FORM 2
THE PATENT ACT 1970
(39 of 1970)
&
The Patents Rules, 2003
COMPLETE SPECIFICATION
(See section 10 and rule 13)
"l. TITLE OF THE INVENTION:
Injectable Formulation of High Concentration Diclofenac 2. APPLICANT:
(a) NAME : Lincoln Pharmaceutical Limited. (
(b) NATIONALITY : An Indian Company j
(c) ADDRESS : Nirav Complex, j
Opposite Navamng School,
! Naranpura,
j Ahmedabad-380014,
Gujarat, India.
STPREMABLE TO THE DESCRIPTION
_ ,
COMPLETE
PROVISIONAL The following specification particularly
The following specification describes the invention and the manner
describes the invention, in which it is to be performed.

Technical field of Invention: ,
The present invention relates to a pharmaceutical formulation in the form of a sterilizable parenteral solution of Diclofenac (or its salts) in high concentration along with pharmaceutically acceptable and clinically safe excipients to provide unique painless and easy to administer dosage form. The injection solution according to invention is stable and is characterised by good compatibility useful in the management of acute pain including post-operative pain
Background of Invention:
Diclofenac and its salts (sodium, potassium or diethylamine) are used for pain relief and inflammation conditions associated with rheumatoid arthritis, ankylosing spondylitis, osteoarthritis, renal colic, gout etc.
Parenteral administration is recommended through intragluteal injection. Intragluteal route is preferred as the injection causes lots of pain if given in deltoid muscles. This pain at the site of injection is due to large volume (3 ml) of injections available in the market. Moreover, these market products contain high volumes of propylene glycol (generally 25% v/v and more) as1 solvent. The high content of this solvent also adds to the pain.
Thus it has always been a need to reduce the volume of injection and to avoid use of high concentration of solvents like propylene glycol.
There is ample literature available on diclofenac injections. Many inventions have been reported in order to avoid use of propylene glycol as solvent and reduce volume of injection to I mi or 2 m\ from 3 ml available in the market
Thus, the present invention aims to provide an injectable formulation comprising diclofenac which is also suitable to administer in deltoid muscles and intravenous for faster onset.
The present invention further aims to provide a formulation (injection) containing high concentration of Diclofenac (or its salts) so as to accommodate 75 mg to 100 mg of Diclofenac salt in 1 ml volume. This less volume (1 ml) of injection results into less pain at the site of injection and also enables administration in the deltoid region.

Object of the invention
The main object is to provide injectable preparation of Diclofenac that is painless to patient and it is also useful to nurses and doctors as it provides ease of administration with more flexibility in the route of administration i.e. intragluteal, intradeltoid and intravenous.
Summary of Invention:
Thus, the above objective is achieved by reducing the volume of injection from 3
ml (75 mg Diclofenac in 3 ml) as available in the market to 1 ml (75 mg Diclofenac in 1
ml) and avoiding use of high concentration of propylene glycol as solvent.
In another aspect, the current invention provides stable injectable formulation comprising
diclofenac (or its salts) 75mg to lOOmg in 1ml along with suitable solvent/solubilizer in
addition to water as principle solvent. The formulations are adjusted to pH 8.0 to
9.0 containing 75 mg to 100 mg of Diclofenac or its salt in water along with solvent, antioxidant, preservative, chelating agent (stabilizer) and buffer.
In another aspect, the present invention provides a pharmaceutical formulation of high concentration of Diclofenac (or its salts) injection that provides ease of administration to the patient and less pain at the site of injection. In this injectable preparation 75 mg to 100 mg of Diclofenac salt is present in 1 ml volume of solution. In a preferred aspect, the soivent/solubilizer used to achieve the present invention is Polyoxyethylene castor oil derivatives like polyoxyl castor oil.
In yet another aspect, the invention provides injectable formulation comprising 75 mg to
lOOmg of diclofenac or its salt in 2 ml injection. •
Detailed description of Invention:
The invention will now be described in detail in connection with certain preferred and optional embodiments, so that various aspects thereof may be more fully understood and appreciated.
Accordingly, in one embodiment, the current invention provides stable injectable formulation comprising diclofenac (or its salts) 75mg to lOOmg in 1 ml along with suitable soivent/solubilizer, in addition to water as principle solvent. The formulation of the present invention further comprises antioxidant, preservatives, chelating agent and buffer. The pH of the formulation is adjusted to 8.0 to 9.0.

In another embodiment, the current invention encompasses stable injectable formulation comprising diclofenac (or its salts) 75mg to lOOmg in 2 ml along with suitable solvent/solubilizer, in addition to water as principle solvent.
Polyoxyethylene castor oil derivatives like polyoxyl castor oil, have been used as solvent/solubilizer in a concentration of 2% to 90% w/v in combination with water as main solvent to prepare injectable formulation containing 75 mg to 100 mg of Diclofenac (or it salts) in 1 ml injection solution. Similarly, 75 mg to 100 mg of Diclofenac (or it salts) in 2 ml injection solution is also prepared using Polyoxyethylene castor oil derivatives like polyoxyl castor oil, as suitable solubilizer.
The polyoxyl castor oil solvent used in the present invention is available in the market with different brand names having different compositions like Cremophor ELP, Prolachem CAH-60, Cremophor ELS Accronon CA-15, Acry'sol K-140, Acrysol K- 150 and like.
In a further embodiment, the invention provides a method of preparation of the stable injectable formulation, which method comprises:
(1) Dispersing/suspending Diclofenac or its salt in polyoxyl castor oil solvent and then adding 4 % v/v benzylalcohol;
(2) Adding a part of water for injection to the above solution with stirring and little warming to dissolve the diclofenac salt;
(3) Dissolving buffer, antioxidant and chelating agent in water for injection and then adding to main solution in step (1). .
(4) Adjusting the pH between 8.0 and 9.0 using alkali; and
(5) Adjusting the final volume by adding water for injection to achieve concentration of 75 mg to 300 mg of Diclofenac salt in 1 ml.
Entire solution preparation, sterile filtration, ampoule/vial filling is carried out in inert environment using inert gas flushing.
Antioxidant can be selected from wide range like sodium bisulphate, sodium sulphite, sodium metabisulphite, monothioglycerol, N-acetyl cysteine, disodium edetate is selected as chelating agent/stabilizer. Benzyl alcohol is used as a co-solvent or a preservative for the purpose of present invention. Phosphate buffer is used as buffering

agent and the pH of the formulation is adjusted using alkali metal hydroxides like sodium or potassium hydroxide.
The following examples, which include preferred embodiments, will serve to illustrate the practice of this invention, it being understood that the particulars shown are by way of example and for purpose of illustrative discussion of preferred embodiments of the invention.
Examples:
Example 1:
Ingredients Quantity per ml
Diclofenac sodium 75.0 mg
Polyoxyl 35 Castor Oil 125 mg '
Benzyl Alcohol 0.04 ml
Sodium sulphite 3.0 mg
Disodium edetate 0.5 mg
Water for Injection q.s. 1.0 ml
Phosphate buffer and sodium hydroxide Quantity sufficient to adjust pH between
8.0 and 9.0
[Solvent used is Cremophor EL (generic name - PolyQxyl 35 Castor Oil) in a concentration of 125 mg per ml] This solvent can be used successfully even at a concentration of 100 mg per ml.

Example 2:
Ingredients I Quantity per 2 ml
Diclofenac sodium 75.0 mg
Polyoxyl 35 Castor Oil 75 mg '
Benzyl Alcohol 0.08 ml
Sodium sulphite 3.0 mg
Disodium edetate 0.5 mg
Water for Injection q.s 2.0 ml
Phosphate buffer and sodium hydroxide Quantity sufficient to adjust pH between
8.0 and 9.0
[Solvent used is Cremaphor EL (generic name - Polyqxyl 35 Castor Oil) in a
concentration of 75 mg per ml]
This solvent can be used successfully even at a concentration of 50 mg per ml Example 3:
Ingredients Quantity per ml
Diclofenac sodium 75.0 mg
Polyoxyl 35 Castor Oil 20 mg
"Benzyl Alcohol 0.10 ml
Sodium sulphite 3.0 mg
Disodium edetate 0.5 mg
Water for Injection q.s 1.0 ml
Phosphate buffer and sodium hydroxide Quantity sufficient to adjust pH between
8.0 and.9.0
u_ _. . ! .

Solvent used is Cremaphor EL (generic name - Polyoxyl 35 Castor Oil) in a
concentration of 20 mg per ml]
This solvent can be used successfully even at a concentration of 50 mg per ml.
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.

We claim:
1. High concentration injectable preparation designed for intradeltoid route,
intragluteal route and slow intravenous route comprising:
a. 75mg to lOOmg of diclofenac or its salts; and
b. 2% to 90% w/v of polyoxyl castor oil as solvent/solubiliser along with
water as main solvent, wherein the diclofenac is solubilized in medium
having a pH of 8-9,
2. High concentration injectable preparation as claimed in claim 1, wherein said injection is prepared as 1ml or 2ml solutions.
3. High concentration injectable preparation as claimed in claim 1, wherein said preparation further comprising a co-soubilizer/preservative like benzyl alcohol, chelating agent/stabilizer like Disodium edetate., antioxidant, pH adjusting agent such as alkali metal hydroxide selected from sodium or potassium hydroxide and a buffering agent like phosphate buffer or bicarbonate buffer.
i
4. High concentration injectable preparation as claimed in claim 1, wherein said antioxidant is selected from sodium bisulphate, sodium sulphite, sodium metabisulphite, monothioglycerol, N-acetyl cysteine.
5. High concentration injectable preparation as claimed in claim 1, wherein the diclofenac salt is selected from sodium, potassium and diethylamine or diethylammonium salt.
6. High concentration injectable preparation as claimed in claim 2, wherein said injectable preparation is prepared by a process comprising the steps of:
a. suspending a water soluble diclofenac salt in a solvent polyoxyl castor oil
in a non-reactive environment, followed by adding benzyl alcohol (4%w/v
to 25% w/v);
b. adding sterile water for injection, buffer and antixidant respectively to the
solution in step (a) followed by adjusting pH to 8-9 with the aid of alkali;

c. adjusting the final volume by adding water for injection to achieve
concentration of 75 mg to 100 mg of Diclofenac salt in 1 ml or 2ml; and
d. subjecting to sterilization by means of autoclave or sterile filtration and
filling in lml/2ml ampoules or 5/10ml multidose vials and flushing with
inert gas prior to sealing.
7. High concentration injectable solution preparation of diclofenac and its salts as claimed in claim 6, wherein benzyl alcohol is present jn an amount of 4% to 45% w/v when used as the sole co-solvent/solubilizer(s) and present in an amount of 10%w/v more preferably 4%w/v when used in combination with other cosolvent(s).
8. High concentration injectable solution preparation as claimed in claim 1, wherein pol.yox.yl hydrogenated castor oil and polyoxyl castor oil is present in an amount ranging from 5% to 90%w/v as solvent or solubiliz,er(s).
9. Process for preparation of high concentration injectable solution of 75mg to lOOmg/ml of diclofenac and its salts as claimed in claim 6 comprising the steps of:
a. suspending 7.5% of water soluble diclofenac sodium in 14%w/v of
polyoxyl castor oil or polyoxyl hydrogenated castor oil in an inert
environment followed by adding 4%w/v benzyl alcohol and sterile water
for injection with stirring, then adding buffer and antioxidant;
b. adjusting the pH of the solution to 8-9 with aid of alkali,
c. adjusting the concentration of the solution to 75mg in 1 ml by diluting it
with sterile water for injection; and
d. subjecting the solution to sterilization by means of autoclave or sterile
filtration followed by filling in 1ml ampoules or 5/1 Oml multidose vials
and flushing with inert gas prior to sealing.
10. The process for the high concentration injectable solution preparation of
diclofenac and its salts as claimed in claim 9, wherein, diclofenac sodium 7.5%.

cremophore EL about 14%, benzyl alcohol about 4% are incorporated in any order and mixed in an inert environment.
11. The process for the high concentration injectable solution preparation of diclofenac and its salts as claimed in claim 9, wherein, diclofenac sodium 7.5%, cremophore EL about 2%, benzyl alcohol about 10% are incorporated in any order and mixed in an inert environment.