FORM 2
THE PATENTS ACT 1970
(39 of l970)
AND
The Patents Rules, 2003
COMPLETE SPECIFICATION
(See section 10 and rule l3)
1. TITLE OF THE INVENTION:
"TOPICAL FORMULATION FOR TREATMENT OF RHEUMATOID
ARTHRITIS"
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 particularly describes the invention and the manner in which it is to be performed.

FIELD OF INVENTION:
The present invention relates to a topical anti-inflammatory formulation comprising a novel combination of a myorelxant, a rubefacient with a counterirritant. More particularly, the instant invention relates to a novel combination of Thiocholcicoside with Methyl Salicylate and Menthol for treatment of rheumatoid arthritis and related symptoms.
BACKGROUND OF INVENTION:
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.
About 1% of the world's population is afflicted by rheumatoid arthritis, women three times more often than men. Onset is most frequent between the ages of 40 and 50, but no age is immune. It can be disabling and painful condition that leads to substantial loss of functioning and mobility. It is diagnosed chiefly on symptoms and signs, but also with blood tests (especially a test called rheumatoid factor) and X-rays.
Various non-pharmacological and pharmacological treatments are available for treatment of Rheumatoid arthritis. Non-pharmacological treatment includes physical therapy and occupational therapy. Pharmacological treatment of Rheumatoid arthritis can be divided into anti-inflammatory agents and analgesics. Analgesics (painkillers), anti-inflammatory drugs, as well as steroids, are used to suppress the symptoms. Further, solutions to the problem include rubbing ointments or creams on the affected area to lower the intense pain in the joints.
Thiocolchicoside [N-[3-(β-D-glucopyranosyioxy)-l, 2-dimethoxy-10-(methyithio)-9-oxo-5,6,7,9-tetrahydrobenzo[a]heptalen-7-yl]acetamide] a semi-synthetic derivative of the naturally occurring compound colchicoside, is a muscle relaxant agent with anti-

inflammatory and analgesic action. It is also used topically for the treatment of muscular spasms and for rheumatologic, orthopedic, and traumatologic disorders. Thiocolchicoside 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:
Further, Thiocolchicoside has been found to displace both [3H] gamma-aminobutyric acid ([3H] GABA) and [3H] strychnine binding, suggesting an interaction with both GABA and strychnine-sensitive glycine receptors.
Methyl salicylate (oil of wintergreen) 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. It also provides pain relief by acting through the peripheral reflux network which is known to provide analgesic action.
Menthol is a waxy, crystalline organic compound made either synthetically or obtained from peppermint or other mint oils. It has local anesthetic and counterirritant qualities. It also acts as a weak Kappa Opioid Receptor Agonist.
WO2007009772 discloses S-demethoxy-S-aminothiocolchicine derivatives having myorelaxant and anti-inflammatory activity.
Ample literature is available on various pharmaceutical combinations for the treatment of rheumatoid arthritis and related symptoms.
FR2735369 discloses pharmaceutical compositions containing a diclofenac salt and thiocolchicoside in the form of oral administration, parenteral, topical or rectal for the treatment of lumbagos, of dorsal and cervical osteoarthritis.

US5998480 discloses a pharmaceutical preparation containing nimesulide (NSAID), a phospholipid, and at least one acid for topical use in rheumatoid arthritis, psoriasis, or a cataract.
US6635659 discloses formulations for arthritis relief based on natural extracts from peppers can be topically applied to an affected area and provide relief to the patient.
US4543251 discloses a gel preparation comprising diclofenac gel composition comprising either menthol or methyl-sal icy late to improve the analgesic effect of composition.
Despite advances in medical science, many people still suffer from such maladies as gout, joint and muscle aches, cramps, swelling, bursitis, and joint pain. Thus there is a need to identify novel synergistic compositions that can be used to treat or ameliorate the symptoms of this chronic inflammatory disease.
In view of the above, the inventors introduce a novel topical gel and ointment formulation comprising a combination of Thiocolchicoside with methyl salicylate and menthol for treatment of Rheumatoid arthritis (RA) and related conditions such as, soft tissue rheumatism, sprain and low back ache.
SUMMARY OF THE INVENTION:
Accordingly, the invention provides a topical anti-inflammatory formulation comprising centrally acting myorelaxant, in combination with rubefacient and counterirritant.
In another aspect, the invention provides and topical anti-inflammatory formulation comprising Thiocolchicoside in combination with Methyl Salicylate and Menthol for treatment of Rheumatoid arthritis (RA) and related conditions such as, soft tissue rheumatism, sprain and low back ache.

DETAILED DESCRIPTION OF INVENTION:
The invention will now be described in details in connection with certain preferred and optional embodiments so that various aspects thereof may be more fully understood and appreciated.
The present invention describes topical anti-inflammatory formulation comprising a centrally acting myorelaxant in combination with a rubefacient and a counterirritant.
In a preferred embodiment, the present invention describes a topical anti-inflammatory formulation comprising a therapeutically effective amount of Thiocolchicoside in combination with methyl salicylate and menthol useful for treatment of Rheumatoid Arthritis (RA) and related conditions such as, soft tissue rheumatism, sprain and low back ache.
It must be noted that as used herein and in the appended claims, the singular forms "a", "an", and "the" include plural reference unless the context clearly dictates otherwise.
In an embodiment, the topical anti-inflammatory formulation of invention comprises Thiocolchicoside in combination with Methyl Salicylate and Menthol along with pharmaceutical excipients selected from gelling agents, or ointment base along with emollients, preservatives, antioxidants, buffering agent, chelating agent pH adjuster along with vehicle, surfactant, solubilizer and combinations thereof.
In an preferred embodiment, the invention provides a topical gel formulation comprising Thiocolchicoside in an amount in range of 0.05 - 0.25% by total weight of the formulation in combination with methyl salicylate in an amount in range of 5 - 15% by total weight of the formulation and Menthol in range of 2.5 - 7.5% by total weight of formulation.
Generally, gel base comprises 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 Hydroxypropyl cellulose, hydroxypropyl methyl cellulose methylcellulose and carboxypolymethylene ('carbopol'); together with one or more preservatives, if required, such as, methyl 4-hydroxybenzoate ('methyl paraben') or phenoxyethanol.
Accordingly the topical gel formulation of current invention comprises gel base consisting of Carbomer 980, Carbomer 940; Hydroxy Propyl Cellulose, Disodium EDTA, Chlorocresol, Ascorbic Acid, Sodium Sulphide, Sodium Metabisulphite, Propylene glycol, Citric acid, Sodium Citrate, Triethanolamine. Sodium Hydroxide, Diethanolamine. Purified Water and 1PA.
Further, the topical gel formulation of current invention is prepared by soaking carbopol in purified water overnight. Active drugs can be dissolved in co-solvent such as Propylene Glycol and added to carbopol gel and mixed properly, followed by adjusting pH with triethanolamine or diethanolamine or sodium hydroxide solution. Other inactives can be added to product.
The gel formulation of invention comprises a gelling agent such as Carbopol 980 in range of0.5-2.0%w/w.
The gel formulation further comprises a co-solvent selected form propylene glycol and/or isopropyl alcohol in range of 5 - 80%w/w.
The gel formulation comprises a buffering agent is citric acid anhydrous in range of 0.01 -0.1%w/w.
The gel formulation comprises a surfactant such as cremophore RH 40 in range of 2-5% w/w.
The gel formulation further comprises a chelating agent is disodium edetate in the range of0.005-0.2%w/w.

The gel formulation further comprises an anti-oxidant such as butylated hydroxy toluene in range of 0.1 - 0.5% w/w.
The gel formulation further comprises a preservative selected from benzyl alcohol and/or methyl paraben in range of 0.05 - 0.25% w/w and/or propyl paraben in range of 0.01 -0.1% w/w in an aqueous vehicle.
In yet another embodiment, the invention provides a topical ointment formulation comprising Thiocolchicoside in an amount from 0.05 - 0.25% by total weight of the formulation in combination with Methyl salicylate in an amount from 5 - 15% by total weight of the formulation and Menthol in range of 2.5 - 7.5% by total weight of formulation.
The ointment composition of invention as above comprises a surfactant such as sorbitan sesquioleate in range of 0.1 - 2.0% w/w.
The ointment further comprises a solubilizer such as propylene glycol in range of 5 -15% w/w.
The ointment further comprises ointment base selected form white soft paraffin in range of 85 - 90%b w/w and/or white bees wax in range of 2 - 10% w/w.
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:

Active ingredient Thiocolchicoside 0.05-0.25%

Methyl Salicylate 5 - 15%

Menthol 2.5 - 7.5%
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%
Surfactant Cremophore RH 40 2-5%
Chelating agent Disodium EDTA 0.005-0.2%
Anti oxidant Butylated Hydroxy Toluene 0.1-0.5%
Preservative Benzyl Alcohol 0.5 - 1.0%

Methyl paraben 0.05-0.25%

Propyl paraben 0.01-0.1%
Vehicle Purified Water q.s
Process For preparation of the Gel formulation of Example 1:
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 Triethanolaimine, to about 4.5 till gel formulation takes place;
4) mixing properly methyl salicylate with isopropyl alcohol and surfactants like cremophor RH 40 till clear solution is obtained;
5) dissolving menthol in methyl salicylate solution of step 4;
6) dissolving or dispersing thiocolchicoside in co-solvent such as propylene glycol;
7) adding and dissolving preservatives and anti-oxidant to solution of step 6;
8) adding solution of step 5 to gel of step 3 and mixing properly;
9) adding solution of step 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:

Active ingredient Thiocolchicoside 0.05 - 0.25%

Methyl Salicylate 5 - 15%

Menthol 2.5 - 7.5%
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

White bees wax 2-10% w/w
Process for preparation of the Ointment formulation of Example 2:
1) Melting ointment base excipients and mixing surfactant to ointment base;
2) adding Thiocolchicoside in bulk either by dissolving or dispersing in solubilizer;
3) dissolving menthol in methyl salicylate and adding to bulk, and
4) cooling and stirring the bulk till ointment formation takes place.
Overages of Thiocolchicoside can be added for the long term stability purpose.
Stability study of the product is carried out as per ICH 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 topical anti-inflammatory formulation comprising a combination of:
(a) a myorelaxant;
(b) a rubefacient, and
(c) a counterirritant.

2. The topical anti-inflammatory formulation as claimed in claim 1, wherein the myorelaxant is thiocholchicoside in range of 0.05 - 0.25% w/w.
3. The topical anti-inflammatory formulation as claimed in claim 1, wherein the rubefacient is methyl salicylate in range of 5 - 15% w/w.
4. The topical anti-inflammatory formulation as claimed in claim 1, wherein the counter-irritant is menthol in range of 2.5 - 7.5% w/w.
5. The topical anti-inflammatory formulation as claimed in claim 1, wherein the formulation is in form of gel or ointment.
6. The topical anti-inflammatory formulation as claimed in claim 5. wherein gel formulation further comprises pharmaceutically acceptable excipients selected from a gelling agent, a co-sofvent. a buffering agent, a surfactant, a chelating agent, an antioxidant and a preservative.
7. The topical anti-inflammatory formulation as claimed in claim 6. 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 and/or isopropyl alcohol in range of 5-80%w/w;
(c) the buffering agent is citric acid anhydrous in range of 0.01 - 0.l%w/w;

(d) the surfactant is cremophore RH 40 in range of 2-5%w/w;
(e) the chelating agent is disodium edetate in the 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 from the group benzyl alcohol in the range 0.5- 1.0% and/or methyl paraben in range of 0.05 - 0.25% w/w and/or propyl paraben in range of 0.01 - 0.1%w/w.

8. The topical anti-inflammatory formulation as claimed in claim 5, wherein ointment formulation further comprises pharmaceutically acceptable excipients selected from a surfactant, a solubilizerand an ointment base.
9. The topical anti-inflammatory formulation as claimed in claim 8, wherein

(a) the surfactant 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, and
(c) the ointment base is selected from white soft paraffin in range of 80-95% w/w or white bees wax in range of 2-10% w/w or combination thereof.
10. The process for preparation of topical anti-inflammatory gel formulation as claimed in
claim 1, 5 and 6 comprises:
(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 methyl salicylate with isopropyl alcohol and surfactants like cremophor RH 40 till clear solution obtained;
(e) dissolving menthol in methyl salicylate in solution of step (d):
(f) dissolving or dispersing thiocolchicoside 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 (e) to gel of step (c) with proper mixing ;
(i) adding solution of step (g) to bulk of step (h) with proper mixing , and

(j) adjusting final weight of bulk with purified water and checking pH which may be around 5.0.
11. The process for preparation of topical anti-inflammatory gel formulation as claimed in claim I, 5 and 8 comprises:
(a) Melting ointment base excipients and mixing surfactant to ointment base;
(b) adding Thiocolchicoside in bulk either by dissolving or dispersing in solubilizer;
(c) dissolving menthol in methyl salicylate and adding to bulk, and
(d) cooling and stirring the bulk till ointment formation takes place.