FORM 2
THE PATENTS ACT, 1970
(39 of 1970)
&
THE PATENTS RULES, 2003
Provisional Specification [See Sections 10 and rule 13]
TITLE: Injectable formulations and process for preparation thereof
Applicant: (a) Intas Pharmaceutical Limited
(b) Nationality: Indian
(c) Chinubhai Centre, Ashram Road Ahmedabad-380009 Gujarat. India.
The following specification describes the invention:

FIELD OF THE INVENTION
The present invention relates to stable injectable formulation of non steroidal antiinflammatory drug(s) or analgesic. The dosage form comprises anti-inflammatory or analgesic drug preferably aceclofenac or its pharmaceutically acceptable salts or additives, pharmaceutically acceptable solvent and optionally other pharmaceutical excepients. This can be multi dose. The present invention also relates to a process of preparing aceclofenac injectable formulation.
BACKGROUND AND PRIOR ART
Non-steroidal anti-inflammatory or analgesic drugs like aceclofenac and diclofenac are known to be used for chronic joint diseases, like rheumatoid arthritis, osteoarthrosis and ankylosing spendylitis, spondilytis as well as for detnalgia, postoperation pain or post-delivery pain. These are having superior prostaglandin inhibition effect compared to other anti-inflammatory analgesic drugs.
Non-steroidal anti-inflammatory or analgesic drugs particularly inhibits the production of interleukin-1 causing the destruction of joint cartilage and promotes the production of glycosaminoglycan found in joint cartilage, thus preventing rheumatoid arthritis, osteoarthrosis and the like from being worse.
WO2005032516 disclosed method for solubilizing aceclofenac using a self-microemulsifying drug delivery system dissolving aceclofenac in a mixed solvent of a hydrophilic solubilizing agent, a surfactant, a stabilizer and oil. The emulsified liquid is filled into the capsule.
WO2003004060 discloses the compressed formulation comprising active pharmaceutical ingredient aceclofenac with water insoluble polymer.
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Parenteral drug formulations have become a very important component in the arsenal of available drug delivery options, particularly for drugs having analgesic effect. Parenteral routes of administration like intramuscular, subcutaneous and intravenous injection, gives very good benefits over oral delivery. On parenteral administration of a drug the attainment of a therapeutically effective blood serum concentration of the drug is in a shorter time than is by oral dosage form and the drug bypass any protein biding or first pass metabolism. Hence the dose of drug is reduced in case of parentaral dosage form. Also it is helpful in case of emergency where fast onset of action is required, unconscious and non-cooperative patient for oral dose.
For the parentaral dosage lyophilized and ready to use formulations are available. Lyophilization is an expensive manufacturing process.
WO 2006054135 discloses the ready to use injectable formulation comprising aceclofenac salt with solubilizer and stabilizer. The stabilizer used in this patent is to stabilize aceclofenac and diclofenac that forms by conversion of aceclofenac thereto and also aceclofenac stabilizer used which is effective to inhibit precipitation of aceclofenac free acid.
Aceclofenac injection is available in ready to use single dose in which conversation to diclofenac is fast and to a great extent. Multi dose parentaral formulation is preferred but there is always chance of microbial contamination after first dosing. Our formulation if prepared in multi dose is stable and devoid of microbial contamination. The conversation into diclofenac is also well controlled below 10%,.preferably 5% or les.
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For beneficial effect of the drug, use of minimum exceipents and to overcome the single and expensive dose, in the present invention a ready to use stable inejctable formulation of aceclofenac is prepared.
OBJECTS OF THE INVENTION
The first object of the present invention is to provide stable inejctable formulation of aceclofenac in ready to use form.
Another object of the present invention is to provide stable multi dose inejctable formulation of aceclofenac in ready to use form.
Further object of the present invention is to provide stable inejctable formulation of aceclofenac in ready to use multi dose form which is stable and devoid of microbial contamination after first dosing.
Still another object of the present invention is to formulate aceclofenca dosage form, which is cost effective and avoids tedious and expensive technology like lyophilization.
Yet another object of the present invention is to develop a process to prepare stable injectable formulation of aceclofenac in ready to use form which can be single dose or multi dose.
SUMMARY OF THE INVENTION
The present invention relates to stable injectable formulation of non-steroidal antiinflammatory or analgesic drugs or analgesic drug preferably aceclofenac in ready to use dosage form. The dosage form comprises active pharmaceutical ingredient
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(drug), solvent and optionally other pharmaceutical excipients. The present invention also relates to a process of preparing aceclofenac injectable formulation in ready to use dosage form.
This invention also relates to stable multi dose inejctable formulation of aceclofenac in ready to use form and process for preparation thereof.
DESCRIPTION OF INVENTION
According to the present invention stable ready to use injectable formulation of anti-inflammatory or analgesic drug preferably aceclofenac comprises drug preferably aceclofenac, pharmaceutically acceptable solvent and optionally other pharmaceutically acceptable excipients. This can be used as multi dose.
'Multi dose' herein defined as dosage form intended to be administered on more than one occasion. This multi dose is stable and remains uncontaminated from micro organisms for prolonged duration. This multi dose can be 5 ml volume or more.
The anti-inflammatory or analgesic drug preferably aceclofenac present in this pharmaceutically composition is in amounts ranging from 10 mg to 500 mg/ml.
The pharmaceutically acceptable solvent used in this pharmaceutically composition is in amounts maximum up to 1 ml and preservative optionally used as 0.01-2.5 ml. w/v
Anti-oxidant used in the present invention is in amount ranging from 0.01 - 0.5
w/v.
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The pharmaceutically acceptable solvent suitable for injection used in the present invention selected from the group comprising but not limited to N-Methyl Pyrrolidone (Pharmasolv, Polyethylene glycols, Ethanol and the like or combination thereof.
Antioxidant prevents oxidation of API and contribute towards the chemical stability of the formulation. Anti-oxidants used in the pharmaceutical preparation of the present invention selected from the group, but are not limited to, butylated hydroxytoluene (BHT), butylated hydroxyanisole (BHA), sodium bisulfite, a-tocorpherol, vitamin C,P-carotin, ascorbylpamitate, tocopherol acetate, fumaric acid, nalic acid, butylated hydroxyanisole, propyl gallate, sodium ascorbate and the like.
Inert gas like nitrogen used to fill headspace of vial and for spurging into the solution to prevent oxidation of the active ingredient in the formulation.
Optionally preservative used to prevent microbial contamination and make the formulation stable for longer duration. The preservative can be benzyl alcohol and the like.
Throughout this specification it is to be understood that the words "comprise" and "include" and variations such as "comprises", "comprising", "includes", "including" are to be interpreted inclusively, unless the context requires otherwise. That is, the use of these words may imply the inclusion of an element or elements not specifically recited.
Example
The present invention has been described by way of example only, and it is to be recognized that modifications thereto falling within the scope and spirit of this specification, and which would be obvious to a person skilled in the art based
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upon the disclosure herein, are also considered to be included within the scope of this invention.
The formulation of the present invention is ready to use injectable can be illustrated as follow:

. Sr.No Ingredients Qty (%)
1. Active Ingredient 2.5-5
2. Solvent q.s to 1 ml
3. Anti-Oxidant 0 - 0.5 w/v
4. Preservative 0 - 0.5 v/v
The present invention can be illustrated by but not limited to following
example(s).
Examaple 1
Sr.No Ingredients Qty (mg/mL)
5. Aceclofenac 150.0
6. N-Methyl Pyrrolidone (Pharmasolv) q.s to 1 mL
Procedure for a batch size of 100 mL:
1. Take 70 mL of N-Methyl pyrrolidone in a beaker
2-. Add Acelcofenac and stir till it dissolves completely
3. Make up the volume to 100 mL with N-Methyl pyrrolidone
4. Filter the solution through a 0.2 micron filter
5. Fill the solution into 10 mL sterilized & depyrogenated vials
6. Stopper the vials using suitable rubber stoppers and crimp them with aluminium flip-off seals
7. Autoclave the vials at 121 °C/15 psi for 15 min.
Examaple 2
Sr.No Ingredients Qty (mg/mL)
1. Aceclofenac 150.0
2. Butylated Hydroxytoluene 0.3
3. Butylated Hydroxyanisole 0.3
4. N-Methyl Pyrrolidone (Pharmasolv) q.s to 1 mL
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Procedure for a batch size of 100 mL:
1. Take 70 mL of N-Methyl pyrrolidone in a beaker
2. Add Butylated Hydroxyanisole and Butylated Hydroxytoluene to step 1 and stir till the antioxidants dissolve.
3. Add Acelcofenac to the solution of step 2 and stir till it dissolves completely.
4. Make up the volume to 100 mL with N-Methyl pyrrolidone
5. Filter the solution through a 0.2 micron filter
6. Fill the solution into 10 mL sterilized & depyrogenated vials
7. Stopper the vials using suitable rubber stoppers and crimp them with aluminium flip-off seals
8. Autoclave the vials at 121°C/15 psi for 15 min.
Examaple3
Sr.No Ingredients Qty (mg/mL)
1. Aceclofenac 150.0
2. Benzyl Alcohol 0.1 mL
3. N-Methyl Pyrrolidone (Pharmasolv) q.s to 1 mL
Procedure for a batch size of 100 mL:
1. Take 70 mL of N-Methyl pyrrolidone in a beaker
2. Add Benzyl alcohol and mix for 5 min.
3. Add Acelcofenac to the solution of step 2 and stir till it dissolves completely.
4. Make up the volume to 100 mL with N-Methyl pyrrolidone
5. Filter the solution through a 0.2 micron filter
6. Fill the solution into 10 mL sterilized & depyrogenated vials
7. Stopper the vials using suitable rubber stoppers and crimp them with aluminium flip-off seals
8. Autoclave the vials at 121°C/15 psi for 15 min.
Examaple 4
Sr.No Ingredients Qty (mg/mL)
1. Aceclofenac 150.0
2. Butylated Hydroxytoluene 0.3
3. Butylated Hydroxyanisole 0.3
4. Benzyl Alcohol 0.1 mL
5. N-Methyl Pyrrolidone (Pharmasolv) q.s to 1 mL
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Procedure for a batch size of 100 mL;
1. Take 70 mL of N-Methyl pyrrolidone in a beaker
2. Add Butylated Hydroxyanisole and Butylated Hydroxytoluene to step 1 and stir till the antioxidants dissolve.
3. Add Benzyl Alcohol to the solution of step 2 and mix for 5 min.
4. Add Acelcofenac to the solution of step 3 and stir till it dissolves completely.
5. Make up the volume to 100 mL with N-Methyl pyrrolidone
6. Filter the solution through a 0.2 micron filter
7. Fill the solution into 10 mL sterilized & depyrogenated vials
8. Stopper the vials using suitable rubber stoppers and crimp them with aluminium flip-off seals
9. Autoclave the vials at 121°C/15 psi for 15 min.
Dated this 7th day of April 2007.

Signature:-
Ketana Laljibhai Babaria
For and on behalf of the applicant.
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