Title of Invention	"PARENTERAL WATER MISCIBLE COMPOSITION OF NON-STEROIDAL ANTI-INFLAMMATORY DRUGS"
Abstract	A Parenteral Water-miscible non-intensely colored injectable composition of Non-steroidal anti-inflammatory drugs is disclosed. The invention utilizes solubilization techniques to achieve sufficiently high concentrations of Nimesulide suitable to deliver therapeutic doses in conveniently small volumes using water and without using any salt form of Nimesulide or any complexing agent. In the composition of the invention all the ingredients of the base are hydrophillic. The hydrophillic base serves the advantage of better miscibility with body fluids, faster drug disposition and better compatibility with the tissue environment.

Title of Invention

"PARENTERAL WATER MISCIBLE COMPOSITION OF NON-STEROIDAL ANTI-INFLAMMATORY DRUGS"

Abstract

A Parenteral Water-miscible non-intensely colored injectable composition of Non-steroidal anti-inflammatory drugs is disclosed. The invention utilizes solubilization techniques to achieve sufficiently high concentrations of Nimesulide suitable to deliver therapeutic doses in conveniently small volumes using water and without using any salt form of Nimesulide or any complexing agent. In the composition of the invention all the ingredients of the base are hydrophillic. The hydrophillic base serves the advantage of better miscibility with body fluids, faster drug disposition and better compatibility with the tissue environment.

Full Text	PARENTERAL WATER-MISCIBLE INJECTABLE PHARMACEUTICAL COMPOSITION OF NSAID'S The present invention relates to novel therapeutic non intensely coloured, water miscible injectable analgesic pharmaceutical compositions of Non-steroidal anti-inflammatory drugs and a process for the manufacture of such drugs. The analgesic injectable composition is very useful in mammals particularly in humans for the treatment of acute painful conditions like post operative trauma, pain associated with cancer, sports injuries, migraine headache, neurological pain, pain associated with sciatica and spondylitis. For these indications some modified route of administrations may also be construed. BACKGROUND OF THE INVENTION Non-steroidal anti-inflammatory drugs such as those belonging to the category of Cyclo-oxygenase-2 inhibitors including Nimesulide are highly hydrophobic compounds and readily precipitate even in the presence of minor amounts of water. It is therefore very difficult to formulate Non-steroidal anti-inflammatory drugs which are inhibitors of Cyclo-oxygenase-2 as an injection for intramuscular or intravenous use. In the past, efforts have been made to make an injectable composition of Nimesulide. An injectable formulation of Nimesulide has been reported in the prior art PCT Patent No. WO 95/34533 which utilizes a salt form of Nimesulide with L-lysine which is in turn further complexed with cyclodextrins which may be dissolved in water to give an injectable preparation. The maximum solubility achieved by this injectable composition was reported to be 2.4 mg/ml which is not sufficient for intramuscular administration as it would require very large volumes to administer therapeutic doses. Moreover making a salt form of Nimesulide and then combining with Cyclodextrins not only makes the process cumbersome but also increase the cost of the formulations. Another reference (Daffonchio. L et al. Inflammatory Research 45: 259-264; 1995) wherein Nimesulide is dissolved in saline for intravenous administration for experimental studies in animals also describes only very dilute solutions which cannot deliver therapeutic doses in humans. The disadvantages of WO 95/34533 and problems associated therewith were overcome by the invention described in Indian Patent No. 186558. This inventions utilizing solubilization techniques was able to achieve sufficiently high concentrations of Nimesulide suitable to deliver therapeutic doses in conveniently small volumes using a base which was oily in nature without using water and without any salt form or complexing agents of Nimesulide. The present invention comprises a composition wherein all the ingredients of the base are hydrophilic. The hydrophilic base serves the advantages of better miscibility with body fluids, faster drug disposition and better compatibility with the tissue environment. It is an objective of the present invention to provide an injectable analgesic hydrophilic composition of Non-steroidal anti-inflammatory drugs which are non-intensely coloured having better miscibility with body fluids. Such hydrophilic compositions described herein can be administered by intravenous routes also in addition to intramuscular route. It is another objective of the present invention to provide a novel process for the preparation of a parenteral hydrophilic injectable composition of NSAIDs. SUMMARY OF THE INVENTION The invention comprises a novel injectable aqueous miscible composition of Cyclo-oxygenase-2 inhibitor such as Nimesulide which comprises: 1. Cyclooxygenase inhibitors 2. Alkyl amides/Alkyl sulphoxides and/or pyrrolidones 3. Glycols 4. 0 to 20% of water. DETAILED DESCRIPTION OF THE INVENTION The Cyclo-oxygenase-2 inhibitors belonging to the category of NSAIDs are selected from the group comprising of Nimesulide, Nabumetone, Tapoxalin and Flosulide and derivatives thereof. The Alkyl amides/ Alkyl sulphoxides or pyrrolidones in accordance with the present invention are selected from the group- Dimethylacetamide, Dimethylformamide and Dimethylsulphoxide or N-Methyl Pyrrolidone. The glycols in accordance with the present invention are selected from the group Polyethylene Glycol MW 200 to 6000, Propylene Glycol, Hexylene glycols, Butylene glycol and Glycol derivatives such as Polyethylene Glycol 660 hydroxy stearate (commercially available as Solutrol HS15). Besides the composition may also comprise the following convention additional ingredients - Surfactants, hydrophilic polymers, solubility enhancing agents i.e. Glycerine, various grades of Polyethylene oxides, p-cyclodextrins like sulfo butyl ether-p-cyclodextrin, Transcutol and Glycofurol, tonicity adjusting agents, local anesthetics, pH adjusting agents and buffers. Preferably the Non-steroidal anti-inflammatory drug belonging to the category of Cyclo-oxygenase-2 inhibitors is Nimesulide and derivatives thereof and is present in the composition from 0.1 to 10% w/v. More preferably Nimesulide is present from 0.5 to 8% w/v. More preferably Nimesulide is present in the composition from 1.2 to 4.8% w/v. Preferably the composition in accordance with the present invention comprises Alkyl amides/ Alkyl sulphoxides or pyrrolidones from 2.0 to 95% w/v. More preferably the composition comprises Alkyl amides/ Alkyl sulphoxides and/or pyrrolidones from 5% to 90%. More preferably Alkyl amides/ Alkyl sulphoxides or pyrrolidones are present from 10% to 20% w/v. Preferably Glycols are present in the composition from 0.1% to 95% w/v. In a preferred embodiment of the invention there is described an injectable water miscible non-intensely coloured analgesic pharmaceutical composition of Nimesulide which comprises: Nimesulide from : 0.1to10%w/v Dimethylacetamide from : 2.0 to 90% w/v Polyethylene Glycols from : 0.1 to 95% w/v Water from : 0 to 20% w/v In accordance with the present invention there is also described a novel process for the manufacture of an injectable water miscible analgesic pharmaceutical composition of a NSAID. The process comprises: a) Dissolving Nimesulide in Dimethylacetamide and adding thereto freshly distilled Benzyl Alcohol and stirring. Adding subsequently to the solution Polyethylene Glycol 400 to the above solution and mixing. Adding to the solution Hydrochloric Acid solution slowly with stirring and then adding to a Propylene Glycol to make volume upto 95% of the actual batch size. The solution formed pH between 2.0 to 3.0. If it is not in this range then adjust it either with Sodium Hydroxide (10% w/v solution) or Hydrochloric Acid solution. Make up the final volume with Propylene Glycol. b) Filter the resultant solution through 0.45 micron nylon membrane filter using a 6 micron glass fiber pre-filter. Collect the filtered solution in a clean fiber-free vessel. Fill the solution in fiber-free sterile 2 ml amber USP Type 1 glass ampoules with pre and post filling nitrogen flushing. c) Sterilize the ampoules by autoclaving. Optically inspect all the ampoules and after release by Quality Control Deptt. Label the good ones. The invention will now be described by the following examples for injectable analgesic composition of NSAIDs. Example 1 (Table Removed) Example 2 (Table Removed) Example 3 (Table Removed) Example 4 (Table Removed) The composition is of the type that has to be diluted prior to use with suitable diluents. Example 5 (Table Removed) On affecting Acute Toxicity studies on Balb/C Mice by intra peritoneal route the LD50 was found to be 160 mg/kg, ED50=3 mg/kg with therapeutic index = 53.3 in mice. This demonstrates high safety of the present invention. The injectable analgesic composition, according to the present invention, on preliminary animals and preclinical trials has shown to posses marked analgesic activity. Further it has been found to non-toxic even on repeated applications on same site. No incidence of tissue necrosis or any other side effect was observed. The analgesic dose range from 0.1 mg/kg to 8.4 mg/kg. Since many apparently different embodiments of the present invention could be made without departing from spirit and scope thereof, it is intended that the description of the invention herein to interpreted as being illustrative only and not limiting in any manner whatsoever. The composition of the present invention is not a mere admixture but is a synergistic composition wherein all the ingredients are not reacting but interacting with each other to produce a water miscible composition. We Claim: 1. A parenteral water-miscible non intensely coloured injectable pharmaceutical composition comprising: a) 0.1 to 10% w/v of atleast one Non-steroidal anti-inflammatory drug (NSAID) belonging cyclo-oxygenase-2 inhibitory category b) 2.0 to 95% w/v Alkyl amides/Alkyl sulphoxide and/or pyrrolidones c) 0.1 to 95% w/v of Glycol(s) d) 0 to 20% w/v of water 2. An parenteral water-miscible non intensely coloured injectable composition as claimed in claim 1, wherein the said NSAID is selected from the group comprising Nimesulide, Tapoxalin and Flosulide. 3. An parenteral water-miscible non intensely coloured injectable composition as claimed in claims 1 and 2 wherein said NSAID is Nimesulide and is present in the composition from 0.1 to 10% w/v. 4. An parenteral water-miscible non intensely coloured injectable composition as claimed in claims 1 to 3, wherein said Alkyl sulphoxides/Alkyl amides and/or pyrrolidones are selected from the group comprising Dimethylacetamide, Dimethylformamide, Dimethylsulphoxide or N-Methyl Pyrrolidone. 5. An parenteral water-miscible non intensely coloured injectable composition as claimed in claim 4, wherein said Alkyl sulphoxide/ Alkyl amide and/or pyrrolidone is Dimethylacetamide and is present in the composition from 2.0 to 95% w/v. 6. An parenteral water-miscible non intensely coloured injectable composition as claimed in claims 1 to 5, wherein said Glycols are selected from the group comprising Polyethylene Glycol MW 200 to 6000, Polypropylene glycol, Hexylene glycol, and Butylene glycol and Glycol derivatives such as Polyethylene Glycol 660 hydroxy stearate. 7. An parenteral water-miscible non intensely coloured injectable composition as claimed in claim 6 wherein said Glycol is Polyethylene Glycol 300 and is present in the composition from 0.1 to 95% w/v. 8. A parenteral water miscible non intensely coloured injectable pharmaceutical composition as claimed in claim 1 comprising: Nimesulide : 0.1 to 10% w/v Dimethylacetamide : 2.0 to 95% w/v Polyethylene Glycol 300 : 0.1 to 95% w/v Water : 0 to 20% w/v

Full Text

PARENTERAL WATER-MISCIBLE INJECTABLE PHARMACEUTICAL COMPOSITION OF NSAID'S
The present invention relates to novel therapeutic non intensely coloured, water miscible injectable analgesic pharmaceutical compositions of Non-steroidal anti-inflammatory drugs and a process for the manufacture of such drugs. The analgesic injectable composition is very useful in mammals particularly in humans for the treatment of acute painful conditions like post operative trauma, pain associated with cancer, sports injuries, migraine headache, neurological pain, pain associated with sciatica and spondylitis. For these indications some modified route of administrations may also be construed.
BACKGROUND OF THE INVENTION
Non-steroidal anti-inflammatory drugs such as those belonging to the category of Cyclo-oxygenase-2 inhibitors including Nimesulide are highly hydrophobic compounds and readily precipitate even in the presence of minor amounts of water.
It is therefore very difficult to formulate Non-steroidal anti-inflammatory drugs which are inhibitors of Cyclo-oxygenase-2 as an injection for intramuscular or intravenous use.

In the past, efforts have been made to make an injectable composition of Nimesulide.
An injectable formulation of Nimesulide has been reported in the prior art PCT Patent No. WO 95/34533 which utilizes a salt form of Nimesulide with L-lysine which is in turn further complexed with cyclodextrins which may be dissolved in water to give an injectable preparation. The maximum solubility achieved by this injectable composition was reported to be 2.4 mg/ml which is not sufficient for intramuscular administration as it would require very large volumes to administer therapeutic doses. Moreover making a salt form of Nimesulide and then combining with Cyclodextrins not only makes the process cumbersome but also increase the cost of the formulations.
Another reference (Daffonchio. L et al. Inflammatory Research 45: 259-264; 1995) wherein Nimesulide is dissolved in saline for intravenous administration for experimental studies in animals also describes only very dilute solutions which cannot deliver therapeutic doses in humans.
The disadvantages of WO 95/34533 and problems associated therewith were overcome by the invention described in Indian Patent No. 186558. This inventions utilizing solubilization techniques was able to achieve sufficiently high concentrations of Nimesulide suitable to deliver therapeutic doses in

conveniently small volumes using a base which was oily in nature without using water and without any salt form or complexing agents of Nimesulide.
The present invention comprises a composition wherein all the ingredients of the base are hydrophilic. The hydrophilic base serves the advantages of better miscibility with body fluids, faster drug disposition and better compatibility with the tissue environment.
It is an objective of the present invention to provide an injectable analgesic hydrophilic composition of Non-steroidal anti-inflammatory drugs which are non-intensely coloured having better miscibility with body fluids. Such hydrophilic compositions described herein can be administered by intravenous routes also in addition to intramuscular route.
It is another objective of the present invention to provide a novel process for the preparation of a parenteral hydrophilic injectable composition of NSAIDs.
SUMMARY OF THE INVENTION
The invention comprises a novel injectable aqueous miscible composition of Cyclo-oxygenase-2 inhibitor such as Nimesulide which comprises:

1. Cyclooxygenase inhibitors
2. Alkyl amides/Alkyl sulphoxides and/or pyrrolidones
3. Glycols
4. 0 to 20% of water.
DETAILED DESCRIPTION OF THE INVENTION
The Cyclo-oxygenase-2 inhibitors belonging to the category of NSAIDs are selected from the group comprising of Nimesulide, Nabumetone, Tapoxalin and Flosulide and derivatives thereof.
The Alkyl amides/ Alkyl sulphoxides or pyrrolidones in accordance with the present invention are selected from the group- Dimethylacetamide, Dimethylformamide and Dimethylsulphoxide or N-Methyl Pyrrolidone.
The glycols in accordance with the present invention are selected from the group Polyethylene Glycol MW 200 to 6000, Propylene Glycol, Hexylene glycols, Butylene glycol and Glycol derivatives such as Polyethylene Glycol 660 hydroxy stearate (commercially available as Solutrol HS15).
Besides the composition may also comprise the following convention additional ingredients - Surfactants, hydrophilic polymers, solubility enhancing agents i.e.

Glycerine, various grades of Polyethylene oxides, p-cyclodextrins like sulfo butyl ether-p-cyclodextrin, Transcutol and Glycofurol, tonicity adjusting agents, local anesthetics, pH adjusting agents and buffers.
Preferably the Non-steroidal anti-inflammatory drug belonging to the category of Cyclo-oxygenase-2 inhibitors is Nimesulide and derivatives thereof and is present in the composition from 0.1 to 10% w/v.
More preferably Nimesulide is present from 0.5 to 8% w/v.
More preferably Nimesulide is present in the composition from 1.2 to 4.8% w/v. Preferably the composition in accordance with the present invention comprises Alkyl amides/ Alkyl sulphoxides or pyrrolidones from 2.0 to 95% w/v.
More preferably the composition comprises Alkyl amides/ Alkyl sulphoxides and/or pyrrolidones from 5% to 90%.
More preferably Alkyl amides/ Alkyl sulphoxides or pyrrolidones are present from 10% to 20% w/v.
Preferably Glycols are present in the composition from 0.1% to 95% w/v.

In a preferred embodiment of the invention there is described an injectable water
miscible non-intensely coloured analgesic pharmaceutical composition of
Nimesulide which comprises:
Nimesulide from : 0.1to10%w/v
Dimethylacetamide from : 2.0 to 90% w/v
Polyethylene Glycols from : 0.1 to 95% w/v
Water from : 0 to 20% w/v
In accordance with the present invention there is also described a novel process for the manufacture of an injectable water miscible analgesic pharmaceutical composition of a NSAID.
The process comprises:
a) Dissolving Nimesulide in Dimethylacetamide and adding thereto freshly distilled Benzyl Alcohol and stirring. Adding subsequently to the solution Polyethylene Glycol 400 to the above solution and mixing. Adding to the solution Hydrochloric Acid solution slowly with stirring and then adding to a Propylene Glycol to make volume upto 95% of the actual batch size. The solution formed pH between 2.0 to 3.0. If it is not in this range then adjust it either with Sodium Hydroxide (10% w/v solution) or Hydrochloric Acid solution. Make up the final volume with Propylene Glycol.

b) Filter the resultant solution through 0.45 micron nylon membrane filter
using a 6 micron glass fiber pre-filter. Collect the filtered solution in a
clean fiber-free vessel. Fill the solution in fiber-free sterile 2 ml amber
USP Type 1 glass ampoules with pre and post filling nitrogen flushing.
c) Sterilize the ampoules by autoclaving. Optically inspect all the ampoules
and after release by Quality Control Deptt. Label the good ones.
The invention will now be described by the following examples for injectable analgesic composition of NSAIDs.
Example 1
(Table Removed)

Example 2
(Table Removed)
Example 3
(Table Removed)
Example 4
(Table Removed)
The composition is of the type that has to be diluted prior to use with suitable diluents.
Example 5
(Table Removed)
On affecting Acute Toxicity studies on Balb/C Mice by intra peritoneal route the LD50 was found to be 160 mg/kg, ED50=3 mg/kg with therapeutic index = 53.3 in mice. This demonstrates high safety of the present invention. The injectable
analgesic composition, according to the present invention, on preliminary animals and preclinical trials has shown to posses marked analgesic activity. Further it has been found to non-toxic even on repeated applications on same site.
No incidence of tissue necrosis or any other side effect was observed. The analgesic dose range from 0.1 mg/kg to 8.4 mg/kg.
Since many apparently different embodiments of the present invention could be made without departing from spirit and scope thereof, it is intended that the description of the invention herein to interpreted as being illustrative only and not limiting in any manner whatsoever.
The composition of the present invention is not a mere admixture but is a synergistic composition wherein all the ingredients are not reacting but interacting with each other to produce a water miscible composition.

We Claim:
1. A parenteral water-miscible non intensely coloured injectable
pharmaceutical composition comprising:
a) 0.1 to 10% w/v of atleast one Non-steroidal anti-inflammatory drug
(NSAID) belonging cyclo-oxygenase-2 inhibitory category
b) 2.0 to 95% w/v Alkyl amides/Alkyl sulphoxide and/or pyrrolidones
c) 0.1 to 95% w/v of Glycol(s)
d) 0 to 20% w/v of water

2. An parenteral water-miscible non intensely coloured injectable composition
as claimed in claim 1, wherein the said NSAID is selected from the group
comprising Nimesulide, Tapoxalin and Flosulide.
3. An parenteral water-miscible non intensely coloured injectable composition
as claimed in claims 1 and 2 wherein said NSAID is Nimesulide and is
present in the composition from 0.1 to 10% w/v.
4. An parenteral water-miscible non intensely coloured injectable composition
as claimed in claims 1 to 3, wherein said Alkyl sulphoxides/Alkyl amides
and/or pyrrolidones are selected from the group comprising
Dimethylacetamide, Dimethylformamide, Dimethylsulphoxide or N-Methyl
Pyrrolidone.
5. An parenteral water-miscible non intensely coloured injectable composition
as claimed in claim 4, wherein said Alkyl sulphoxide/ Alkyl amide and/or
pyrrolidone is Dimethylacetamide and is present in the composition from 2.0 to 95% w/v.
6. An parenteral water-miscible non intensely coloured injectable composition
as claimed in claims 1 to 5, wherein said Glycols are selected from the
group comprising Polyethylene Glycol MW 200 to 6000, Polypropylene
glycol, Hexylene glycol, and Butylene glycol and Glycol derivatives such
as Polyethylene Glycol 660 hydroxy stearate.
7. An parenteral water-miscible non intensely coloured injectable composition
as claimed in claim 6 wherein said Glycol is Polyethylene Glycol 300 and
is present in the composition from 0.1 to 95% w/v.
8. A parenteral water miscible non intensely coloured injectable
pharmaceutical composition as claimed in claim 1 comprising:
Nimesulide : 0.1 to 10% w/v
Dimethylacetamide : 2.0 to 95% w/v
Polyethylene Glycol 300 : 0.1 to 95% w/v
Water : 0 to 20% w/v

Documents:

57-del-1998-abstract.pdf

57-del-1998-claims.pdf

57-del-1998-correspondence-others.pdf

57-del-1998-correspondence-po.pdf

57-del-1998-description (complete).pdf

57-del-1998-form-1.pdf

57-del-1998-form-19.pdf

57-del-1998-form-2.pdf

57-del-1998-form-3.pdf

57-del-1998-gpa.pdf

57-del-1998-petition-138.pdf

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Patent Number

209110

Indian Patent Application Number

0057/DEL/1998

PG Journal Number

35/2007

Publication Date

31-Aug-2007

Grant Date

20-Aug-2007

Date of Filing

12-Jan-1998

Name of Patentee

PANACEA BIOTEC LIMITED

Applicant Address

102 ASHOK PLAZA, 24 SCHOOL LANE, NEW DELHI-110 001, INDIA.

Inventors:

#	Inventor's Name	Inventor's Address
1	AMARJIT SINGH	C/O 102 ASHOK PLAZA, 24 SCHOOL LANE, NEW DELHI-110 001, INDIA.
2	RAJESH JAIN	C/O 102 ASHOK PLAZA,24 SCHOOL LANE, NEW DELHI-110 001, INDIA.

PCT International Classification Number

A61K 31/00

PCT International Application Number

N/A

PCT International Filing date

PCT Conventions:

#	PCT Application Number	Date of Convention	Priority Country
1			NA