onset of action, also is well suited for challenging patient who is unable to take orally.

CLAIMS,
I claim,
1. An efficient intravenous injectable formulation as claimed in claim 1, the process of
preparation comprises;
(a) Dissolving Solubilizing agent in 0.5 ml of water for injection;
(b) Adding antimicrobial agent and antioxidant to step (a) solution under continuous stirring and dissolving using a mechanical sifter;
(c) Adding Diclofenac sodium in to step (b) solution under continuous stirring and dissolving Diclofenac sodium using a mechanical sifter;
(d) Adding stabilizing agent in to step (c) solution continuous stirring and dissolving using a mechanical sifter;
(e) Maintaining the pH using buffering agent; checking the clarity and
(f) Making the final volume by adding water for injection followed by filtering.

2. An efficient intravenous injectable formulation as claimed in claim 1, wherein high concentration Diclofenac sodium as an active ingredient, pharmaceutically acceptable excipients are selected from Solubilizing agent, stabilizing agent, anti microbial agent, antioxidant and pH adjusting agents.
3. An efficient intravenous injectable formulation as claimed in claim 1, comprises of Solubilizing agent wherein it is selected from cyclodextrin, beta-cyclodextrin, alpha-cyclodextrin and like in amount of 10.0 % w/v to 50.00 % w/v.
4. An efficient intravenous injectable formulation as claimed in claim 1, comprises of stabilizing agent wherein it is selected from alpha-amino acid, beta-amino acid, gama-amino acid like Arginine, Aspartic acid, Glutamine, Glycin and Lysine in the concentration of 0.001 % w/v 1.0 % w/v.

5. An efficient intravenous injectable formulation as claimed in claim 1, comprises of anti microbial agent is selected from sodium sulfite, benzyl alcohol, methy paraben, propyl paraben in the concentration of 0.01 % w/v 1.0 % w/v.
6. An efficient intravenous injectable formulation as claimed in claim 1, comprises of antioxidant is selected from sodium sulfite, ascorbic acid, butyletd hydroxytoluene in the concentration of 0.01 % w/v 1.0 % w/v.
7. An efficient intravenous injectable formulation as claimed in claim 1, comprises of pH adjusting agents include hydrochloric acid, glacial acetic acid, and amino acid in the concentration of 0.001 % w/v 1.0 % w/v to and it was adjusted between 2.0 to 8.0.
8 An efficient intravenous injectable formulation as claimed in claim 1, the major advantages of the invention is that being less viscous reduces phlebitis, swelling, erythema at site of injection and causes less pain; Reduces the time of administration; and I.V infusion leads to direct availability of the drug to systemic circulation thereby providing faster onset of action, also is well suited for challenging patient who is unable to take orally.