FORM 2
THE PATENTS ACT 1970
(39 of 1970)
&
The Patents Rules, 2003
PROVISIONAL SPECIFICATION
(See section 10 and rule13)
1. TITLE OF THE INVENTION:
"PHARMACEUTICAL COMPOSITION COMPRISING ETODOLAC AND
PARACETAMOL"
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:
This invention relates to a pharmaceutical composition comprising a combination of Non-Steroidal Anti-Inflammatory Drug with an orally effective analgesic drug, most preferably, Etodolac with Paracetamol 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. The invention further relates to the process for preparation thereof.
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 (NSAIDs) are among the most widely used drugs, probably due to their therapeutic properties 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.
Paracetamol or acetaminophen is a widely used over-the-counter analgesic (pain reliever) and antipyretic (fever reducer). It is commonly used for the relief of fever, headaches, and other minor aches and pains, and is a major ingredient in numerous cold and flu remedies. Paracetamol is also used in combination with non-steroidal anti-inflammatory drugs (NSAIDs) or opioid analgesics. Paracetamol, particularly in combination with weak opioids, is more likely than NSAIDs to cause rebound headache (medication overuse headache), although less of a risk than ergotamine or triptans used for migraines.
Hence, Paracetamol is very useful in managing more severe pain, alongwith lower dosages of additional NSAID thereby minimizing overall side-effects. The marketed product combination of non-steroidal anti-inflammatory drugs (NSAIDs) and Paracetamol are as follows:
1. NOPAIN FORTE - (Ibuprofen + Paracetamol),
2.. NIMOTIZ MR - (Nimesulide + Tizanidine)
3. MELODOL TAB - (Meloxicam + Paracetamol)
4. INMECIN-P CAP - (Indometacin + Paracetamol)
5. ANAFLAM TAB- (Ibuprofen + Paracetamol)
6. ADENIM PLUS SUSP-(Nimesulide + Paracetamol)
7. ACTIMOL TAB - (Diclofenac + Paracetamol)
8. ABATE TAB - (Aceclofenac + Paracetamol)
US6599529 titled "Modified Release Multiple-Units Compositions of Non-Steroid Anti-Inflammatory Drug Substances (NSAID)" discloses an oral pharmaceutical modified release multiple-units composition in unit dosage form for administration of a therapeutically and/or prophylactically effective amount of a non-steroid anti¬inflammatory drug substance (such as fenbufen, Etodolac, tolfenamic acid, sulindac, phenylbutazone, fenoprofen, tolmetin etc), a unit dosage form comprising at least two


NSAID-containing fractions, i) a first NSAID-containing fraction of multiple-units for quick release of the NSA1D substance, and ii) a second NSAID-containing fraction of multiple-units for extended release of the NSAID substance, wherein said composition comprises a further active drug substance such as Paracetamol, Penicillamine, Sulfasalazine and/or Auranorfin.
US20080200549 titled "Pharmaceutical Composition oflbuprofen and Paracetamol. and Methods of using the same" discloses a pharmaceutical composition for the treatment of pain comprising an excipients; ibuprofen, ibuprofen salt, ibuprofen ester, or ibuprofen complex; and paracetamol, paracetamol salt, paracetamol ester, or paracetamol complex; wherein a weight ratio of paracetamol, paracetamol salt, paracetamol ester, or paracetamol complex to ibuprofen, ibuprofen salt, ibuprofen ester, or ibuprofen complex is between about 3 to 1 and about 4 to 1.
US20080085308 titled "Granules Comprising Paracetamol, a NSAID and a Sugar Alcohol Made by Melt Extrusion" claims a pharmaceutical composition comprising a granular component comprising a plurality of solidified melt granules of a sugar alcohol having a salt of a non-steroidal anti-inflammatory drug (NSAID salt) and paracetamol contained therein.
WO/2007/034135 titled "Composition Comprising a NSAID and Paracetamol discloses a process for producing a granular composition comprising a plurality of solidified melt granules including a non-steroidal anti-inflammatory drug (NSAID) and paracetamol, the process comprising the steps of: (a) forming a melt mixture by mixing a molten NSAID free acid and paracetamol, optionally with one or more excipients; and (b) forming the melt mixture into solidified melt granules.
Though there are prior arts having NSAID and Paracetamol in combination none of them specifically discloses Etodolac and Paracetamol combination. Thus, the present inventors have combined Etodolac with Paracetamol, which provided faster relief to pain and increased duration of analgesic to 8-12 hours, when used for the treatment of acute pain associated with traumatic origin, dental extraction, osteoarthritis, rheumatoid arthritis.


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 analgesic drug, most preferably, Etodolac with Paracetamol 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. 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 with an orally effective analgesic drug, most preferably, EtodoJac with Paracetamol 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. The invention further relates to the process for preparation thereof
DETAILED DESCRIPTION:
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.
Rationale:
Paracetamol reduces the production of prostaglandins (pro-inflammatory chemicals) but does not inhibit the production of the pro-clotting chemicals thromboxanes. Due to Paracetamol's partial similarity of aspirin's action, unlike Aspirin it also inhibits the CycJooxygenase (COX) family of enzymes. The COX family of enzymes is responsible for the metabolism of arachidonic acid to prostaglandin H2, an unstable molecule, which is, in turn, converted to numerous other pro-inflammatory compounds. Classical anti-inflammatory, such as the NSAIDs, block this step.


Paracetamol reduces the oxidized form of the COX enzyme, preventing it from forming pro-inflammatory chemicals.
In view of above fact, the present inventors have come up with a novel combination of Paracetamol which is very useful in managing more severe pain, along with lower dosage of NSAID especially Etodolac for minimizing overall side-effects.
Therefore, the present invention describes a pharmaceutical composition comprising a combination of Etodolac with Paracetamol in a solid dosage form, preferably a film coated tablet and the process for preparation thereof.
The said combination of Etodolac alongwith Paracetamol in solid dosage form, more particularly a film coated tablet is used for the treatment of pain, inflammation in the body caused by osteoarthritis and rheumatoid arthritis.
According to a preferred embodiment, a pharmaceutical composition comprising Etodolac and Paracetamol in a solid dosage form preferably a film coated tablet along . with the pharmaceutically 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 Paracetamol 500 mg is twice a day dose. Composition: Each film coated tablet contains:
Etodolac 400 mg
Paracetamol 500 mg
Excipients q. s
According to the present invention, the pharmaceutical composition comprising Etodolac and Paracetamol in a tablet form is prepared by wet granulation method where both Etodolac and Paracetamol 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 Paracetamol in a tablet form is prepared using diluents selected from microcrystalline cellulose, lactose, maize starch, dibasic calcium phosphate, individually or in combination to give desired product parameters.
According to the present invention, the pharmaceutical composition comprising Etodolac and Paracetamol in a tablet form is prepared using binders such as purified water, Isopropyl alcohol, mixture of lsopropyl alcohol and purified water alone or in combination with ethyl cellulose, poly vinyl pyrrolidone (PVP K-30) in optimum concentrations.
According to the present invention, the pharmaceutical composition comprising Etodolac and Paracetamol in a tablet form is prepared using wetting agents such as sodium lauryl sulphate or Polysorbate 80 to improve dissolution.
According to the present invention, the pharmaceutical composition comprising Etodolac and Paracetamol in a tablet form is prepared using disintegrants such as croscarmellose sodium, croslinked povidone, sodium starch glycollate, maize starch, pregelatinised starch, alone or in combination.
According to the present. invention, the pharmaceutical composition comprising . Etodolac and Paracetamol in a tablet form is prepared using lubricants such as Magnesium stearate, colloidal silicon dioxide, talc alone or in combination.
According to the present invention, the tablets are film coated using coating polymer alongwith plasticizer, opacifier, colouring pigment and suitable solvents
In a preferred embodiment, the process for manufacturing the pharmaceutical composition comprising Etodolac and Paracetamol in a film coated tablet form is as follows:


1) Passing Etodolac, Paracetamol, Lactose Monohydrate, Microcrystalline cellulose, part of. Crosscarmellose sodium, and part of Colloidal silicon dioxide through 40# mesh and mixing it for 5 minutes;
2) Dissolving Povidone K - 30 & Polysorbate SO in water;
3) Granulating the blend of step 1 with solution of step 2, and sifting the wet mass through 12# mesh and drying it at 60°C for sufficient period;
4) Passing the dried granules through 18# mesh;
5) Passing Crosscarmellose sodium, Sodium starch glycolate, Colloidal silicon dioxide through 40# mesh and mixing it with the above sized, dried granules;
6) Passing Magnesium stearate through 40# mesh and mixing it with step 5 granules;
7) Compressing the lubricated granules using capsule shape biconcave punches; and
8) Film coating the compressed tablets.
The process for preparation of film coated tablets further comprises film coating using any of 3 coating solutions as mentioned below, wherein said coating process further comprises:
a) Coating the compressed tablets obtained in step 7 with a non aqueous
coating solution, prepared by Opadry 02F82502 ready mix coating
powder manufactured by colorcon mix with Isopropyl alcohol and
Methylene chloride and passed through colloidal mill.
Non-aqueous coating comprises:
i. Opadry 02F82502 8%
ii. Isopropyl alcohol 40%
iii. Methylene Chloride 52%
b) Coating the compressed tablets obtained in step 7 with an aqueous
coating solution prepared by Opadry 02F82502 ready mix coating
powder manufactured by colorcon, mix with distilled water and passed
through colloidal mill.


Aqueous coating comprises:
i. Opadry02F82502 8%
ii. Distilled water 92%
c) Coating the compressed tablets obtained in step 7 with in-housely prepared non aqueous coating solution prepared by dispersing Hypromellose (E5), Diethylphthalate, Polyethylene Glycol 4000, Titanium dioxide, Talc and color, Quinoline yellow lake in Isopropyl alcohol & Methylene Chloride mixture and pass through colloidal mill. .
In-housely prepared Non-aqueous coating solution comprises:
i. Hypromelllose (E5) 3%
ii. Diethylphalate . 0.45%
iii. Polyethylene Glycol 4000 0.45%
iv. Titanium dioxide 1.1%
v. Talc 0.7%
vi. Color: Quinoline yellow lake 0.1%
vii. Isopropyl alcohol 40%
viii. Methylene chloride 54.2%
Therapeutic justification:
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.
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.
Etodolac 200 mg provided efficacy comparable to that obtained with 650 mg aspirin.