The present invention relates to a novel Therapeutic Injectable Analgesic pharmaceutical Composition containing Nimesulide which is N-(4-nitro, 2-phenoxyphenyl) methanesulfonamide, for intramuscular administration and a process for the manufacture thereof.
The use of Nimesulide through intra-muscular administration as an analgesic agent has not been successful because Nimesulide being practically insoluble in water and its formulations in conventional oily bases or as suspensions result in depot formation in the muscular tissues which defied the main objective of quick relief.
The market and literature survey shows that no parenteral dosage form of Nimesulide is reported. (Drugs, 48 (3) 431-454, 1994)
It is an object of the present invention, to provide a Novel Therapeutic Injectable Analgesic Composition containing Nimesulide for intra-muscular . administration from which the Nimesulide is rapidly absorbed and distributed in body fluids.
It is a further object of the present invention to provide a process for the preparation of the novel Therapeutic Injectable Analgesic Composition containing Nimesulide, according to the present invention, for intra-muscular administration.
Accordingly the present invention provides a novel therapeutic Injectable Analgesic pharmaceutical Composition for intramuscular administration which composition comprises:
1. Nimesulide : 2.5 % to 10 % w/v
2. Parenteral absorption
enhancing vehicle base : 90 % to 97.5 % w/v
The said Parenteral absorption enchancing vehicle base comprises
1. Dimethylacetamide : 5 % to 12 % w/v.
2. . Benzyl benzoate : 20 % to 50 % w/v.
3. Benzyl alcohol : 0 % to 10' % w/v.
4. Ethyl oleate : 30 % to 65 % w/v. According to a preferred embodiment of the present invention, the novel Therapeutic Injectable Analgesic Composition comprises:

1. Nimesulide : 5 % w/v.
2. Dimethylacetamide : 10% w/v.
3. Benzyl benzoate : 40 % w/v.
4. Benzyl alcohol : 2 % w/v.
5. Ethyl oleate : 30 % to 65 % w/v. According to another preferred embodiment of the present invention, the Benzyl benzoate used is replaced in part by 5% to 10% w/v of Cremophor EL.
According to another preferred embodiment of the present invention, a conventionally known anti-oxidant such as ascorbyl palmitate, butyl hydroxy anisole, butyl hydroxy toluene, propyl gallate and a-tocopherol is added to the said Injectable analgesic composition.
The present invention also provides a process for the preparation of the novel Therapeutic Injectable Analgesic Composition, according to the present invention, which process comprises the
following steps:
(a) . 5% to 12% w/v of Dimethylacetamide and 20% to 505 w/v of
Benzyl benzoate are mixed in a container fitted with a Stirrer at slow speed (1000-1500 rpm) and to that 3% to 7% w/v of Nimesulide is added and stirred till completely dissolved.
(b) 0% to 10% w/v of Benzyl alcohol and a portion of 30% to 65% w/v of Ethyl oleate are mixed in a container fitted with a stirrer.
(c) The mixture obtained in step (a) is added to the mixture obtained in step (b) under slow stirring and the volume of the mixture obtained is made upto 100 ml by the rest of the amount of Ethyl Oleate resulting in the preparation of the desired Injectable analgesic Composition.
According to a preferred embodiment of the Process according to the present invention, in the step (a) of the said process 10% w/v of Dimethylacetamide and 40% w/v of Benzyl benzoate are mixed and to that 5% w/v of Nimesulide are added. In the step (b) of the. said process, 2% w/v of Benzyl alcohol and a portion of 30% to 65% w/v of Ethyl oleate are mixed.
Preferably the step (c) of the said process is carried out under continuous nitrogen flushing and- the resulting solution obtained is passed through 0.22 u nylon.membrane filter.
According to another preferred embodiment, of the present invention, a conventionally known anti-oxidant such as ascorbyl
palmitate, butyl hydroxy anisole, butyl hydroxy toluene, propyl .gallate and' oc-tocopherol is added to the said Injectable analgesic composition, as prepared.
The present invention is exemplified by the following examples for the preparation of the Injectable Analgesic composition.
Example 1
(a) Mix 10 g of Dimethylacetamide and 40 g of Benzyl benzoate in a container fitted with a stirrer at slow speed (1000-1200 rpm) at a temperature between 25°-30°. Add 5 g of Nimesulide in small increments and stir till completely dissolved.
(b) Mix 10 g of Cremophor EL and an amount of Ethyl oleate in a container fitted with a stirrer at room temperate.
(c) Add the mixture obtained in step (a) to the mixture obtained in step (b) under slow stirring and stir for about 30 minutes. Make up the volume upto 100 ml with Ethyl oleate and filter through 0.22 u nylon membrane filter to make it sterile.
Example II
(a) Mix 20 g of Dimethylacetamide and 76 g of Benzyl benzoate in a container fitted with a stirrer at slow speed at a temperature between 25°-30°C. Add to the mixture obtained 10 g of Nimesulide in smal1 amounts at a time and stirred till completely dissolved.
(b) Mix 4 g of Benzyl alcohol and an amount of Ethyl oleate in a container fitted with a stirrer at room temperature.
, (c)' Add the mixture obtained in step (a) to the mixture obtained in . step (b) under slow stirring and stir for about 3 0 minutes. Make up the volume upto 200 ml with Ethyl oleate and filter through 0.22 u nylon membrane filter to make it sterile.
The Injectable Analgesic composition, according to the present invention, on preliminary animal and preclinical trials has shown to possess marked analgesic activity. Further it has been found to be non-toxic even on repeated applications on the same site. No incidence of tissue necrosis or any other side effect was observed. The analgesic dose ranges from 0.16 mg/kg to 8.4 mg/kg. This analgesic composition is very effective and useful for the treatment of acute painful conditions like post-operative trauma, pain associated with cancer, sports injuries and the like.
The analgesic activity of the therapeutic composition, prepared according to the present invention, was found to be dose dependent and passed the tests • of subacute toxicity and undue toxicity.
The therapeutic Injectable Analgesic Composition, according to the present invention, is not a mere admixture but has properties different from the sum total of the properties of its ingredients, as stated herein above.
Since many apparently different embodiments of the present invention could be made without departing from the spirit and scope thereof, it is intended that the description of the
invention herein be interpreted as being illustrative only and not' limiting 'in any manner whatsoever.

We claim:
1. A novel therapeutic analgesic pharmaceutical composition for intra-muscular administration
comprising the following ingredients:
Nimesulide 2.5% to 10% w/v
Parenteral absorption enhancing vehicle base 90% to 97.5% w/v
wherein said parenteral absorption enhancing base comprises:
Dimethylacetamide 5% to 12% w/v
Benzyl benzoate 20% to 50% w/v
wherein the benzyl benzoate used is replaced in part by 5% to 10% w/v of Cremophor EL.
Benzyl alcohol 0% to 10% w/v
Ethyl oleate 30% to 65% w/v
and optionally an anti-oxidant is added to the composition.
2. The novel therapeutic analgesic pharmaceutical composition as claimed in claim 1, wherein
the parenteral absorption enhancing vehicle base comprises the following ingredients:
Dimethylacetamide : 10% w/v
Benzyl benzoate : 40% w/v
Benzyl alcohol : 2% w/v
Ethyl oleate : 30% to 65% w/v.
3. A process for the preparation of novel therapeutic analgesic pharmaceutical composition
containing nimesulide for intra-muscular administration as claimed in claim 1, which
comprises the following steps:
a) mixing 5% to 12% w/v of dimethylacetamide and 20% to 50% w/v of benzyl benzoate in a container and adding thereto 2.5% to 10% w/v of nimesulide and stirring till completely dissolved,
b) mixing separately 0% to 10% w/v of benzyl alcohol and a portion of 30% to 65% w/v of ethyl oleate,
c) adding the mixture obtained in step (a) to the mixture obtained in step (b) under slow stirring resulting in the preparation of the desired analgesic composition.
4. The process as claimed in claim 3, wherein in step (a), 10% w/v of dimethylacetamide and 40% w/v of benzyl benzoate are mixed and to that is added 5% w/v of nimesulide.
5. The process as claimed in claim 4, wherein in step (b), 2% w/v of benzyl alcohol and a portion of 30% to 65% w/v of ethyl oleate are mixed.
6. The process as claimed in claim 5, wherein the benzyl benzoate used in step (a) is replaced in part by 5% to 10% w/v of Cremophor EL.
7. The process as claimed in claim 5, wherein an antioxidant is added to the analgesic composition as prepared.