FORM 2
THE PATENT ACT 1970
(39 of 1970)
&
The Patents Rules, 2003
COMPLETE SPECIFICATION
(See section 10 and rule 13)
1. TITLE OF THE INVENTION:
"Stable Non-aqueous Aceclofenac gel formulation for topical use"
2. APPLICANT (S)
(a) NAME: LYKA LABS LIMITED.
(b)NATIONALITY: Indian Company incorporated under the Companies Act 1956
(c) ADDRESS: 77, Nehru Road, Vile Parle (East) Mumbai - 400 099, Maharashtra, India
3. PREAMBLE TO THE DESCRIPTION:
The following specification particularly describes the invention and the manner in which it is to be performed.

Technical field of the invention:
The present invention relates to the topical formulation containing Non-steroidal antiinflammatory drugs (NSAIDs), particularly Aceclofenac in the form of stable nonaqueous gel. The topical formulation is in the form of non-aqueous gel particularly useful for relief of pain and inflammation associated with acute musculo-skeletal pain in adults like, backache, arthritis, strains and sprains etc.
Background and prior art:
Non-steroidal anti-inflammatory drugs (NSAIDs) are most widely used for treating pain, inflammation, fever, and to treat and prevent atherosclerosis. Though these drugs are highly effective, oral administration of many NSAIDs can cause serious gastrointestinal disorders or ulcerative problems. Extended use of these drugs can cause liver and kidney damages. To avoid/minimize these adverse effects associated with oral administration, non-oral delivery of NSAIDs has been extensively investigated in recent years.
Transdermal delivery of NSAIDs is particularly useful for treatment of rheumatoid arthritis and related conditions, which are characterized by painful and swollen joints due to inflammation in the musculoskeletal tissues of the joints. However, although topical administration of certain NSAIDs has been shown to deliver the drug to the local musculoskeletal tissues of joints where arthritic conditions often develops, due to the low solubility of NSAIDs in water, the effectiveness of topical administration of NSAIDs is limited by the inability of these drugs to permeate the skin.
Aceclofenac is an NSAID of the phenyl acetic acid group which has anti-inflammatory, analgesic and anti-pyretic action. Aceclofenac provides symptomatic relief in a variety of clinical conditions associated with pain and inflammation. Efficacy of Aceclofenac is comparable to other NSAID with regard to relief of pain and control of inflammation. US 6,818,224 discloses pharmaceutical compositions for sustained release of at least one active substance, such that the composition has a property of gelling instantaneously in the presence of an aqueous phase for treating periodontitis, gingivitis, dental abscesses, mouth ulcers and mycoses.
2

The prior art are appreciated for their ingenuity to provide for a formulations for treatment of pain/inflammation, however, there is a need for a more therapeutically selective approach for treatment of such pain/inflammation disorders.
The present invention therefore aims to provide for topical non-aqueous gel formulation of Aceclofenac which is useful for the treatment of relief of pain and inflammation associated with musculo skeletal disorders, backache, arthritis, strains and sprains
Object of the invention:
The object of the invention is to provide stable topical formulation comprising Aceclofenac, Methyl Salicylate, menthol and Linseed oil in the form of gel substantially non-aqueous gel useful for alleviating pain/inflammation associated with acute musculoskeletal pain, backache, arthritis, strains and sprains etc.
Summary of the invention:
The present invention relates to the topical stable non-aqueous gel formulation of Aceclofenac which is useful for the treatment of relief of pain and inflammation associated with musculo skeletal disorders, backache, arthritis, strains and sprains. The Aceclofenac gel formulation comprises three fast active pain relievers- Aceclofenac, Methyl Salicylate and Menthol.
Detailed Description
The present invention describes a topical non-aqueous gel formulation comprising three fast active pain relievers - Aceclofenac, Methyl Salicylate and Menthol. The topical formulation has the distinct advantage over aqueous based gel in terms of better stability of Aceclofenac drug.
A stable topical gel formulation according to the present invention comprises Aceclofenac (1.5 % w/w), Methyl Salicylate (10 % w/w), menthol (5 % w/w), Linseed oil ( 3 % w/w) and other pharmaceutically acceptable excipients for the treatment of relief of pain and inflammation related disorders.
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The analgesic effect of Aceclofenac on the pain induced experimentally and mechanical stimuli was nearly equal to that of Indomethacin and Diclofenac.
Methyl salicylate and Menthol are external analgesics, which stimulate sensory receptors of warmth and or cold. This produces a counter irritant response, which provides temporary relief of aches and pains of muscles and joints.
Linseed oil contains predominantly Essential Fatty acids. On percutaneous absorption, alpha- Linolenic acid gets converted to Eicosapentanoic acid (EPA). EPA is acted upon by cyclooxygenase enzyme to produce prostaglandin E3, which is a weak inflammatory agent. Presence of EPA prevents the action of cyclooxygenase on Arachidonic Acid which reduces its conversion to PGE2, (a highly inflammatory agent). Presence of PGE3 itself modulates the inflammatory response through a feedback mechanism.
Aceclofenac is easily soluble in organic solvent and slightly soluble in water. With nonaqueous base it forms homogeneous gel formulation which is opaque with non-aqueous base and has distinct advantage over aqueous based gel in terms of better stability of Aceclofenac drug.
A topical formulation of the present invention comprises the pharmaceutical excipients selected from the group of gel former, co-solvent and pharmaceutically acceptable solvent or combination thereof.
The gel former is Carbomer 980 and used in an amount ranging from 2.0 - 4 % w/w, preferably 2.85 % w/w.
The co-solvent is propylene glycol and used in an amount ranging from 30-70 % w/w, preferably 57 wt%.
The pharmaceutically acceptable solvent is isopropyl alcohol in an amount of 10-30 % /w, preferably 20 % w/w.
4

The topical non aqueous gel formulation is manufactured by the process comprising the
steps of;
i) filter propylene Glycol and transfer to an S.S. vessel. Add Carbomer 980 (Acrypol 980)
under stirring. Give fast stirring and keep overnight, a clear thick gel will be formed;
ii) filter propylene Glycol and linseed oil in S. S. vessel under stirring and mix well;
iii) transfer methyl Salicylate in an S. S. vessel and add Menthol under slow stirring. Mix
till Menthol is completely dissolved;
iv) filter the solution of step iii) and add slowly to the contents of step ii) mix well;
v) add Aceclofenac powder to solution of step iv) (mixture of propylene glycol, Linseed
oil, Methyl salicylate and Menthol)under constant stirring till all Aceclofenac get
uniformly dispersed;
vi) add Isopropyl Alcohol to step v) under constant stirring for 20 minutes till solution
becomes almost clear (solution A);
vii) transfer Carbomer gel of step i) to anchor mixer and rinse the S.S. vessel using
filtered Propylene Glycol;
viii) transfer the solution A of step vi) to anchor mixer of step vii) under constant stirring.
Give rinsing with mixture of Iso propyl alcohol and propylene glycol. Mix well till the
solution and carbomer forms uniform consistency, mix for sufficient time in anchor mixer
till smooth translucent gel is formed.
This technique, however, may be used to prepare stable topical gel formulation comprising NSAIDS such as Etoricoxib, Nimesulide etc as an active ingredient in therapeutically effective amount.
Two experimental trials of aceclofenac, methyl salicylate, menthol and linseed oil utilising "aqueous" base gel were prepared using the following ingredients: Aceclofenac, methyl salicylate, menthol, linseed oil, carbomer 980 (acrypol 980), polyoxy 40 hydrogenated castor oil (cremophor RH 40), disodium EDTA, benzyl alcohol, butylated hydroxy toluene, propylene glycol, citric acid (anhydrous), isopropyl alcohol, diethyl amine and purified water.
The batches were kept for stability studies. Aceclofenac assay was found to drop from initial 105.12% to 85 .32% and from 104.86% to 84 .71% at 6M/ 30°C/60%RH.
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As Aceclofenac was found unstable in "aqueous" base gel, a non-aqueous gel formulation consisting of aceclofenac, methyl salicylate, menthol and linseed oil were prepared and studied for increasing the stability of Aceclofenac in the gel formulation. At accelerated conditions of stability, the "non-aqueous" gel formulation is found to be stable for the studied period.
Stability data of Aceclofenac "non aqueous" gel wherein the overage is Aceclofenac
7% , methyl salicylate 2% and menthol 5% having proposed shelf life of 18 months
and the assay for aceclofenac is within limits during the period of study.
The stability results of trial experiments of Non-aqueous gel formulation are tabulated as
follows;
TRIAL-I

TEST INITIAL 30°C, 60% RH6 Months 30°C, 60% RH12 Months
Description * NSC NSC
PH (Limit: (2.5 to 4.5) 3.09 3.16 3.15
Assay (Limit: 90% to 110%)
a) Content of Aceclofenac BP 105.41% 103.99% 101.84%
b) Content of Methyl Salicylate IP 103.5% 101.11% 101.26%
c) Content of Menthol BP 107.0% 106.23 % 103.0 %
Remark: * Description: A white opaque homogenous gel
NSC = No Significant change TRIAL -II

TEST INITIAL 30°C, 60% RH6 Months 30°C, 60% RH12 Months
Description * NSC NSC
PH (Limit: (2.5 to 4.5) 3.12 3.16 3.19
Assay (Limit: 90% to 110%)
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a) Content of AceclofenacBP 106.6% 104.8% 102.16%
b) Content of Methyl Salicylate IP 103.8% 105.1 % 101.49%
c) Content of Menthol BP 105.6% 105.12% 103.9 %
Remark: * Description: A white opaque homogenous gel NSC = No Significant change
TABLE -III

TEST INITIAL 30°C, 60% RH6 Months 30°C, 60% RH12 Months
Description * NSC NSC
PH (Limit: (2.5 to 4.5) 3.12 3.16 3.19
Assay (Limit: 90% to 110%)
a) Content of AceclofenacBP 105.6% 103.8 % 101.90%
b) Content of Methyl Salicylate IP 103.8% 102.1 % 101.59%
c) Content of Menthol BP 105.6% 104.12% 102.9%
Remark: * Description: A white opaque homogenous gel NSC = No Significant change
It will be readily apparent to one skilled in the art that varying substitutions and modifications may be made to the invention disclosed herein without departing from the scope of the invention. Thus, it should be understood that although the present invention has been specifically disclosed by preferred embodiments and optional features, modification and variation of the concepts herein disclosed may be resorted to by those skilled in the art, and that such modifications and variations are considered to be falling within the scope of the invention.
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The present invention is illustrated by the examples that follow, it being understood, however, that the invention is not limited to the specific details of these Examples While we disclose here specific examples of our invention, it is possible for one of skill in the art to use our teachings to develop variations on our specific examples to achieve the goals of our invention. Thus, we intend the scope of our patent to be defined not by the specific examples recited here, but by the claims we append here.
EXAMPLES Example 1:
Each 500 gm gel formulation comprises:

Ingredients Qty./lotof500gm O/A(overages)
Aceclofenac 8.025 gm 7%
Methyl Salicylate 51.00 gm 2%
Menthol 26.25 gm 5%
Linseed oil 15.3 gm 2%
Acrypol 980 (Carbomer 980) 14.25 gm
Propylene Glycol 286.00 gm -
Isopropyl Alcohol 100.00 gm -
The process of preparation of the gel formulation is as follows:
i) filter 225 gm of propylene Glycol and transfer to an S.S. vessel. Add Carbomer 980
(Acrypol 980) under stirring and keep overnight; a clear thick gel is formed;
ii) filter 25 gm propylene Glycol and 15.3 gm linseed oil in S. S. vessel and mix well by
stirring;
iii) transfer 51 gm of methyl Salicylate in an S. S. vessel, add 26.25 gm Menthol under
slow stirring Mix till Menthol is completely dissolved;
iv) filter solution of step iii) and slowly add to the contents of step ii) mix well;
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v) add Aceclofenac powder to solution of step iv) (mixture of propylene glycol, Linseed
oil, Methyl salicylate and Menthol) under constant stirring till all Aceclofenac uniformly
dispersed;
vi) add 80 gm Isopropyl Alcohol to step v) under constant stirring and stirred for 20
minutes till solution became almost clear (solution A)
vii) transfer Carbomer gel of step i) to anchor mixer, give rinsing to container using 10
gm of filtered Propylene Glycol;
viii) make a solution of 26 gm filtered Propylene Glycol and 20 gm Iso propyl alcohol;
ix) transfer the solution A of step vi) to anchor mixer under constant stirring. Give rinsing
with isopropyl alcohol and propylene glycol mixture of step viii). Mix well till the
solution and carbomer forms uniform consistency
x) stir the gel for sufficient time in anchor mixer till smooth transluscent gel is formed.
Check the pH of the gel and weigh the bulk;
xi) send sample of the gel to Quality Assurance department for analysis;
xii) store gel in air-conditioned area, preferably overnight.
xiii) after release of batch, start tube filling and packing as per packaging specifications.
Example 2
Each 500 gm gel formulation comprises:

Ingredients Qty./lotof500gm O/A (overages)
Aceclofenac 8.025 gm 7%
Methyl Salicylate 51.00 gm 2%
Menthol 26.25 gm 5%
Linseed oil 15.3 gm 2%
Acrypol 980 (Carbomer 980) 15.00 gm
Propylene Glycol 285.0 gm -
Isopropyl Alcohol 100.00 gm -
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The method of manufacture of the gel formulation is as follows:
i) filter 224 gm propylene Glycol and transfer to an S.S. vessel. Add Carbomer 980
(Acrypol 980) under stirring and keep overnight, a clear thick gel will be formed;
ii) filter 25 gm propylene Glycol and 15.3 gm linseed oil in S. S. vessel under stirring and
mix well;
iii) transfer 51 gm of methyl Salicylate in an S. S. vessel. Add 26.25 gm Menthol under
slow stirring. Mix till Menthol is completely dissolved;
iv) filter the solution of step iii) and add slowly to the contents of step ii) mix well;
v) add Aceclofenac powder to solution of step iv) ( mixture of Methyl salicylate,
Menthol, Linseed oil and propylene glycol) under constant stirring till all Aceclofenac get
uniformly dispersed;
vi) add 80 gm Isopropyl Alcohol to step v) under constant stirring, stir for 20 minutes till
solution becomes almost clear (solution A).
vii) transfer Carbomer gel of step i) to anchor mixer, give rinsing to container using 10
gm of filtered Propylene Glycol;
viii) make a solution of 26 gm filtered Propylene Glycol and 20 gm Isopropyl Alcohol;
ix) transfer solution A to anchor mixer under constant stirring. Give rinsing with
isopropyl alcohol and propylene glycol mixture of step viii). Mix well till the solution and
carbomer forms uniform consistency
x) Stir the gel for sufficient time in anchor mixer till smooth translucent gel is formed.
Check the pH of the gel and weigh the bulk;
xi) send sample of the gel to Quality Assurance department for analysis;
xii) store gel in air-conditioned area, preferably overnight.
xiii) after release of batch, start tube filling and packing as per packaging specifications.
Although the present invention has been disclosed and illustrated with reference to certain specific embodiments thereof, other different specific embodiments will readily occur to those skilled in the art based upon the teachings herein. The present invention should only be limited, therefore, by all embodiments which are covered by the spirit and scope of the appended claims.
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We claim,
1. A stable topical non aqueous gel formulation comprising particularly Aceclofenac as an active ingredient (1.5 % w/w), methyl salicylate (10 % w/w ), menthol ( 5 % w/w) , linseed oil ( 3 % w/w) and pharmaceutically acceptable excipients useful for the relief of pain and inflammation.
2. Stable topical formulation as claimed in claim 1, wherein pharmaceutical excipients are selected from gel former, co-solvent and pharmaceutically acceptable solvent or combination thereof.
3. Stable topical formulation as claimed in claim 1 and 2, wherein the gel former is Carbomer 980 and used in an amount ranging from 2 - 4 % w/w, preferably 2.85 % w/w.
4. Stable topical formulation as claimed in claim 1 and 2, wherein the co-solvent is propylene glycol and used in an amount ranging from 30-70 % w/w, preferably 57 % w/w.
5. Stable topical formulation as claimed in claim 1 and 2, wherein the pharmaceutically acceptable solvent is isopropyl alcohol in an amount of 10-30 % w/w, preferably 20 % w/w.
6. The process of manufacture of stable topical non aqueous gel formulation as claimed in claim 1 comprises the steps of;
i) filtering propylene glycol and transferring to an .vessel, adding Carbomer 980
(Acrypol 980) under stirring and kept overnight to form a clear thick gel;
ii) filtering propylene glycol and linseed oil in S. S. vessel under stirring and
mixed well;
iii) transferring methyl salicylate in an S. S. vessel, adding menthol under slow
stirring and mixed well till menthol is completely dissolved;
iv) filtering the solution of step iii) and slowly adding to the contents of step ii)
followed by mixing;
v) adding aceclofenac powder to solution of step iv) ( mixture of Methyl
salicylate, Menthol, Linseed oil and propylene glycol) under constant stirring till
all aceclofenac get uniformly dispersed;
vi) adding isopropyl alcohol to step v) under constant stirring for 20 minutes till
solution becomes almost clear(Solution A);
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vii) transferring the carbomer gel of step i) to anchor mixer and give rinsing to the container using filtered Propylene Glycol; and
viii) make a solution of 26 gm filtered Propylene Glycol and 20 gm Isopropyl Alcohol;
ix) transfer solution A to anchor mixer under constant stirring. Give rinsing with isopropyl alcohol and propylene glycol mixture of step viii) followed by stirring for sufficient time in anchor mixer till smooth transluscent gel is formed. 7. A topical non aqueous gel formulation as substantially described herein with reference to the forgoing examples 1 to 3.
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Abstract:
A stable topical non-aqueous gel formulation comprising NSAID, particularly Aceclofenac, methyl salicylate and linseed oil useful for the treatment of relief of pain and inflammation associated with acute musculo-skeletal pain in adults like backache, arthritis, strains and sprains etc.