FORM 2
THE PATENTS ACT 1970
(39 of 1970)
&
The Patents Rules, 2003
PROVISIONAL SPECIFICATION
(See section 10 and rulel3)
1. TITLE OF THE INVENTION:
"PHARMACEUTICAL COMPOSITION COMPRISING ETODOLAC AND
THIOCOLCHICOSIDE"
2. APPLICANT
(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:

TECHNICAL FIELD OF INVENTION:
The present invention relates to an oral pharmaceutical composition comprising a combination of Non-Steroidal Anti-Inflammatory Drug (NSAID) with an orally effective muscle relaxant agent, most preferably, Etodolac with Thiocolchicoside in a solid dosage form, preferably a film coated tablet and process for preparation thereof. The said formulation is useful for the treatment of acute pain associated with traumatic origin, dental extraction, osteoarthritis, rheumatoid arthritis and symptomatic treatment of muscle spasms.
BACKGROUND OF THE INVENTION:
Etodolac is a member of the pyranocarboxylic acid group of Non-Steroidal Anti-Inflammatory Drug (NSAIDS) that exhibits anti-inflammatory, analgesic and antipyretic activities in animal models. It is most effective in treating fever, pain, and inflammation in the body. Chemically, Etodolac is 2-(l, 8-Diethyl-4,9-dihydro-3H-pyrano[3,4-b]indol-l-yl)acetic acid having structural formula as follows:

Non-steroidal anti-inflammatory drugs (NSAlDs) are among the most widely used drugs, probably due to their therapeutic properties such as anti-inflammatories, analgesics, anti¬pyretics, and anti-thrombolics and are used to treat a variety of clinical conditions manifesting such symptoms as pain, inflammation, fever, and to treat and prevent atherosclerosis. While these drugs are highly effective, monotherapy of many NSAIDs can causes serious adverse effects such as gastrointestinal bleeding and ulceration, liver and kidney damages, and central nervous system and cutaneous disturbances, particularly after extended use. Therefore, in an effort to minimize the adverse effects associated with

oral administration of NSAIDs alone hence there has been extensive investigation in recent years to combine NSAIDs with analgesic and antipyretic agents.
Colchicine is a toxic natural product and secondary metabolite, originally extracted from plants of the genus Colchicum (Autumn crocus, Colchicum autumnale, also known as the "Meadow saffron"). Originally used to treat rheumatic complaints and especially gout, it was also prescribed for its cathartic and emetic effects. Its present medicinal use is mainly in the treatment of gout; as well, it is being investigated for its potential use as an anti¬cancer drug. It can also be used as initial treatment for pericarditis and preventing recurrences of the condition. In neurons, axoplasmic transport is disrupted by colchicine.
A colchicine derivative 3-demethyl-thiocolchicine glucoside, also commonly known as
Thiocolchicoside; is a muscle relaxant agent with anti-inflammatory and analgesic
actions. Chemically, Thiocolchicoside is N-[3-(p-D-glucopyranosyloxy)-l,2-dimethoxy-
10-(methylthio)-9-oxo-5,6,7,9-tetrahydrobenzo[a]heptalen-7-yl]acetamide having
structural formula as follows:

It is used topically for the treatment of muscular spasms and for rheumatologic, orthopedic, and traumatologic disorders. Thiocoichicoside's activity is ascribed to its ability to interact with the strychnine-sensitive glycine receptors and therefore being endowed with glycino-mimetic activity, it is used in the rheumatologic-orthopedic field for its myorelaxant properties.
WO2008047208 discloses a modified release pharmaceutical composition in capsules with coated Microsphere, combining two active ingredients, namely a Muscle Relaxant (Tizanidine) and a Non-Steroidal Anti-Inflammatory Drug (Meloxicam), pharmaceutically acceptable excipients or vehicles, as well as a method for producing the

composition and the use of said combination for the preparation of a drug having a synergic therapeutic effect in the treatment of spasticity, disorders related to skeletal muscle and/or muscular ailments and moderate to severe pain in general.
US2002066691 discloses a blister card provides for combined morning, afternoon, and bedtime doses of two tablets or capsules, respectively, of a muscle relaxant drug such as cyclobenzaprine hydrochloride and an NSAID such as Etodolac.
WO2002/011700 disclosed is a local skeletal muscle relaxant and a non-steroidal anti¬inflammatory drug in a topical composition for topical application to a patient for relief of pain. More particularly and in its preferred form, the invention involves a combination of diazepam and diclofenac in a composition for topical application to the skin of a patient as a colorless transparent gel.
Though there are prior arts having non-steroidal anti-inflammatory drug (NSAID) and muscle relaxing agent in combination none of them specifically discloses Etodolac and Thiocolchicoside combination. Thus, the present inventors have combined Etodolac with Thiocolchicoside, which will be very useful in managing severe pain along with muscle relaxation, with a lower dosage of NSAID especially Etodolac for minimizing overall side-effects, when used for the treatment of acute pain associated with traumatic origin, dental extraction, osteoarthritis, rheumatoid arthritis and symptomatic treatment of muscle spasms.
OBJECT OF THE INVENTION:
The main object of the current invention is to provide a pharmaceutical composition comprising a combination of Non-Steroidal Anti-Inflammatory Drug with an orally effective muscle relaxant agent, most preferably, Etodolac with Thiocolchicoside in a solid dosage form, preferably in a film coated tablet useful for the treatment of acute pain associated with traumatic origin, dental extraction, osteoarthritis, rheumatoid arthritis and symptomatic treatment of muscle spasms. The invention further relates to the process for preparation thereof.

SUMMARY OF THE INVENTION:
This invention relates to a pharmaceutical composition comprising a combination of Non-steroidal Anti-Inflammatory Drug and muscle relaxant agent, most preferably, Etodolac with Thiocolchicoside in a solid dosage form, preferably a film coated tablet useful for the treatment of acute pain associated with traumatic origin, dental extraction, osteoarthritis, rheumatoid arthritis and symptomatic treatment of muscle spasms.
The invention further relates to the process for preparation comprising following steps:
1) Weighing and passing Etodolac, Thiocolchicoside, Lactose DCL 11, M.C.C. pH102 through 40 # and mix for 5 min;
2) Dissolving PVP K-30, Polysorbate 80, in sufficient quantity of distilled water;
3) Granulating the blend of Step 1 with Step 2;
4) Passing the wet mass through 12 #;
5) Drying the granules in a tray dryer at 60°C for 90 min;
6) Passing the dried granules through 18 #;
7) Weighing & passing the sodium starch glycolate, magnesium stearate, M.C.C. pH102 through 40 #;
8) Mixing step 6 and 7 for 3 min;
9) Compressing the blend on bi-convex, Lyka embossed capsule shape punch.
DETAILED DESCRIPTION OF THE INVENTION:
The invention will now be described in detail in connection with certain preferred and optional embodiments, so that various aspects thereof may be more fully understood and appreciated.
Etodolac is a non steroidal anti-inflammatory drug that exhibits anti inflammatory, analgesic and antipyretic action in experimental animals. The mechanism of action is related to prostaglandin synthesis inhibition.

Thiocolchicoside possesses GABA-mimetic and glycinergic action. It has anti¬inflammatory and analgesic actions. Thiocolchicoside is a centrally acting muscle relaxant.
The present invention describes a pharmaceutical composition comprising a combination of Etodolac with Thiocolchicoside in a solid dosage form, preferably a film coated tablet and the process for preparation thereof.
The said combination of Etodolac alongwith Thiocolchicoside in solid dosage form, more particularly a film coated tablet is useful in managing severe pain along with muscle relaxation, with a lower dosage of NSAID especially Etodolac for minimizing overall side-effects. Further, the combination provides relief of pain and relieves muscle spasm in patients suffering from back pain, osteoarthritis and ankylosing spondylitis.
According to a preferred embodiment, a pharmaceutical composition comprising Etodolac and Thiocolchicoside in a solid dosage form preferably a film coated tablet along with the pharmaceutical^ acceptable excipients selected from the group comprising diluents, binders, wetting agents, disintegrant and lubricants. Film coating can be done using coating polymer alongwith plasticizer, opacifier, coloring pigment and suitable solvents.
According to the present invention, the usually recommended dose of Etodolac 400 mg with Thiocolchicoside 4 mg.
Composition:
Each film coated tablet contains:
Etodolac...USP 400 mg
Thiocolchicoside 4 mg
Excipients q. s.
In further embodiment, controlled clinical trials in analgesia were single dose randomized, double blind parallel studies in three pain models including dental

extraction. The analgesic effective dose for etodolac in acute pain models was 200 to 400 mg. The onset of analgesia occurred approximately 30 minutes after oral administration.
The peak analgesic effect observed was between 3 to 2 hours. Duration of relief averaged 4 to 5 hours for 200 mg of etodolac and 5 to 6 hours for 400 mg of etodolac.
For the management of the signs and symptoms of back 3che, osteoarthritis or rheumatoid arthritis, the recommended dose of Etodolac with Thiocolchicoside (400+4) mg is one tablet twice a day.
According to the present invention, the pharmaceutical composition comprising Etodolac and Thiocolchicoside in a tablet form is prepared by wet granulation method where both Etodolac and Thiocolchicoside are mixed with other suitable diluents, granulated by appropriate binding agent, dried, lubricated and compressed into tablets, which are further film coated..
According to the present invention, the pharmaceutical composition comprising Etodolac and Thiocolchicoside in a tablet form is prepared using diluents selected from microcrystalline cellulose, lactose, maize starch, dibasic calcium phosphate, and can be used individually or in combination to give desired product parameters.
According to the present invention, the pharmaceutical composition comprising Etodolac and Thiocolchicoside in a tablet form is prepared using binders such as purified water, isopropyl alcohol, mixture of isopropyl alcohol and purified water alone or in combination with ethyl cellulose, poly vinyl pyrolidine (PVP K-30) may be used in optimum concentrations.
According to the present invention, the pharmaceutical composition comprising Etodolac and Thiocolchicoside in a tablet form is prepared using wetting agents such as sodium lauryl sulphate or Polysorbate 80 may be added to improve dissolution.
According to the present invention, the pharmaceutical composition comprising Etodolac and Thiocolchicoside in a tablet form is prepared using disintegrants such as

croscarmellose sodium, crosslinked povidone, sodium starch glycolate, maize starch, pregelatinized starch alone or in combination may be added.
According to the present invention, the pharmaceutical composition comprising Etodolac and Thiocolchicoside in a tablet form is prepared using lubricants such as magnesium stearate, colloidal silicon dioxide, talc alone or in combination may be used.
According to the present invention, the tablets are film coated using hydroxy propyl methyl cellulose with plasticizer, opacifier, colouring pigment and suitable solvents.
In a preferred embodiment, the process for manufacturing the pharmaceutical composition comprising Etodolac and Thiocolchicoside in a film coated tablet form is as follows:
1) Weighing and passing Etodolac, Thiocolchicoside, Lactose DCL 11, M.C.C. pH102 through 40 # and mix for 5 min;
2) Dissolving PVP K-30, Polysorbate 80, in sufficient quantity of distilled water;
3) Granulating the blend of Step 1 with Step 2;
4) Passing the wet mass through 12 #;
5) Drying the granules in a tray dryer at 60°C for 9() min;
6) Passing the dried granules through 18 #;
7) Weighing & passing the sodium starch glycolate, magnesium stearate, M.C.C. pH102 through 40 #;
8) Mixing step 6 and 7 for 3 min;
9) Compressing the blend on bi-convex, Lyka embossed capsule shape punch. Average Weight = 765 mg ± 5.0%
Hardness = 6.0 kg / cm2 to 9.0 kg / cm2
D.T. = NMT 15 min
The following example, which includes preferred embodiments, will serve to illustrate the practice of this invention, it being understood that the particulars shown are by way of example and for purpose of illustrative discussion of preferred embodiments of the invention.

EXAMPLE :
Etodolac and Thiocolchicoside Tablet (400+4) mg

No. Ingredients Qty/Tablet Range
I. Etodolac 400.0 mg
2. Thiocolchicoside 4.0 mg
3. Lactose DCL 11 150.0 mg 135-165 mg
4. PVP K-30 20.0 mg 15-25mg
5. Polysorbate-80 (Tween-80) 0.5 mg 0.25 - 0.75 mg
6. Sodium starch glycolate 20.0 mg 15-25mg
7. Magnesium stearate 8.0 mg 7-9 mg
8. MC.C pH102 162.0mg 145-180 mg
9. Distilled water q.s.
764.5 mg

Dr. P. Aruna Sree Agent for the Applicant