FORM 2
THE PATENT ACT 1970
(39 of 1970)
&
The Patents Rules, 2003
COMPLETE SPECIFICATION
(See section 10 and rulel3)
l.TITLE OF THE INVENTION:
"DICLOFENAC INJECTABLE PREPARATION"

2. APPLICANT:
(a) NAME: M/S. INDOCO REMEDIES LIMITED.
(b) NATIONALITY: Indian Company incorporated under the Indian
Companies ACT, 1956.
(c) ADDRESS: Indoco House, 166 C. S. T. Road, Santacruz (East),
Mumbai - 400 098. Maharashtra, India.
3. PREAMBLE TO THE DESCRIPTION:
The following specification particularly describes the invention and the manner in which it is to be performed.

FIELD OF THE INVENTION
The present invention relates to a Diclofenac composition in a solvent system suitable for preparing a stabilized injectable composition.
BACKGROUND OF THE INVENTION
Diclofenac is a benzene acetic acid derivative, also characterized as a non-steroidal anti¬inflammatory drug (NSAID). The exact mechanism of action is not entirely known, but it is thought that the primary mechanism responsible for its anti-inflammatory / antipyretic / analgesic action is inhibition of cyclooxygenase.
Diclofenac has found wide acceptance for the relief of signs and symptoms of osteoarthritis, rheumatoid arthritis, ankylosing spondilitis, and actinic keratoses and is also used in various countries for the management of fever.
Currently in the USA, the marketed formulations of Diclofenac sodium are available as delayed release tablet, ophthalmic drops and gels; however, these formulations are associated with no. of disadvantages like non uniform dosing, slow release of medicament (Tablet) and the possibility of local irritation, itching and erythema (gels).
For several years, the desirability of a suitable injectable pharmaceutical composition of diclofenac sodium which can be given during emergency conditions has been recognized. However, the limitation to the oral and gel dosage form only has arisen principally due to the physico-chemical property of the drug like poor aqueous solubility, tendency to crystallization both at room and refrigerated temperatures and susceptibility to oxidation.
The above-mentioned problems in preparing injectable pharmaceutical preparations have been attempted to overcome essentially by
• Using a non-aqueous solvent, which is capable of solubilizing the drug, is compatible with the drug, safe and to produce a composition having good shelf life.
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• Addition of antioxidants like sulphite salts.
Further, numerous attempts have also been made by the formulators to prepare a stable Diclofenac sodium composition for injectable preparation. For e.g. patent publication no. WO 2006/095363 A2 by Patel et al claims an injectable preparation of Diclofenac and its salts comprising 4 to 85% of monohydric alcohol, 27 to 90% v/v of polyhydric alcohol or 18% to 90% v/v of glycofurol in combination with water a.s principal solvent. Similarly, Stetten et al in US patent No. 4,711,906 claim an injectable composition comprising polyethylene glycol, propylene glycol and reducing agent as stabilizer and Jain et al in patent publication no. WO 2006/126214 A2 claim an injectable composition of Diclofenac Sodium comprising polyethylene glycol, propylene glycol, alkalizing and buffering agents. Both US Publication no. US 20070232567 by Wright et al and US Publication no. US 20050282776 by Zoppetti et al disclose a composition comprising NSAID and beta-cyclodextrin. Further, US Patent No. US 5,679,660 by Bodley et al claim an injectable composition comprising Diclofenac and 2-hydroxypropyl beta-cyclodextrin. Another approach utilized in preparing a stable parenteral preparation of Diclofenac sodium has been made by Holl et al in US Patent no. 5,554,650 which claims a parenteral preparation of Diclofenac sodium comprising polyoxyethylene castor oils as a surfactant and monohydric and polyhydric alcohols as cosurfactant.
Although all these solvents have been effective in solubilizing Diclofenac sodium to prepare a suitable formulation, however, the use of the same are associated with many disadvantages. For e.g., use of polyoxyethylene castor oils is associated with increase in patient toxicity hypersensitivity reactions in certain individuals where as beta-cyclodextrin is associated with the nephrotoxicity. Also, high concentrations of polyhydric alcohols like Propylene glycol are associated with potential problems like ototoxicity, cardiovascular effects, seizures, and rashes on the chest and arms and use of more than 40% v/v Polyethylene glycol 300 in the preparation exhibits hemolytic effects in humans.
Additionally, most of the compositions disclosed in the prior art utilizes the combination of solvents like monohydric alcohol with polyhydric alcohol or polyoxyethylene castor
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oils with monohydric and polyhydric alcohols; raising the level of solvents in the final preparation which may further accentuate the incidence of the side effects. For e.g. the commercial European 3 ml intramuscular injection of Diclofenac Sodium contains benzyl alcohol and propylene glycol as solvents and sodium metabisulphite as an antioxidant. Thus, the mixtures of solvent especially with the higher concentration of the propylene glycol and larger volume of the commercial European intramuscular injection of Diclofenac Sodium composition (3 ml) which is injected into the muscle may lead to both pain at the site of injection and a no. of side effects as mentioned herein before. Hence, from the foregoing, it would be apparent that no universal method has been disclosed in the prior art for the preparation of Diclofenac sodium solution, which is simple, convenient, safe, stable, non irritant and circumvent the side effects associated with the use of the abovementioned solvents.
The present invention is a step forward in this direction and attempts to overcome most, if not all the problems encountered in the prior art during the preparation of Diclofenac sodium composition viz., larger volume, unstability, crystallization of Diclofenac sodium both at the room and refrigerated temperatures and use of high amounts of solvents which are associated with no. of side effects.
OBJECTS OF THE INVENTION
The main object of the present invention is to provide injectable pharmaceutical composition of diclofenac sodium comprising 75 to 100 mg of Diclofenac sodium in a minimum quantity of solvents.
Another object of the present invention is to provide a pharmaceutical composition of diclofenac sodium which is stable on storage at room temperature for pharmaceutically acceptable duration of time and also free from side effects.
It is yet another object of the present invention to provide a process for the preparation of a stable pharmaceutical composition of diclofenac sodium, which is simple, convenient and economical.
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SUMMARY OF THE INVENTION
The present invention discloses a novel, stable aqueous pharmaceutical injectable composition of Diclofenac sodium in benzyl alcohol, which is free from side effects. The invention further discloses process for preparation of a stable pharmaceutical composition of diclofenac sodium, by a simple, convenient and economical method.
DETAILED DESCRIPTION OF THE INVENTION
The present invention arose from the observation by the inventors that commercially available injectable pharmaceutical compositions of diclofenac sodium available in Europe as well as in many other countries are marketed as 3ml intramuscular injections. These intramuscular injections utilize not only the mixtures of non aqueous solvents like propylene glycol and polyethylene glycols (PEGs) but also makes use of these in such a high concentration that it leads to pain at the site of injection as well as no. of side effects like ototoxicity, cardiovascular effects, seizures and rashes on the chest and arms, local irritation and hemolysis in patients.
However, in their endeavor to find a suitable method for the preparation of Diclofenac sodium intramuscular injectable solution which overcomes most of the above mentioned side effects, the present inventors have found to their surprise that such a stable composition can be prepared by the use of benzyl alcohol alone as a solvent.
Benzyl alcohol is an organic compound and is a natural constituent of variety of essential oils like jasmine, hyacinth and ylang-ylang. It is commonly exploited as a solvent for variety of pharmaceutical products and as per the Inactive Ingredient Database of the USFDA (IIG), it can be used in maximum concentration of 10.96 % for intramuscular injections.
The present inventors have observed that the concentration of benzyl alcohol in the commercially available 3 ml intramuscular injection is 4 % v/v. Surprisingly, it has been found that when benzyl alcohol alone is used in the same concentration as that of marketed 3 ml intramuscular injection, it effectively solubilizes diclofenac sodium and
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evades the necessity of addition of other solvents like PEG, propylene glycol and excipients like sodium metabisulphite.
Since the addition of PEG and propylene glycol is avoided in the final formulation, it has
been possible to reduce the overall volume of the injection from 3 ml to 1 ml.
This not only diminishes the frequency of side effects which are associated with the
solvents like PEG and propylene glycol but also solves the problem of local irritation and
pain at the site of injection which are associated with the high volume of the final dosage
form.
It was yet another surprising finding that the compositions prepared according to the
present invention have been found to possess not only remarkable long storage life both
at room and refrigerated temperatures but also, exhibit no side effects.
Thus, in a first embodiment, the invention provides a novel, stable aqueous
pharmaceutical injectable composition of Diclofenac sodium and benzyl alcohol.
In a second embodiment, the invention provides a novel, stable aqueous pharmaceutical
injectable composition of Diclofenac sodium and benzyl alcohol, which is free of side
effects and evades the inclusion of any other solvent.
In a third embodiment, the invention provides process for the preparation of novel, stable
aqueous pharmaceutical injectable composition of Diclofenac sodium and benzyl alcohol.
The stable pharmaceutical composition of the present invention could be prepared by a
process, which comprises of the following steps:
i) adding benzyl alcohol to diclofenac sodium, in a quantity sufficient to solubilize diclofenac sodium to obtain a clear solution;
ii) adding water (quantity sufficient to 1ml) to the solution of step (i);
iii) filtering the solution of step (ii); and
iv) filling the clear solution of step (iii) into the glass ampoules.
The amounts of diclofenac sodium used in the formulation according to the present invention may vary from about 75 mg/ml to about 100 mg/ml and the quantity of benzyl alcohol used in the formulation may be around 10 % to 12 %.
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Sterilization of the injection can be carried through various physical and chemical methods known in the art. The physical methods, most widely utilized to sterilize the parenteral solution are filtration and steam sterilization (autoclaving). However, in the present context, it has been found that diclofenac sodium injection when sterilized by autoclaving leads to the production of l-(2,6 diclorophenyl) indolin-2-one; which is an impurity. Thus, filtering the solution prior to filling into ampoules is a much preferred means of sterilization.
The solution after sterilization is filled in glass container which is a USP Type I hydrolytic glass container. As used herein the term "conventional and untreated glass" refers to USP Type I glass, commonly known as "normal hydrolytic class-I glass" or borosilicate glass as classified by United States Pharmacopoeia. Example of such glasses are, but not limited to, Corning.RTM. Pyrex.RTM. 7740 and Wheaton 180, 200, and 400. Following example, illustrating the embodiments of the present invention is provided; however, these are exemplary only and should not be regarded as limitations of the present invention.
Example 1 : Diclofenac sodium Injection (75mg/ml)
Sr. No Ingredients Quantity/100 ml
1 Diclofenac Sodium 7.5 gm
2 Benzyl alcohol 12 ml
3 Water q.sto 100 ml
Procedure:
i) taking specified quantity (7.5 gm) of Diclofenac sodium into a vessel;
ii) adding Benzyl alcohol (12ml) to step (i) with continuous stirring;
iii) mixing the solution till the Diclofenac sodium completely solubilizes;
iv) adding the water for injection to make quantity sufficient to 100 ml;
v) filtering the solution through membrane filter; and
vi) filling the sterilized solution into the suitable glass ampoules.


The vials were subjected to stability testing at refrigerated temperature and at 25 °C/60 RH and observed for 3 months. Their stability was evaluated with respect to the clarity of solution and appearance of particulate matter. It was found that the compositions comprising 10% to 12 % of Benzyl alcohol were clear and stable.
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.
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We claim,
1) A stable aqueous pharmaceutical preparation of Diclofenac Sodium as 1 ml
injection comprising: 75 mg to 100 mg of Diclofenac sodium; and benzyl alcohol
' as a lone excipient in quantity sufficient to solubilize Diclofenac sodium.
2) The pharmaceutical preparation as claimed in claim 1, wherein the solution
comprises 10% to 12 % of benzyl alcohol.
3) A novel pharmaceutical preparation of claim 1 wherein the composition of
diclofenac sodium is free of side effects and stable on storage at room and
refrigerated temperature for pharmaceutically acceptable duration of time.
4) A process for the preparation of novel pharmaceutical preparation of Diclofenac
Sodium comprising the steps of
i) adding benzyl alcohol to diclofenac sodium, in quantity sufficient to
solubilize diclofenac sodium to obtain a clear solution; ii) adding water (quantity sufficient to 1ml) to the solution of step (i); iii) filtering the solution of step (ii); iv) filling the clear solution of step (iii) into ampoules.
Dated this 19th day of August, 2008

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