FORM 2
THE PATENTS ACT 1970
(39 of 1970}
AND
The Patents Rules, 2003
PROVISIONAL SPECIFICATION
(See section 10 and rulel3)
1. TITLE OF THE INVENTION:
"PHARMACEUTICAL COMBINATION CONTAINING ETOR1COXIB, THIOCOLCHICOSIDE AND METHYL SALICYLATE"
2. APPLICANTS:
(a) NAME: LYKA LABS LIMITED
(b) NATIONALITY: Indian Company incorporated under the
Indian Companies ACT, 1956
(c) ADDRESS: 101, Shivshakti Industrial Estate, Andheri-Kurla Road,
Andheri (East), Mumbai - 400059, Maharashtra, India.
3. PREAMBLE TO THE DESCRIPTION
The following specification describes the invention.

Field oflnvention:
The present invention relates to a pharmaceutical combination such as gelor ointment containing an NSA1D, more particularly a COX-2 inhibitor in combination with a muscle relaxant, as well as a therapeutically effective amount of rubefacient and the process for preparations thereof.
More particularly, the current invention relates to combination of Etoricoxib, Thiocolchicoside and Methyl Salicylate in a gel or ointment formulation and processes for preparations thereof.
Background in invention:
Rheumatoid arthritis is the most common reversible disability in the world. Rheumatoid arthritis (RA) is a chronic, systemic inflammatory disorder that may affect many tissues and organs, but principally attacks the joints producing an inflammatory synovitis that often progresses to destruction of the articular cartilage and ankylosis (stiffness) of the joints. Rheumatoid arthritis can also cause diffuse inflammation in the lungs, pericardium, pleura and sclera and also nodular lesions most common in subcutaneous tissue under the skin. Although the cause of rheumatoid arthritis is unknown, autoimmunity plays a pivotal role in its chronicity and progression.
Soft tissue rheumatism is one of the most common and most misunderstood categories of disorders facing the primary care physician. Among the more common types are subacromial bursitis, epicondylitis, trochanteric bursitis, anserine bursitis, and fibromyalgia. The keys to the diagnosis of soft-tissue rheumatism are the history and, more importantly, the physical examination. Extensive laboratory testing and radiographs are not as helpful in evaluating patients with these complaints. Treatment consists of nonsteroidal anti-inflammatory drugs (NSAIDs) and nonnarcotic analgesics. Especially in patients with localized disorders, intralesional injections of corticosteroids are particularly effective and safe and should be part of the armamentarium of the primary care practitioner. Fibromyalgia is a particularly challenging form of nonarticular rheumatism. The clinical presentation is rather characteristic, with the patient typically being a woman 30-60 years of age who presents with diffuse somatic pain. Patients often give a history of sleep disturbance, may be depressed, and show characteristic tender areas, or trigger

points. Laboratory findings are normal. Management includes reassurance, correction of the underlying sleep disturbance with low doses of a tricyclic antidepressant, treatment with muscle relaxants and nonnarcotic analgesics or NSAIDs, and an exercise program with a strong aerobic component.
Osteoarthritis (OA, also known as degenerative arthritis, degenerative joint disease), is a group of diseases and mechanical abnormalities entailing degradation of joints, including articular cartilage and the subchondral bone next to it. Clinical symptoms of OA may include joint pain, tenderness, stiffness, inflammation, creaking, and locking of joints.
Essentially, all the above disorders are characterized by acute to chronic pain.
With a view of alleviating pain and muscular spasms in patients suffering from Osteoarthritis, Rheumatoid Arthritis, soft tissue rheumatism, sprain and low back ache a novel, effective pharmaceutical combination of Etroicoxib, Thiocholchicoside and methyl salicylate is introduced herein.
Etoricoxib is a COX-2 selective inhibitor (approx. 106.0 times more selective for COX-2 inhibition over COX-1) from Merck & Co. Etoricoxib was first disclosed in US Patent No. 5861419 assigned to Merck Frosst Canad, Inc. which has following structure

Chemically etoricoxib is 5-chloro-6'-methyl-3-[4-(methylsulfonyl)phenyl]-2,3'-bipyridine and the empirical formula for the same is C18H15ClN2O2S.
Like any other COX-2 selective inhibitor, Etoricoxib selectively inhibits isoform 2 of cyclooxigenase enzyme (COX-2). This reduces the generation of prostaglandins (PGs)

from arachidonic acid. Among the different functions exerted by PGs, their role in the inflammation cascade should be highlighted. COX-2 selective inhibitor showed less marked activity on type 1 cyclooxigenase compared to traditional non-steroidal anti-inflammatory drugs (NSA1D). This reduced activity is the cause of reduced gastrointestinal toxicity, as demonstrated in several large clinical trials performed with different coxibs.
Thiocolchicoside or 3-demethyl-thiocolchicine glucoside is a muscle relaxant agent with anti-inflammatory and analgesic actions, also used topically for the treatment of muscular spasms and for rheumatologic, orthopedic, and traumatologic disorders. Thiocolchocoside was first disclosed in French patent FR1113761 dated May 10, 1954 granted to Usines Chimiques Des Laboratories Francais (U.C.L.A.F.), Structurally Thiocolchicoside can be represented as follows:

Chemically Thiocolchicoside is known as N-[3-(P-D-glucopyranosyloxy)-l,2-dimethoxy-10'(methylthio)-9-oxo-5,6,7,9-tetrahydrobenzo[a]heptalen-7-yl]acetamide.
Thiocolchicoside is semi-synthetic derivative of the naturally occurring compound colchicoside with a relaxant effect on skeletal muscle. Thiocolchicoside displaces both [3H] gamma-am inobutyric acid ([3H] GAB A) and [3H] strychnine binding, suggesting an interaction with both GABA and strychnine-sensitive glycine receptors.
Methyl salicylate is also known as wintergreen oil. Methyl salicylate is methyl ester of salicylic acid. Methyl Salicylate is widely used topically in rubefacient preparations for the relief of pain; it causes vasodilation due to its effect on 'C-fiber' which carries sensory impulses. Methyl Salicylate provides pain relief by acting through the peripheral reflux network which is known to provide analgesic action. The empirical formula of methyl salicylate is C8H8O3 having chemical structure as below:


Summary of invention
The main object of the invention is to provide a combination of COX-II inhibitor, a muscie relaxant and rubifacient to alleviate pain and muscular spasms in patients suffering from Osteoarthritis, Rheumatoid Arthritis, soft tissue rheumatism, sprain and low back ache. Preferably the instant invention provides a combination of Etoricoxib, thiocolchicoside and methyl salicylate in gel or ointment formulation.
Detailed Description of Invention:
The invention will now be described in details m connection with certain preferred and optional embodiments so that various aspects thereof may be more fully understood and appreciated
The present invention describes a pharmaceutical combination of COX-II inhibitor, a muscle relaxant and rubifacient, preferably a combination of etoricoxib, thiocolchicoside and methyl salicylate in gel or ointment formulation for alleviating pain and muscular spasms in patients suffering from Osteoarthritis, Rheumatoid Arthritis, soft tissue rheumatism, sprain and low back ache.
The present invention relates to a topical gel based formulation comprising a therapeutically effective amount of Etoricoxib. Thiocolchicoside in combination with Methyl Salicylate.
In an embodiment, the gel composition of current invention comprises etoricoxib in range of 0.5 to 1.5% w/w, thiocolchicoside in range of 0.05 to 0.25% w/w and methyl salicylate in range of 5 to 15% w/w in gel base.
A suitable gel base would comprise semi-solid system in which a liquid phase is constrained within a three dimensional polymeric matrix with a high degree of cross-

linking. The liquid phase may conveniently comprise water, together with from 0 to 50% of water-miscible additives, for example glycerol, polyethylene glycol, ethoxydiglycol, ethanol or propylene glycol, and a thickening agent, which may be a natural product, for example tragacanth, pectin, carrageen, agar and alginic acid, or a synthetic or semi-synthetic compound, for example methylcellulose and carboxypolymethylene ('carbopol'); together with one or more preservatives, if required, such as, methyl 4-hydroxybenzoate ('methyl paraben'), propyl paraben or phenoxyethanol.
The topical gel based composition further comprises pharmaceutically acceptable excipients selected from a gelling agent, a co-solvent, a buffering agent, a surfactant, a chelating agent, an anti-oxidant, a preservative and a vehicle.
In preferred embodiment the gel formulation as above comprises a gelling agent such as, carbopol 980 in a range of 0.5 to 2.0% w/w.
The gel formulation further comprises a co-solvent selected form propylene glycol in range of 5 to 80% w/w and/or isopropyl alcohol.
The gel formulation further comprises a buffering agent such as, citric acid anhydrous in range of 0.01 to 0.1% w/w.
The gel formulation further comprises of a surfactant such as, cremophore RH 40 in range of 2 to 5%w/w.
The gel formulation further comprises of a chelating agent such as, disodium edtate in range of 0.005 to 0.2% w/w.
The gel formulation further comprises of an antioxidant such as, butylated hydroxyl toluene in range of 0.1 to 0.5% w/w.
The gel formulation further comprises of a preservative selected from benzyl alcohol in range of 0.5 - 1.0% w/w and/or methyl paraben 0.05 to 0.25% w/w and/or propyl paraben in range of 0.01 to 0.1% w/w.

In another embodiment the composition of present invention comprises etoricoxib in range of 0.5 to 1.5% w/w, thiocolchicoside in the range of 0.05 to 0.25% w/w and methyl salicylate in the range of 5 to 15% w/w in ointment base.
The topical ointment composition further comprises a surfactant, and a solubilizer.
In a preferred embodiment, the ointment formulation as above comprises a surfactant such as, sorbitan sesquioleate in range of 0.1 to 2.0% w/w.
The ointment formulation further comprises a solubilizer such as, propylene glycol in range of 5 to 15% w/w.
The ointment formulation further comprises of an ointment base selected from white soft paraffin in range of 80-95% w/w and/or white bees wax in range from 2 to 10% w/w or a combination thereof.
The instant invention is more specifically explained by following examples. However, it should be understood that the scope of the present invention is not limited by the examples in any manner. It will be appreciated by any person skilled in this art that the present invention includes following examples and further can be modified and altered within the technical scope of the present invention.
Examples: EXAMPLE 1
Composition for the preparation of gel is as follows:

Active ingredient Etoricoxib 0.5 - 1.5%w/w

Methyl Salicylate 5-15% w/w/

Thiocolchicoside 0.05-0.25%w/w
Gelling agent Carbopol 980 0.5-2.0%w/w
Co-solvent Propylene Glycol 5-80% w/w

Isopropyl Alcohol

Buffering agent Citric acid anhydrous 0.01-0.1% w/vv
Surfactant Cremophore RH 40 2-5% w/w
Chelating agent Disodium EDTA 0.005-0.2% w/w
Ariti oxidant Butylated Hydroxy Toluene 0.1-0.5% w/w
Preservative Benzyl Alcohol 0.5 - 1.0% w/w

Methyl paraben 0.05-0.25% w/w

Propyl paraben 0.01-0.1% w/w
Vehicle Purified Water q.s
1) Preparing carbopol 980 slurry in sufficient quantity of purified water;
2) dissolving chelating agent and buffering agent in sufficient quantity of purified water and adding to carbopol slurry of step 1;
3) adjusting pH of the slurry, with Diethanolamine or Triethanolamine, to about 4.5 till gel formation takes place;
4) mixing properly methyl salicylate with isopropyl alcohol and surfactants like cremophor RH 40 till clear solution is obtained;
5) dissolving or dispersing thiocolchicoside in co-solvent such as propylene glycol;
6) dissolving or dispersing Etoricoxib in co-solvent such as propylene glycol:
7) adding and dissolving preservatives and antioxidant to solution of step 6;
8) adding solution of step 4 to gel of step 3 and mining properly;
9) adding solution of step 5 & 7 to bulk of step 8 and mixing properly, and
10) adjusting final weight of bulk with purified water and checking pH which may be around 5.0.
EXAMPLE 2
Composition for the preparation of Ointment is as follows:

Active ingredient Etoricoxib 0.5-1.5%w/w

Methyl Salicylate 5-15% w/w/

Thiocolchicoside 0.05~0.25%w/w
Surfactants Sorbitan Sesquioleate 0.1-2.0% w/w
Solubilizer Propylene glycol 5-15% w/w
Ointment base White soft paraffin 80-95% w/w

1 Ointment base 1 White bees wax 1 2-10%w/w
Process for preparation of the Ointment formulation of Example 3:
1) Melting ointment base excipients and mixing surfactant to ointment base;
2) adding Thiocolchicoside in bulk either by dissolving or dispersing in solubilizer;
3) adding Etoricoxib in bulk either by dissolving or dispersing in solubilizer;
4) adding methyl salicylate to bulk, and mixing properly
5) cooling and stirring the bulk till ointment formation takes place.
Overages of Thiocolchicoside and Etoricoxib can be added for the long term stability purpose.
Stability study of the product is carried out as per 1CH guideline for 6 months at accelerated condition of 40°C / 75% RH and real time condition of 30°C / 65%RH Product is stable.

We claim,
1) A pharmaceutical combination comprising:
(a) Etoricoxib in range of 0.5-1.5% w/w;
(b) Thiocolchicoside in range of 0.05-0.25% w/w, and
(c) Methyl Salicylate in range of 5-15% w/w along with pharmaceutically acceptable excipients.

2) The pharmaceutical combination as claimed in claim 1 is formulated as gel or ointment.
3) The pharmaceutical combination as claimed in claim 2, wherein the gel formulation further comprises a gelling agent, a co-solvent, a buffering agent, a surfactant, a chelating agent, an anti-oxidant, a preservative.
4) The pharmaceutical combination as claimed in claim 3, wherein;

(a) The gelling agent is Carbopol 980 in range of 0.5-2.0% w/w;
(b) The co-solvent is selected form Propylene Glycol in range of 5-80% w/w and isopropyl Alcohol;
(c) The buffering agent is citric acid anhydrous in range of 0.01-0.1% w/w;
(d) The surfactant is Cremophore RH 40 in range of 2-5% w/w;
(e) The chelating agent is disodium EDTA in range of 0.005-0.2% w/w;
(f) The antioxidant is Butylated Hydroxy Toluene in range of 0.1-0.5% w/w; and
(g) The preservative is selected form Benzyl Alcohol in range of 0.5 - 1.0% w/w Methyl paraben in range of 0.05-0.25% w/w, Propyl paraben in range of 0.01-0.1 % w/w or combinations thereof.

5) The pharmaceutical combination as claimed in claim 2, wherein the ointment formulation further comprises, a surfactant, a solubilizer and an ointment base.
6) The pharmaceutical combination as claimed in claim 5, wherein,

(a) The surfactants is Sorbitan Sesquioleate in range of 0.1-2.0% w/w
(b) The solubilizer is Propylene glycol in range of 5-15% w/w
(c) The ointment base is selected from White soft paraffin in range of 80-95% w/w, White bees wax in range of 2-10% w/w, or combination thereof.

7) The pharmaceutical combination according to claim 3 and 4 is manufactured by
process comprising of:
(a) Preparing carbopol 980 slurry in sufficient quantity of purified water;
(b) dissolving chelating agent and buffering agent in sufficient quantity of purified water and adding to carbopol slurry of step (a);
(c) adjusting pH of the slurry, with Diethanolamine or Triethanolamine, to about 4.5 till gel formation takes place;
(d) mixing properly methyl salicylate with isopropyl alcohol and surfactants like cremophor RH 40 till clear solution is obtained;
(e) dissolving or dispersing thiocolchicoside in co-solvent such as propylene glycol;
(f) dissolving or dispersing Etoricoxib in co-solvent such as propylene glycol;
(g) adding and dissolving preservatives and anti-oxidant to solution of step (f);
(h) adding solution of step (d) to gel of step (c) and mixing properly;
(i) adding solution of step (e) & (g) to bulk of step (h) and mixing properly, and (j) adjusting final weight of bulk with purified water and checking pH which may be around 5.0.
8) The pharmaceutical combination according to claim 5 and 6 is manufactured by
process comprising of:
(a) Melting ointment base excipients and mixing surfactant to ointment base;
(b) adding Thiocolchicoside in bulk either by dissolving or dispersing in solubilizer;
(c) adding Etoricoxib in bulk either by dissolving or dispersing in solubilizer;
(d) adding methyl salicylate to bulk, and mixing properly, and
(e) cooling and stirring the bulk till ointment formation takes place.