Indian Patents. 270372:STABLE ANTI-INFLAMMATORY AND ANALGESIC INJECTABLE FORMULATIONS

Title of Invention	STABLE ANTI-INFLAMMATORY AND ANALGESIC INJECTABLE FORMULATIONS
Abstract	Disclosed herein is a stable aqueous injectable pharmaceutical composition of 75mg of Diclofenac Sodium in I ml solution having viscosity of 0.5 to 1.5 mm2 / sec, wherein said composition is characterized by comprising a single co-solvent/solubilizer in an amount of 20 to 60% and water as principle solvent.

Full Text	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 FORMULATIONS" 2. APPLICANT (S): (a) NAME: NEON LABORATORIES LTD. (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 - 401 404. 3. PREAMBLE TO THE DESCRIPTION: The following specification particularly describes the invention: 21 JUL 2008 Technical field: The present invention is to provide stable anti-inflammatory and analgesic injectable formulations of 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. 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.Diclofenac works by preventing the production of irritant chemicals that cause pain and inflammation in the body. Diclofenac is available in tablet, soluble tablet, suppository and injection form. Diclofenac is an inhibitor of cyclo-oxygenase. It is metabolised in the liver to 4-hydroxydiclofenac and other hydroxylated forms. After glucoronidallon and sulphation, the metabolites are excreted in the urine (65%) and bile (35%). 2 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 C14H10C12NNaO2. There are various commercially available preparations of Diclofenac sodium. Prior art provides various compositions of Diclofenac parenteral preparations. 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. 3 Indian Application No 96/MUM/2005 discloses 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 l00mg 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. 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. Object of the invention: The main object of the present invention is to provide stable anti-inflammatory and analgesic injectable formulations of 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 having strength of 75 mg of Diclofenac Sodium in 1 ml of water. 4 Summary of the invention: The present invention discloses stable anti-inflammatory and analgesic injectable formulations of 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, stabilizers, preservatives and antioxidant along with other pharmaceutically acceptable excipients and process for preparation thereof. The active ingredient Diclofenac is used in the form of its sodium salt and is used at a concentration of 7.5% to 7.625%XF 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 Sodium sulphate or Sodium metabisulphite/Sodium sulphite and are used in the range of 0.330% to 0.355%. 5 Substance X is selected from the group consisting of soluble salt of phosphate buffer such as sodium phosphate, potassium phosphate and calcium phosphate which are used in the different range of percentages in all the formulations given in examples below. Stabilizers: Solvent X belongs to Ether group or Solvent Y is Polyethylene Glycol/Propylene Glycol The stabilizers mentioned hereinabove are used in the range of 20-60%. Alkali hydroxide is used to dissolve and adjust the pH of the composition which is used in the range of 0.15% to 0.25%. 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%. 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 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. The process for preparation of Diclofenac sodium Injection is as follows: Preparation of Water - a. Obtaining a sample from the water for injection source to be used for rinsing and mixing and verify that it meets conductivity limit of NMT 3.0 µS and pH range of 5 to 7. b. Testing the rinse draining from the tank for conductivity and oxidizable substances prior to batch preparation. 6 Solution Preparation - 1. Charging a suitable manufacturing tank with warm & Nitrogen bubbled water for Injection -1ml [Note down the temp of water. It should be about 40°c. Also ensure that the distilled water used for manufacture of the entire batch must be freshly distilled or from continuous circulated loop maintained temperature above 80°c], 2. Sparging the filtered Nitrogen gas in the manufacturing tank throughout the solution preparation, 3. Adding & dissolving in to the manufacturing tank solution a soluble salt of chelating agent, 4. Stopping Nitrogen bubbling & only Maintaining Nitrogen blanket over the solution surface to avoid any loss of S02. Add & dissolve into the Manufacturing tank. Soluble salt of Antioxidant (Stir to dissolve) not to more # agitate otherwise S02 escapes from the Solution. It will result in precipitations in the solution; decrease in pH, yellow colour will develop in the solution due to Oxidation. Get the done Bulk solution for analysis of S02 content. (It should be in between 0.162 % to 0.180 % BULK and should not be less than 0.153% - S02 content in FINISHED). While adding 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, 05. Adding & dissolving into the manufacturing tank solution: Substance X (Soluble salt of Phosphate Buffer) and Solvent Y (Solvent Y is Polyethylene Glycol or Propylene Glycol) — 40% to 60% OR Solvent X (belong to Ether group) —20-30% Check the pH of the solution, 7 6. Checking Benzyl Alcohol suitability by preparing solution of 2 ml Benzyl Alcohol in 60 ml 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 ahead. Taking in a separate container Benzyl Alcohol (Preservative) and Solvent XI Y. Mix it properly and adding Diclofenac Sodium to the above container of step no. 6 under Nitrogen Bubbling. Stirring to get a SLURRY / CLEAR SOLUTION, 7. Adding this SLURRY / CLEAR SOLUTION into step no. 5 and checking the initial pH of the solution which remains TURBID / CLEAR SOLUTION, 8. Take a separate container with water for injection, adding & dissolving to the above container Alkali Hydroxide and making up the volume of solution with cooled Nitrogen bubbled. Water for Injection Adding 3/4 quantity of Alkali Hydroxide solution into step no.5, Stirring & checking the clarity of the solution. OR Taking in separate container water for injection, adding & dissolving to the above container Alkali Hydroxide then make up the volume of solution with cooled Nitrogen bubbled. Water for Injection Adding 3/4 quantity of Alkali Hydroxide solution into step no.5, 9. Adding this SLURRY / CLEAR SOLUTION OF step no. 6 into step no. 5, Stir & check the clarity of the solution & it should be clear solution, 10. Using remaining Alkali Hydroxide solution to adjust the pH of the solution to 8.5±0.05. Stop the stirring and let the solution be stationary. Note down Qty. of Alkali Hydroxide solution used & discarded and 11. Making up the volume of the solution in manufacturing tank with cooled Nitrogen bubbled and water for injection Q.S. to 1ml. Stir the solution for 5 minutes and check the pH. It should be 8.5±0.05. 8 Examples: Formula 1; 1) Diclofenac Sodium (Soluble Salt of Diclofenac) Quantity in % is 7.5% to 7.625% XF 2) Chelating Agent Quantity in % is 0.01% to 0.020% (Disodium EDTA) 3) Antioxidant Quantity in % is 0.330% to 0.355% (Sodium Sulphite /Sodium metabisulphite) 4) Substance X (Soluble Salt of Phosphate Buffer) Quantity in % is 0.6% to 0.7% (Sodium Phosphate/Potassium Phosphate /Calcium Phosphate) 5) Solvent Y (Polyethylene Glycol/Propylene Glycol) —Quantity in % is 40% to 60% 6) Alkali Hydroxide Quantity in % is 0.15% to 0.25% (Sodium Hydroxide) 7) Benzyl Alcohol Preservative Quantity in % is 4.0% to 6.0% 8) Water for injection Q.S to 3ml Diclofenac sodium injection 75mg/ ml 1ML Ampoule Sr. No. Ingredients Quantity in % 1. Diclofenac sodium (soluble salt ofDiclofenac) 7.5% to 7.625% XF 2. Chelating agent 0.01% to 0.020% 3. Antioxidant 0.330% to 0.335% 4. Substance X . Soluble salt of phosphate buffer 0.6% to 0.7% 5. Solvent Y 40% to 60% 6. Alkali Hydroxide 0.15% to 0.25% 7. Benzyl alcohol 4.0% to 6.0% 8. Water for injection qs to 1ml 9 NOTE: Potency of Active ingredient should be adjusted to 100% by applying factor Example: Formula 2: 1) Diclofenac Sodium (Soluble Salt of Diclofenac) Quantity in % is 7.5% to 7.625% XF 2) Chelating Agent Quantity in % is 0.01% to 0.020% (Disodium EDTA) 3) Antioxidant Quantity in % is 0.330% to 0.355% (Sodium Sulphite /Sodium Metabisulphite) 4) Substance X (Soluble Salt of Phosphate Buffer) Quantity in % is 0.6% to 0.7% (Sodium Phosphate/Potassium Phosphate /Calcium Phosphate) 5) Solvent X —Quantity in % is 20% to 30% (Stabilizer) 6) Alkali Hydroxide Quantity in % is 0.15% to 0.25% (Sodium Hydroxide) 7) Benzyl Alcohol Preservative Quantity in % is 4.0% to 6.0% 8) Water for injection Q.S to 1ml Diclofenac sodium injection 75mg/ ml 1ML Ampoule Sr. No. Ingredients Quantity in % 9. Diclofenac sodium (soluble salt of Diclofenac) 7.5% to 7.625% XF 10. Chelating agent 0.01% to 0.020% 11. Antioxidant 0.330% to 0.335% 10 12. Substance X Soluble salt of phosphate buffer 0.6% to 0.7% 13. Solvent X (Stabilizer) 20% to 30% 14. Alkali Hydroxide 0.15% to 0.25% 15. Benzyl alcohol 4.0% to 6.0% 16. Water for injection qs to 1ml NOTE: Potency of Active ingredient should be adjusted to 100% by applying factor 100 100 Dated this 21st day of July, 2008 Dr. Gopakumar G. Nair Agent for the Applicant 11

Full Text

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
FORMULATIONS"
2. APPLICANT (S):

(a) NAME:

NEON LABORATORIES LTD.

(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 - 401 404.
3. PREAMBLE TO THE DESCRIPTION:
The following specification particularly describes the invention:

21 JUL 2008

Technical field:
The present invention is to provide stable anti-inflammatory and analgesic injectable formulations of 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.
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.Diclofenac works by preventing the production of irritant chemicals that cause pain and inflammation in the body. Diclofenac is available in tablet, soluble tablet, suppository and injection form.
Diclofenac is an inhibitor of cyclo-oxygenase. It is metabolised in the liver to 4-hydroxydiclofenac and other hydroxylated forms. After glucoronidallon and sulphation, the metabolites are excreted in the urine (65%) and bile (35%).
2
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 C14H10C12NNaO2.

There are various commercially available preparations of Diclofenac sodium. Prior art provides various compositions of Diclofenac parenteral preparations.
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.

3

Indian Application No 96/MUM/2005 discloses 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 l00mg 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.
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.
Object of the invention:
The main object of the present invention is to provide stable anti-inflammatory and analgesic injectable formulations of 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 having strength of 75 mg of Diclofenac Sodium in 1 ml of water.
4

Summary of the invention:
The present invention discloses stable anti-inflammatory and analgesic injectable formulations of 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, stabilizers, preservatives and antioxidant along with other pharmaceutically acceptable excipients and process for preparation thereof.
The active ingredient Diclofenac is used in the form of its sodium salt and is used at a concentration of 7.5% to 7.625%XF
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 Sodium sulphate or Sodium metabisulphite/Sodium sulphite and are used in the range of 0.330% to 0.355%.
5

Substance X is selected from the group consisting of soluble salt of phosphate buffer such as sodium phosphate, potassium phosphate and calcium phosphate which are used in the different range of percentages in all the formulations given in examples below.
Stabilizers:
Solvent X belongs to Ether group or
Solvent Y is Polyethylene Glycol/Propylene Glycol
The stabilizers mentioned hereinabove are used in the range of 20-60%.
Alkali hydroxide is used to dissolve and adjust the pH of the composition which is used in the range of 0.15% to 0.25%. 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%.
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 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.
The process for preparation of Diclofenac sodium Injection is as follows:
Preparation of Water -
a. Obtaining a sample from the water for injection source to be used for rinsing
and mixing and verify that it meets conductivity limit of NMT 3.0 µS and pH
range of 5 to 7.
b. Testing the rinse draining from the tank for conductivity and oxidizable
substances prior to batch preparation.
6

Solution Preparation -
1. Charging a suitable manufacturing tank with warm & Nitrogen bubbled water for Injection -1ml [Note down the temp of water. It should be about 40°c. Also ensure that the distilled water used for manufacture of the entire batch must be freshly distilled or from continuous circulated loop maintained temperature above 80°c],
2. Sparging the filtered Nitrogen gas in the manufacturing tank throughout the solution preparation,
3. Adding & dissolving in to the manufacturing tank solution a soluble salt of chelating agent,
4. Stopping Nitrogen bubbling & only Maintaining Nitrogen blanket over the
solution surface to avoid any loss of S02. Add & dissolve into the
Manufacturing tank. Soluble salt of Antioxidant (Stir to dissolve) not to more #
agitate otherwise S02 escapes from the Solution. It will result in
precipitations in the solution; decrease in pH, yellow colour will develop in
the solution due to Oxidation. Get the done Bulk solution for analysis of S02
content. (It should be in between 0.162 % to 0.180 % BULK and should not
be less than 0.153% - S02 content in FINISHED). While adding 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,
05. Adding & dissolving into the manufacturing tank solution:
Substance X (Soluble salt of Phosphate Buffer) and
Solvent Y (Solvent Y is Polyethylene Glycol or Propylene Glycol) — 40% to
60%
OR
Solvent X (belong to Ether group) —20-30%
Check the pH of the solution,
7

6. Checking Benzyl Alcohol suitability by preparing solution of 2 ml Benzyl Alcohol in 60 ml 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 ahead. Taking in a separate container Benzyl Alcohol (Preservative) and Solvent XI Y. Mix it properly and adding Diclofenac Sodium to the above container of step no. 6 under Nitrogen Bubbling. Stirring to get a SLURRY / CLEAR SOLUTION,
7. Adding this SLURRY / CLEAR SOLUTION into step no. 5 and checking the initial pH of the solution which remains TURBID / CLEAR SOLUTION,
8. Take a separate container with water for injection, adding & dissolving to the above container Alkali Hydroxide and making up the volume of solution with cooled Nitrogen bubbled.
Water for Injection
Adding 3/4 quantity of Alkali Hydroxide solution into step no.5, Stirring &
checking the clarity of the solution.
OR
Taking in separate container water for injection, adding & dissolving to the above container Alkali Hydroxide then make up the volume of solution with cooled Nitrogen bubbled. Water for Injection Adding 3/4 quantity of Alkali Hydroxide solution into step no.5,
9. Adding this SLURRY / CLEAR SOLUTION OF step no. 6 into step no. 5, Stir & check the clarity of the solution & it should be clear solution,
10. Using remaining Alkali Hydroxide solution to adjust the pH of the solution to 8.5±0.05. Stop the stirring and let the solution be stationary. Note down Qty. of Alkali Hydroxide solution used & discarded and
11. Making up the volume of the solution in manufacturing tank with cooled Nitrogen bubbled and water for injection Q.S. to 1ml. Stir the solution for 5 minutes and check the pH. It should be 8.5±0.05.
8

Examples: Formula 1;
1) Diclofenac Sodium (Soluble Salt of Diclofenac) Quantity in % is 7.5% to 7.625% XF
2) Chelating Agent Quantity in % is 0.01% to 0.020% (Disodium EDTA)
3) Antioxidant Quantity in % is 0.330% to 0.355% (Sodium Sulphite /Sodium metabisulphite)
4) Substance X (Soluble Salt of Phosphate Buffer) Quantity in % is 0.6% to 0.7% (Sodium Phosphate/Potassium Phosphate /Calcium Phosphate)
5) Solvent Y (Polyethylene Glycol/Propylene Glycol) —Quantity in % is 40% to 60%
6) Alkali Hydroxide Quantity in % is 0.15% to 0.25% (Sodium Hydroxide)
7) Benzyl Alcohol Preservative Quantity in % is 4.0% to 6.0%
8) Water for injection Q.S to 3ml
Diclofenac sodium injection 75mg/ ml 1ML Ampoule

Sr. No. Ingredients Quantity in %
1. Diclofenac sodium (soluble salt ofDiclofenac) 7.5% to 7.625% XF
2. Chelating agent 0.01% to 0.020%
3. Antioxidant 0.330% to 0.335%
4. Substance X .
Soluble salt of phosphate buffer 0.6% to 0.7%
5. Solvent Y 40% to 60%
6. Alkali Hydroxide 0.15% to 0.25%
7. Benzyl alcohol 4.0% to 6.0%
8. Water for injection qs to 1ml
9

NOTE: Potency of Active ingredient should be adjusted to 100% by applying factor

Example: Formula 2:
1) Diclofenac Sodium (Soluble Salt of Diclofenac) Quantity in % is 7.5% to 7.625% XF
2) Chelating Agent Quantity in % is 0.01% to 0.020% (Disodium EDTA)
3) Antioxidant Quantity in % is 0.330% to 0.355% (Sodium Sulphite /Sodium Metabisulphite)
4) Substance X (Soluble Salt of Phosphate Buffer) Quantity in % is 0.6% to 0.7% (Sodium Phosphate/Potassium Phosphate /Calcium Phosphate)

5) Solvent X —Quantity in % is 20% to 30% (Stabilizer)
6) Alkali Hydroxide Quantity in % is 0.15% to 0.25% (Sodium Hydroxide)
7) Benzyl Alcohol Preservative Quantity in % is 4.0% to 6.0%
8) Water for injection Q.S to 1ml
Diclofenac sodium injection 75mg/ ml 1ML Ampoule

Sr. No. Ingredients Quantity in %
9. Diclofenac sodium (soluble salt of Diclofenac) 7.5% to 7.625% XF
10. Chelating agent 0.01% to 0.020%
11. Antioxidant 0.330% to 0.335%
10

12. Substance X
Soluble salt of phosphate buffer 0.6% to 0.7%
13. Solvent X (Stabilizer) 20% to 30%
14. Alkali Hydroxide 0.15% to 0.25%
15. Benzyl alcohol 4.0% to 6.0%
16. Water for injection qs to 1ml
NOTE: Potency of Active ingredient should be adjusted to 100% by applying factor
100 100

Dated this 21st day of July, 2008

Dr. Gopakumar G. Nair Agent for the Applicant
11

Documents:

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Patent Number

270372

Indian Patent Application Number

1548/MUM/2008

PG Journal Number

51/2015

Publication Date

18-Dec-2015

Grant Date

16-Dec-2015

Date of Filing

21-Aug-2008

Name of Patentee

NEON LABORATORIES LTD.

Applicant Address

57 & 60 PALGHAR TALUKA IND. CO-OP. ESTATE LTD.,BOISAR ROAD, PALGHAR,

Inventors:

#	Inventor's Name	Inventor's Address
1	TOLAT, JASWANT JAMIETRAM	A/307, SAI RATNAM, CABIN ROAD, BHYANDAR (E), THANE-401 105,

PCT International Classification Number

A61K31/195; A61K31/196; A61K31/724

PCT International Application Number

N/A

PCT International Filing date

PCT Conventions:

#	PCT Application Number	Date of Convention	Priority Country
1			NA