FORM-2
THE PATENTS ACT, 1970
(39 OF 1970)
&
The Patent Rules, 2003
COMPLETE SPECIFICATION Sec10-Rule 13
"High Dose, Low Volume Injectable Preparation of Diclofenac."
INDOCO REMEDIES LIMITED
Indian
R-92-93, T.T.C Industrial Area, Thane Belapur Road, Rabale MIDC
Navi Mumbai-400701
The following specification describes the invention.

Field of the Invention:
The present invention relates to a low volume, high dose injectable preparation of Diclofenac and/or its acceptable salts including other pharmaceutically acceptable excipients and process of its preparation. The injectable dosage form of the current invention is targeted towards causing lesser amount of pain at the site of injection.
Background & Prior Art:
Diclofenac is a non-steroidal anti-inflammatory agent, which is used to reduce inflammation; it also acts as an analgesic, especially finding use in treating post-operative pain. It acts by inhibition of prostaglandin synthesis by inhibition of cyclooxygenase (COX).
The Diclofenac injections currently on the market are 75mg/3ml, which tend to cause pain at the site of injection. The problem with these injections lies in the volume of the injection being administered. It was observed that reducing this volume for injection can help to reduce the pain at the site of injection and increase patient compliance. Some low volume Diclofenac injections can be traced in prior art. they are as cited below.
96/MUM/2005 provides for a 75mg/lml Diclofenac sodium injection. The invention discloses an injectable preparation containing Diclofenac sodium using combination of solubilizers selected from a group comprising glycofurol, benzyl alcohol, Polyethylene glycol 400 and propylene glycol. The invention cites examples of formulation, which predominantly shows use of a combination of glycofurol and benzyl alcohol as solvents for solubilizing diclofenac. Single solvent system using glycofurol. Polyethylene glycol 400, and propylene glycol alongwith water as principal solvent are also described in the invention.

1382/MUM/2008 also discloses a Diclofenac injection preparation. The solubilizer used in this invention is Polyoxyl 35 castor oil A combination of Polyoxyl 35 castor oil and benzyl alcohol is used to solubilize Diclofenac sodium to provide a low volume 1 ml injection. There are however some drawbacks associated with the use of Polyoxyl 35 castor oil. Acute and chronic toxicity tests in animals have shown polyoxyethylene castor oil derivatives to be essentially nontoxic and nonirritant materials. However, there are reports of cardiovascular changes and nephrotoxicity in various species of animals. Several serious anaphylactic reactions, cardiotoxicity, nephrotoxicity, neurotoxicity, and pulmonary toxicty have also been observed in humans and animals following parenteral administration of formulations containing polyoxyethylene castor oil derivatives. The precise mechanism of the reaction is not known (Rowe et al, Handbook of Pharmaceutical excipients, 5th Edition, Pg 574)
1322/DEL/2010 discloses a process to prepare a parenteral formulation of Diclofenac using solvents such as Polyoxyethylenglyceroltriricinoleat, and Polyglyceryl-10-diisostearate. Polyoxyethylenglyceroltriricinoleat is Polyoxyl 35 castor oil. The dosage of diclofenac provided in the invention is also 75mg/l ml.
1548/MUM/2008 provides for a 1ml Diclofenac injection employing Polyethylene glycol, propylene glycol or dimethylisosorbide as solubilizers in combination with water as principal solvent; however use of propylene glycol suffers from drawbacks of causing irritation. Polyethylene glycol is required to be used in larger quantities in order to dissolve diclofenac thus effectively increasing the viscosity and consequently contributing to pain at the site of injection.
In light of the cited prior art and requirement of a low volume, high concentration drug, the inventors of the present invention seek to provide a novel injectable formulation of

Diclofenac which overcomes the drawbacks of the prior art. The current invention provides a diclofenac preparation containing Macrogol 15 hydroxystearate as a co-solvent along with water as principal solvent, and other acceptable excipients suitable for parentral use
The main problem in development of a low volume, high concentration Diclofenac injection has been solubilizing Diclofenac in lesser volume of solvents. The inventors of the present invention have successfully solved the aforementioned problem with the use of Macrogol 15-Hydroxystearate. This solvent has an advantage of being an excellent solubilizer and capable of being used alone i.e. without combining it with other solvents and at much lesser quantities than that compared to the prior art solvents which have been employed. Use of a single solvent system thus makes the process of manufacture relatively simpler.
Object of the Invention:
The principal object of the present invention is to provide an injectable composition comprising Diclofenac and/or its acceptable salts, Macrogol 15 Hydroxystearate and pharmaceutically acceptable excipients.
Another object of the present invention is to provide a process for preparing injectable composition comprising Diclofenac and/or its acceptable salts. Macrogol 15 Hydroxystearate and pharmaceutically acceptable excipients.
Yet another object of the present invention is to provide an injectable composition comprising Diclofenac and/or its acceptable salts, Macrogol 15 Hydroxystearate and pharmaceutically acceptable excipients, which causes less pain and irritation at the site of injection.

Another object of the present invention is to provide an injectable composition comprising Diclofenac and/or its acceptable salts, which is stable on storage at room temperature and also free from side effects.
Further object of the present invention is to provide a novel, simpler and effective process to prepare injectable composition comprising Diclofenac and/or its acceptable salts, Macrogol 15 Hydroxystearate and pharmaceutically acceptable excipients.
Further object of the present invention is to provide high dose, low volume injectable composition comprising Diclofenac and/or its acceptable salts, Macrogol 15 Hydroxystearate and pharmaceutically acceptable excipients.
Further object of the present invention is to provide an injectable composition comprising Diclofenac and/or its acceptable salts, for the pain and inflammation management associated with musculoskeletal system, dysmenorrhoea, during post operative and post traumatic period. Additionally it is also given in chronic inflammatory conditions like rheumatoid arthritis and osteoarthritis.
Summary of the Invention:
The present invention provides a low volume, high dose injectable preparation of Diclofenac and/or its pharmaceutically acceptable salts i.e. 75-100mg per ml of Diclofenac and/or its salts, Macrogol 15 Hydroxystearate as a solubilizer, including other pharmaceutically acceptable excipients with water as a principal solvent and a method of preparing the same.

Description of the Invention:
The present invention provides an injectable composition comprising Diclofenac and/or its acceptable salts, Macrogol 15 Hydroxystearate and pharmaceutically acceptable excipients.
In particular, the present invention provides a low volume, high dose injectable preparation of Diclofenac and/or its pharmaceutically acceptable salts i.e. 75-100mg per ml of diclofenac and/or its slats, Macrogol 15 Hydroxystearate as a solubilizer, including other pharmaceutically acceptable excipients with water as a principal solvent and a method of preparing the same.
Macrogol 15 Hydroxystearate has high chemical stability. It can be used upto 50% concentration to solubilise Diclofenac, Vitamin K etc. It is non-toxic and nonirritant excipient. Further it is reported that Macrogol 15 hydroxystearate is non mutagenic in bacteria, mammalian cell cultures and mammals.
Macrogol 15 Hydroxystearate (Solutol HS 15). a non-ionic solubilizer, was developed to fulfill an unmet need for a safe and effective excipient for parenteral and solid oral dose formulations containing poorly soluble APIs. Chemically, Solutol HS 15 is composed of polyglycol mono- and di-esters of 12-hydroxy-stearic acid and contains approximately 30% polyethylene glycol. Solutol HS 15 is listed as Macrogol 15 hydroxystearate in the European Pharmacopoeia (PhEur). The excipient has been used in approved drugs in some countries, including Canada and Argentina.
Macrogol 15 Hydroxystearate is also known as 12-hydroxyoctadecanoic acid polymer with a- hydro-ro-hydroxypoly(oxy-l. 2-ethanediyl); 12-hydroxystearic acid polyethylene glycol copolymer; Macrogol 15 hydroxystearas; polyethylene glycol-15-hydroxystearate; and polyethylene glycol 660 12-hydroxystearate.

The process to prepare an injectable pharmaceutical composition comprising Diclofenac and/or its salts, Macrogol 15 hydroxystearate comprises of following steps:
a) Dissolving Diclofenac and/or its salts in a mixture of sterile water for injection and Macrogol 15- Hydroxystearate.
b) Add benzyl alcohol to step a) solution under stirring.
c) Dissolve chelating agent in water for injection.
d) Add step c) solution to step b) under stirring.
e) Dissolve antioxidant in sterile water for injection and transfer to step d.
f) Adjust pH to 8-9 using buffering agent.
g) Make up the volume to 1 ml using sterile water for injection.
h) Sterilize the solution of step g) by autoclaving or through sterilizing grade filters.
In accordance with the present invention an injectable pharmaceutical composition comprises Diclofenac and/or its acceptable salts, Macrogol 15 Hydroxystearate and one or more of antioxidants, preservatives, chelating agents, buffers and water as principal solvent.
Antioxidants which could be used include, but are not limited to, Potassium Metabisulphite, Sodium Metabisulphite, Sodium Trisulfite, and Sodium Sulfite.
Preservatives which could be used include, but are not limited to. Methyl Paraben, Propyl Paraben, Sodium Methyl Paraben, Sodium Propyl Paraben, Benzyl Alcohol and Ethyl Paraben.
Chelating agents which could be used include, but are not limited to, Disodium Edetate, Potassium Edetate, and Edetic Acid.

Buffers which could be used include, but are not limited to, Sodium Phosphate, Phosphoric Acid, Potassium Phosphate, Sodium Hydroxide, and Hydrochloric Acid.
An injectable pharmaceutical composition of the present invention contains the active ingredient in the range of 75mg to 100 mg per ml, preferably 75mg per ml.
According to the present invention, an injectable composition comprising Diclofenac and/or its pharmaceutically acceptable salts having viscosity of 3-5 cps (centipoises) contains 7.5 to 10% w/v of diclofenac or its salts, 3 to 80 % w/v of Macrogol 15 hydroxystearate, 0.1 to 1 % w/v of antioxidant, 0.5 to 2 % w/v of chelating agent and 1.5 to 10 % v/v of preservative agent.
The Diclofenac salts used are Diclofenac Sodium and Diclofenac Potassium, preferably Diclofenac Sodium.
The examples given below are provided for the purpose of illustrating the disclosed invention and in no way should be considered as limiting the invention.
Although the invention has been described with reference to specific embodiments, this description is not meant to be construed in a limiting sense. Various modifications of the disclosed embodiments, as well as alternate embodiments of the invention, will become apparent to person skilled in the art upon reference to the description. It is therefore contemplated that such modifications can be made without departing from the spirit or scope of the present invention as defined.
The invention is further exemplified with following example and is not intended to limit the scope of the invention.

Examples:
A low volume, high dose diclofenac injectable preparation can be prepared as given in examples below.
Example 1.

Sr.No Ingredients Qty per ml (%) Concentration
1 Diclofenac Sodium 75.0mg 7.5
2 Macrogol 15 Hydroxystearate 140 mg 14
3 Benzyl alcohol 0.036ml 3.6
4 Disodium edetate 0.8 mg 0.08
5 Sodium metabisulphite 6mg 0.6
6 Sodium hydroxide q.s to pH 8-9
7 Water for injection 1ml
Process:
1. Diclofenac Sodium was suspended in a mixture of sterile water for injection and Macrogol 15 Hydroxy stearate.
2. Benzyl alcohol was added to step 1 under stirring.
3. Disodium edetate was added to water for injection and was mixed with step 2 under stirring.
4. Sodium metabisulphite was added to water for injection.
5. The solution of step 4 was added to step 3.
6. The pH 8-9 was adjusted using sodium hydroxide.
7. The final volume was adjusted to 1ml using sterile water for injection to get product of viscosity 3-5 cps.
8. The above solution of step 3 was sterilized either by autoclaving or through
sterilizing grade filters.

Example 2.

Sr.No Ingredients Qty per ml (%) Concentration
1 Diclofenac Sodium 75.0mg 7.5
2 Macrogol 15 Hydroxystearate 260 mg 26
3 Sodium metabisulphite 3 mg 0.3
4 Sodium hydroxide q.s to pH 8-9
5 Water for injection 1 ml
Process:
1. Diclofenac Sodium was suspended in a mixture of sterile water for injection and
Macrogol 15 Hydroxy stearate.
2. Soduium metabisulphite was added to step 1.
3. The pH 8-9 was adjusted using sodium hydroxide
4. The final volume was adjusted to 1ml using sterile water for injection to get product of viscosity 3-5 cps.
5. The above solution of step 3 was sterilized either by autoclaving or through
sterilizing grade filters.

Example 3.

Sr.No Ingredients Qty per ml (%) Concentration
1 Diclofenac Sodium 75.0mg 7.5
2 Macrogol 15 Hydroxystearate. 200 mg 20
3 Benzyl alcohol 0.04 ml 4.0
4 Disodium edetate 0.5 mg 0.05
5 Sodium metabisulphite 3 mg 0.3
6 Sodium hydroxide q.s to pH 8-9
7 Water for injection 1ml
Process:
1. Diclofenac Sodium was suspended in a mixture of sterile water for injection and Macrogol 15 Hydroxy stearate.
2. Benzyl alcohol was added to step 1 under stirring.
3. Disodium edetate was added to water for injection and was mixed with step 2 under stirring.
4. Sodium metabisulphite was added to water for injection.
5. The solution of step 4 was added to step 3:
6. The final volume was adjusted to 1ml using sterile water for injection to get product of viscosity 3-5 cps.
7. The pH 8-9 was adjusted using sodium hydroxide.
8. The above solution of step 3 was sterilized either by autoclaving or through
sterilizing grade filters.

Example 4.

Sr.No Ingredients Qty per ml (%) Concentration
1 Diclofenac Sodium 78.0mg 7.8
2 Macrogol 15 Hydroxystearate 80 mg 8.0
3 Benzyl alcohol 0.08 ml 8.0
4 Disodium edetate 5mg 0.5
5 Sodium metabisulphite 3 mg 0.3
6 Sodium hydroxide q.s to pH 8-9
7 Water for injection 1 ml
Process:
1. Diclofenac Sodium was suspended in a mixture of sterile water for injection and
Macrogol 15 Hydroxy stearate.
2. Benzyl alcohol was added to step 1 under stirring.
3. Disodium edetate was added to water for injection and was mixed with step 2 under stirring.
4. Sodium metabisulphite was added to water for injection.
5. The solution of step 4 was added to step 3.
6. The pH 8-9 was adjusted using sodium hydroxide.
7. The final volume was adjusted to 1ml using sterile water for injection to get product of viscosity 3-5 cps.
8. The above solution of step 3 was sterilized either by autoclaving or through
sterilizing grade filters.

Stability Data:
Table 1.
Name of product: Diclofenac Sodium Injection.
Strength : 75mg/lml
Batch No : DI/D/124.
Storage Condition: 40° C ± 2° C / 75% ± 5% RH

Tests Specification Diclofenac Sodium
Initial 1 month 2 Months 3 Months 6 Months
Description Clear pale yellow coloured solution Complies Complies Complies Complies Complies
Assay
Diclofenac 95-105% 100.9 103.3 98.0 100.1 100.3
Sodium
Benzyl 95-105% 101.4 100.8 100.0 99.8 98.2
Alcohol
PH Between 8.1 to 9 8.3 8.3 8.31 8.32 8.30
Remark: The data from table 1 shows that the product is stable at 40° C ± 2° C / 75% ± 5% RH for the period of 6 months.
Table 2.
Name of product: Diclofenac Sodium Injection.
Strength : 75mg/lml
Batch No : DI/D/124.
Storage Condition: 30° C ± 2° C / 65% ± 5% RH

Tests
Specification Diclofenac Sodium
Initial 1 month 2 Months 3 Months 6 Months
Description Clear pale yellow coloured solution. Complies Complies Complies Complies Complies
Assay
Diclofenac 95-105% 100.9 103.6 102.7 104.6 100.9
Sodium
Benzyl 95-105% 101.4 101.8 100.7 100.05 99.7
Alcohol
pH Between 8.1 to 9 8.3 8.19 8.21 8.19 8.16
Remark: The data from table 2 shows that the product is stable at 30° C ± 2° C / 65% ± 5% RH for the period of 6 months.
Table 3.
Name of product: Diclofenac Sodium Injection.
Strength : 75mg/lml
Batch No : DI/D/124.
Storage Condition: 25° C ± 2° C / 60% ± 5% RH

Tests Specification Diclofenac Sodium
Initial 1 month 2 Months 3 Months 6 Months
Description Clear pale yellow coloured solution. Complies Complies Complies Complies Complies
Assay
Diclofenac 95-105% 100.9 102.0 100.7 99.4. 101.2

Sodium

Benzyl Alcohol 95-105% 101.4 100.9 100.6 99.8 99.8
pH Between 8.1 to 9 8.3 8.20 8.1 8.02 8.12
Remark: The data from table 3 shows that the product is stable at 25° C ± 2° C / 60% ± 5% RH for the period of 6 months.

We Claim:
1. An injectable pharmaceutical composition comprising diclofenac and/or its
acceptable salts. Macrogol 15 Hydroxystearate and pharmaceutically acceptable
excipients.
2. The pharmaceutical composition of claim 1, wherein the active ingredient is used in the range of 75-100mg per ml.
3. The pharmaceutical composition of claim 1, wherein water is used as a principal solvent.
4. The pharmaceutical composition of claim 1. wherein the viscosity of the composition is 3-5 cps.
5. The pharmaceutical composition of claim 1, wherein the concentration of Macrogol 15 Hydroxystearate is 3 to 80%.
6. The process to prepare pharmaceutical composition of claim 1, comprises of
following steps:
a) Dissolving diclofenac and/or its salts in a mixture of sterile water for injection and Macrogol 15- Hydroxystearate.
b) Add benzyl alcohol to step a) solution under stirring.
c) Dissolve chelating agent in water for injection.
d) Add step c) solution to step b) under stirring.
e) Dissolve antioxidant in sterile water for injection and transfer to step d).
f) Adjust pH to 8-9 using buffering agent.
g) Make up the volume to 1ml using sterile water for injection.

h) Sterilize the solution of step g) by autoclaving or through sterilizing grade filters.