FORM 2
THE PATENT ACT 1970
(39 of 1970)
&
The Patents Rules, 2003
PROVISIONAL SPECIFICATION
(See section 10 and rule 13)
1. TITLE OF THE INVENTION:
"Stable anti-inflammatory and analgesic injectable compositions"
2. APPLICANT (S)
(a) NAME: Neon Laboratories Limited.
(b) NATIONALITY: an Indian Company incorporated under the
Indian Companies ACT, 1956
(c) ADDRESS: 57& 60 Palghar Taluka Ind. Co-Op. Estate Ltd. Boisar Road,
Palghar - 401404, Maharashtra, India
3. PREAMBLE TO THE DESCRIPTION
The following specification particularly describes the invention.

Technical field of the invention:
The present invention relates to stable pharmaceutical compositions for parenteral administration comprising Diclofenac sodium as the active ingredient and a chelating agent, buffer and antioxidant along with other pharmaceutical ly acceptable excipients used for the treatment of analgesia and inflammation. The present invention further relates to a stable aqueous injectable formulation free of propylene glycol.
Background and prior art:
Diclofenac sodium is a NSAID (non-steriodal anti-inflammatory drug) used to treat the inflammation and pain of musculoskeletal complaints arthritis osteoarthritis, rheumatoid arthritis, and ankylosing spondylitis and juvenile forms of arthritis and to treat mild to moderate post-operative or post-traumatic pain, particular when inflammation is also present, and is also effective against menstrual pain.
Chemically Diclofenac sodium of formula I is 2-[(2, 6-dichlorophenyl) amino] benzeneacetic acid, monosodium salt. The molecular weight is 318.14 and the molecular formula is CnH1oCl2NnaC2.
^ ,CH2COONa


a

Formula I
There are various commercially available preparations of Diclofenac sodium. Prior art provides various compositions of Diclofenac parenteral preparations.
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US5554650 discloses an antiphlogistic, analgesic, antipyretic parenteral preparation comprising diclofenac, its salt, or both, as effective components. This parenteral preparation provides sustained release of the drug, along with substantial reduction of side effects upon and after administration.
US4711906 discloses a stable, liquid diclofenac preparation, for the parenteral application, consisting of a solution of diclofenac or one of its salts in an amount of 1.5-6.0 weight % diclofenac in a solvent, wherein the solvent consists of 10-70 weight % of a mixture of propylene glycol and polyethylene glycol and 30-90 weight % water, and the weight ratio of propylene glycol to polyethylene glycol is between 9.5:0.5 and 0.5:9.5.
EP1609481 discloses an injectable pharmaceutical composition in the form of an aqueous solution, comprising sodium diclofenac at a concentration greater than 25 mg/ml of water and a beta-cyclodextrin, wherein said composition comprises at least a polysorbate in an amount ranging between 0.01 and 0.06% by weight with respect to the total volume of the solution.
US20040068007 discloses a group of novel pharmaceutically acceptable salts, each containing local anesthetic and anti-inflammatory activities. The preferred pharmaceutical acceptable salt in this group is diclofenac salt of lidocaine. The pharmaceutically acceptable salts are particularly suitable for use in topical treatment or parenteral injection to treat patients with localized pain, including, but not limited to, muscle pain, joint pain, pain associated with herpes infection, and/or wound pain (such as surgical pain or burn pain). Methods for making the pharmaceutically acceptable salts are also disclosed.
Diclofenac injections are formulated conventionally using propylene glycol as solvent. But the commercially available Diclofenac injections have several disadvantages like it produces pain and irritation at the site of injection. Due to these drawbacks the Diclofenac injections made using propylene glycol provides less patient compliance.
Therefore in view of the disadvantages associated with prior art compositions a need arises for safe, convenient and stable Diclofenac compositions which can overcome the disadvantages of the prior art.
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Object of the invention:
The main object of the present invention is to provide stable pharmaceutical compositions for parenteral administration comprising Diclofenac sodium as the active ingredient and a chelating agent, buffer and antioxidant along with other pharmaceutically acceptable excipients and the process of preparation thereof.
Another object of the present invention is to provide stable, aqueous pharmaceutical injectable formulation free from propylene glycol thereby free from the drawbacks of pain and irritation at the site of injection.
Summary of the invention:
The present invention discloses stable, aqueous pharmaceutical composition for parenteral administration comprising Diclofenac sodium as the active ingredient and a chelating agent, buffer and antioxidant along with other pharmaceutically acceptable excipients used for the treatment of analgesia and inflammation. The present invention further discloses the process of preparation of the said composition using chelating agent for the stabilization of the parenteral preparation.
Detailed description of the invention:
The present invention describes stable, aqueous pharmaceutical compositions for parenteral administration comprising Diclofenac sodium as the active ingredient and a chelating agent, buffer and antioxidant along with other pharmaceutically acceptable excipients.
The stable parenteral composition as per the present invention is free from propylene glycol and is stabilized using a chelating agent. The active ingredient Diclofenac is used in the form of its sodium salt and is used at a concentration of 2.5% to 2.625%.
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Antioxidant and soluble salt of phosphate buffer are used to stabilize the composition and are used in variable ranges accordingly. Chelating agent is incorporated in the injectable formulation in variable proportions to eliminate excess particulate matter.
Pharmaceutically acceptable excipients used are selected from the group consisting of antioxidants, stabilizers, chelating agent, buffers, preservatives and the like. As per the present invention the antioxidants used for formulation of the Diclofenac sodium are selected from the group consisting of soluble salt of bisulphate or sulphite and are used in the range of 0.330% to 0.355%.
Stabilizer substance x or y or xy are selected from the group consisting of soluble salt of phosphate buffer and are used in the different range of percentages in all the formulations given in examples below.
Alkali hydroxide is used to dissolve and adjust the pH of the composition. Preservatives used are selected from the group consisting of Benzyl alcohol and the like are used in the range of 4.0 % to 6.0%.
Pharmaceutically acceptable excipients are incorporated along with Diclofenac sodium in the formulation of the parenteral preparation. The Pharmaceutically acceptable excipients used are selected from the group consisting of antioxidants, stabilizers, buffers, preservatives and the like.
The present investigation is more specifically explained by following examples. However, it should be understood that that the scope of the present invention is not limited by the examples in any manner. It will be appreciated by any person skilled in this art that the present investigation includes the following examples and further can be modified and altered within the technical concept of the present investigation.
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EXAMPLES
Example 1:
Diclofenac sodium injection 75mg/3ml

Sr. No. Ingredients Quantity in %
1. Diclofenac sodium (soluble salt of Diclofenac) 2.5% to 2.625
2. Chelating agent 0.1% to 0.020%
3. Antioxidant 0.330% to 0.335%
4. Soluble salt of phosphate buffer(X) 0.6% to 0.7%
5. Alkali Hydroxide 0.15% to 0.25%
6. Benzyl alcohol 4.0% to 6.0%
7. Water for injection qs to 1 ml
Example 2:
Diclofenac sodium injection 75mg/3ml

Sr. No. Ingredients Quantity in %
1. Diclofenac sodium (soluble salt of Diclofenac) 2.5% to 2.625
2. Chelating agent 0.1% to 0.020%
3. Antioxidant 0.330% to 0.335%
4. Soluble salt of phosphate buffer (X) 0.34%
5. Soluble salt of phosphate buffer (Y) 0.416%
6. Alkali Hydroxide 0.15% to 0.25%
7. Benzyl alcohol 4.0% to 6.0%
8. Water for injection Qs to 1ml
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Example 3:
Diclofenac sodium injection 75mg/3ml

Sr. No. Ingredients Quantity in %
1. Diclofenac sodium (soluble salt of Diclofenac) 2.5% to 2.625
2. Chelating agent 0.1% to 0.020%
3. Antioxidant 0.330% to 0.335%
4. Soluble salt of phosphate buffer 0.8% to 0.85%
5. Alkali Hydroxide 0.15% to 0.25%
6. Benzyl alcohol 4.0% to 6.0%
7. Water for injection qs to 1 ml
Note: Potency of active ingredient should be adjusted to 100 % by applying factor.
F = 100 X 100 X 1
Assay on dried basis 100 - LOD
Example 4:
Process for manufacturing:
Preparation of water is as follows:
a. Collect sample from the water for injection source to be used for rinsing and
mixing and verify that it meets conductivity limit of NMT 3.0uS and pH range of
5 to 7.
b. Test the rinse draining from the tank for conductivity and oxidizable substances
prior to batch preparation.
Solution Preparation is given as follows:
01. Charge a suitable manufacturing tank with warm and nitrogen bubbled water for injection. [The temperature of water should be about 40°C. Also ensure that the distilled water used for manufacturing of the entire batch must be freshly
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distilled or from continuous circulated loop maintained temperature above 80°C].
2. Sparge the filtered nitrogen gas in the manufacturing tank throughout the solution preparation.
3. Add & dissolve into the manufacturing tank solution, the soluble salt of chelating agent.
4. Stop Nitrogen bubbling & only maintain Nitrogen blanket over the solution surface to avoid any loss of SO2..
5. Add & dissolve into the manufacturing tank, soluble salt of Antioxidant and stir to dissolve (Note: Do not agitate more otherwise SO2 escapes from the solution resulting in precipitations in the solution, decrease in pH, yellow colour development in the solution due to oxidation). Perform the bulk solution analysis for SO2 content, it should be in between 0.180% to 0.162% in the bulk solution and in finished solution should not be less than 0.153% - SO2 content. While addition of antioxidant, potency should be adjusted to 100%. Antioxidant should be selected in such a way that it should be stable according to pH of the Diclofenac Injection.
6. Add & dissolve into the manufacturing tank solution, substance X OR Y OR XY comprising a soluble salt of Phosphate Buffer. Check the pH of the solution.
7. Check Benzyl Alcohol Suitability:
Prepare solution of 2ml benzyl alcohol in 60ml water for injection by mixing thoroughly, wait for 5 minutes. If this solution is clear and not turbid and if there are no oil globules on the surface of this solution, proceed with the next step. In a separate container take benzyl alcohol (preservative) add to the above solution under nitrogen bubbling diclofenac sodium. Stir to get slurry.
8. Add this slurry into step no. 06. Check the initial pH of the solution, which remains a turbid solution.
9. In a separate container take water for injection. Add and dissolve to the above container alkali hydroxide. Make up the volume of solution with cooled nitrogen bubbled water for injection. Add 3/4th quantity of alkali hydroxide solution into step no. 06, stir and check the clarity of the solution.
Or
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In a separate container take water for injection. Add and dissolve to the above container alkali hydroxide and make up the volume of solution with cooled nitrogen bubbled water for injection. Add 3/4th quantity of alkali hydroxide solution step no.06.
10. Add this slurry of step no.07 into step no.06. Stir and check the clarity of the solution and it should be clear solution.
11. Remaining alkali hydroxide solution can be used to adjust the pH of the solution to 8.4±0.05. Stop the stirring and let the solution be stationary. Note down quantity of alkali hydroxide solution used and discarded.
12. Make up the volume of the solution in manufacturing tank with cooled nitrogen bubbled water for injection (qs). Stir the solution for 5 minutes and check the pH, it should be 8.4±0.05. Perform bulk analysis of the bulk sample. (Bulk: The bulk material should be stored in a well-closed container. Protected from light, in a cool dry place)
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 invention may be embodied in other specific forms without departing from the essential attributes thereof, and it is therefore 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 changes which come within the meaning and range of equivalency of the claims are therefore intended to be embraced therein.
Dated this 05th day of December 2006
Dr. Gopakumar G. Nair Agent for the Applicant
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