FORM 2
THE PATENT ACT 1970
(39 of 1970)
AND
The Patents Rules, 2003
PROVISIONAL SPECIFICATION
(See section 10 and rulel3)
1. TITLE OF THE INVENTION:
"A NOVEL COMBINATION THERAPY FOR THE TREATMENT OF INFLAMMATION AND PAIN"
2. APPLICANT:
(a) NAME: INDOCO REMEDIES LIMITED

(b)NATIONALITY: Indian Company incorporated under the Indian Companies ACT, 1956
(c) ADDRESS: Indoco House, 166 C. S. T. Road, Santacruz (East), Mumbai - 400 098, Maharashtra, India.
3. PREAMBLE TO THE DESCRIPTION:
The following specification describes the invention.

TECHINCAL FIELD OF THE INVENTION:
The present invention relates to a novel combination comprising Iomoxicam, serratiopeptidase and paracetamol for the treatment of acute painful and inflammatory conditions associated with musculoskeletal and dental problems in mammals.
BACKGROUND OF THE INVENTION:
The concept of combination therapy is well recognized and exploited in the pharmaceutical areas. The combinations like diuretics, anti-hypertensives, anti-lipidemic and one other blood pressure medications are well known and most widely used. In all cases, these combination medications are mixtures of two existing drugs that have already been marketed. Although combination therapies may seem costlier than monotherapies in the short term but offer significant advantages like lower treatment failure rate and slower development of resistance, rapid effect and the ease of use which increases patient's compliance and therefore treatment effectiveness.
Further, treatment of a disease by combining two or more agents that target the same pathogen or biochemical pathway sometimes results in greater efficacy and diminished side effects relative to the use of the therapeutically relevant dose of each agent alone.
While a number of combination products are in clinical use, mainly for the treatment of disease like AIDS/HIV, malaria, cancer, leprosy, tuberculosis, or in the field of cardiovascular and ophthalmics, however, other desirable combinations have not been fully exploited, particularly the combinations for the treatment of conditions like inflammation and pain.
Inflammation is a complex biological response of vascular tissues to harmful stimuli, such as infectious agents, ischemia, antigen-antibody interaction, and thermal or other physical injury and is often associated with fever and pain. Several classes of leukocytes and prostaglandins like COX, IL-1, IL-8, TNF, PGG.2, PGH2 and PGE2 are said to play
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a major role in the pain and inflammation process and the inhibition of these has been a common target of anti-inflammatory drug discovery.
Some of the widely used drugs are non-steroidal anti-inflammatory drugs (NSAlDs), which alleviate pain and inflammation by counteracting the cyclooxygenase (COX) enzyme such as aspirin, ibuprofen, naproxen etc. However, use of high doses of most common NSAIDs can produce severe side effects, including life-threatening ulcers, gastrointestinal (GI) toxicity and platelet dysfunction that limit their therapeutic potential. Further, the concurrent use of NSAIDS is also associated with the thrombocytopenia and may even lead to kidney and liver failure.
Several strategies have been employed to reduce the toxicities caused by NSAIDS of which using the combination of two or more drugs is most favorable. Studies have shown that the combined use of two or more drugs may produce super-additive effects upon administration and due to the super-additive effect the overall dose and accordingly the risk of undesired side effects can be reduced. For e.g. Yamada et al in Chemotherapy 2007 (53) describes the role of ciprofloxacin in its synergistic effect with Fosfomycin on drug-resistant strains of Pseudomonas aeruginosa.
Similarly, Mc Clay in US6288111 discloses the synergistic effect of cisplatin and tamoxifen for the treatment of a wide variety of human cancers. Trivedi et al in US 6165447 claims an oral antiplaque composition of Triclosan and hydrogenated lupulone. Achterrath-Tuckerman, et al. in US5068233 claims a synergistic composition containing a combination of azelastine and theophylline for the treatment of asthmatic, antiallergic and antihistaminic symptoms.
Also, medicament with synergistic action containing a combination of amantadine and selegiline is described in US 4812481 for the treatment of parkinsonism by Reischig et al. Further combinations are disclosed in CA265 73 75, EP1904068, EP1741431, EP1196160,US 20020169141, US 20050163775, US 20070020261, US 20070015687, US 20080113969, US 20090105129 etc.
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Thus, the present invention is a step forward in the direction of unearthing a novel combination therapy which can be used for the treatment of acute painful and inflammatory conditions associated with musculoskeletal and dental problems in mammals and also overcomes the limitation of the prior art.
OBJECTS OF THE INVENTION:
Thus, it is an object of the present invention to provide drug combinations which could revolutionize the treatment of inflammation and pain associated with musculoskeletal and dental problems in mammals.
Another object of the present invention is to provide drug combinations which exhibited superior effectiveness, wherein the effectiveness is greater than the known activity of individual component and also exhibited fewer undesired side effects, better patient compliance with overall disease management compared to its individual components.
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.
The invention pertains to a novel combination therapy for treating pain and inflammation by the oral administration of two or more drugs.
In particular, invention pertains to the novel combination therapy comprising lornoxicam, serratiopeptidase and paracetamol for the treatment of acute painful and inflammatory conditions associated with musculoskeletal and dental problems in mammals.
Lornoxicam is a non-steroidal anti-inflammatory drug (NSAID) of the oxicam class with analgesic, anti-inflammatory and antipyretic properties, is available in oral and parenteral

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formulations. It inhibits both COXl and COX 2 and is mainly used for the treatment of inflammatory disease of the joints osteoarthritis and pain following surgery.
Further, Serratiopeptidase is a proteolytic enzyme (protease) produced by enterobactenum Serratia species E15. It acts upon inflammation by thinning the fluids in the body that collect around injured areas and increases fluid drainage. Also, serratiopeptidase reduces pain through its ability to block the release of pain-inducing amines from inflamed tissues and unlike NSAID pain medications, it does not cause dangerous internal bleeding nor is it addictive like many pain medications It has been used successfully in India, Europe, Japan and USA for the treatment of pain and inflammation due to arthritis, trauma, surgery, sinusitis, bronchitis, carpal tunnel and painful swelling of the breasts.
Still further, Paracetamol is a widely used over-the-counter analgesic and antipyretic drug which acts by inhibitor of COX. It is often used in combination with opioids like codeine, dihydrocodeine, oxycodone, hydrocodone or propoxyphene napsylate in USA, Europe, Canada India and many other countries. The drug is generally considered as safe for human use at recommended doses; however, acute overdoses of paracetamol may cause potentially fatal liver damage.



Paracetamol

The present inventors have found that the combination of the three drugs viz. Ioraoxicam, serratiopeptidase and paracetamol are useful for the treatment of various musculoskeletal inflammation and pain caused by chemical irritants, toxins , infection by pathogens, physical injury or pain due to inflammatory arthritis, osteoarthritis, infectious arthritis.
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Further, the combination can also be used for the treatment of dental inflammation including gingivitis, periodontitis, and temporomandibular joint (TMJ) syndrome.
The said pharmaceutical composition can be prepared in any oral dosage form like capsule or tablet; however, tablet dosage form is more preferred and is prepared by the methods known in the art like direct compression, wet granulation or dry granulation.
Various excipients that can be employed for the preparation of tablets are disintegrants, fillers, binders, glidants, surfactants and lubricants.
Tablets prepared can be film coated or sugar coated. However, since searratiopeptidase is absorbed through the intestines and transported directly into the bloodstream and if the enzyme is consumed in unprotected capsules or tablets it is destroyed by the acid in the stomach before it gets to the small intestine. Hence, to be effective, serratiopeptidase is enterically coated.
Some typical examples illustrating the embodiments of the present invention are provided; however, these are exemplary only and should not be regarded as limitations of the present invention. EXAMPLES:
Example 1:

S.No Ingredients Quantity (mg/tablet)
1. Lornoxicam 8.0
2. Paracetamol 500.0
3. Macrocrystalline cellulose 125.0
4. Starch 30.0
5. Sodium starch Glycolate 30.0
6. Povidone 30.0
7. Purified Talc 7.5
8. Serratiopeptidase (enteric coated granules) 15.0
9. Magnesium stearate 7.0
10. Hypromellose 7.5
11. Titanium dioxide 3.0
12.| Propylene glycol 1.5
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13. Color Iron oxide yellow 0.3
14. Purified Water q.s
Procedure:
a. Lornoxicam, paracetamol, microcrystalline cellulose (part of the total
quantity), starch (part of the total quantity), and sodium starch glycolate were
dry mixed in rapid mix granulator.
b. Starch (remaining quantity) and povidone were dissolved in water.
c. Dry mix was granulated with the solution of step b in RMG.
d. The wet granules were then dried in a vacuum drier, passed through the sieve
and subjected to sizing.
e. Sodium starch Glycolate, microcrystalline cellulose (remaining quantity),
purified talc, serratiopeptidase (enteric coated granules) and magnesium
stearate were added to the granules of step d.
f. Passing through sieve, blended and compressed to get tablets.
g. Finally the tablets were coated using hypromellose, titanium dioxide,
propylene glycol.
Example 2:

S.No Ingredients Quantity
(mg/tablet)
1. Lornoxicam 8.0
2. Paracetamol 500.0
3. Microcrystalline cellulose 124.5
4. Starch 30.0
5. Povidone 30.0
6. Croscarmellose sodium 30.0
7. Purified Talc 5.0
8. Serratiopeptidase (enteric coated granules) 15.0
9. Magnesium stearate 7.5
10. Opadry II 15.0
11. Purified water q.s
Procedure:
a. Lornoxicam, paracetamol, microcrystalline cellulose (part of the total
quantity) and starch, were dry mixed in rapid mix granulator.
b. Povidone was dissolved in water.
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c. Dry mix of step a was granulated with the solution of step b in RMG.
d. The wet granules were then dried in a vacuum drier, passed through the sieve
and subjected to sizing.
e. Purified talc, croscarmellose sodium, microcrystalline cellulose (remaining
quantity), serratiopeptidase (enteric coated granules)and magnesium stearate
were granulated and added to the granules of step d after passing it through
the sieve.
f. Granules of step d and step e are blended and compressed to get tablets.
g. Finally the tablets were coated.
Example 3:

S.N
0 Ingredients Quantity
(mg/tablet)
1. Lomoxicam 8.0
2. Paracetamol 500.0
3. Microcrystalline cellulose 124.5
4. Starch 60.0
5. Crospovidone 30.0
6. Purified Talc 5.0
7. Serratiopeptidase (enteric coated granules) 15.0
8. Magnesium stearate 7.5
9. Instacoat Aqua 15.0
10. Purified water Os
Procedure:
a. Lomoxicam, paracetamol, microcrystalline cellulose (part of the total
quantity), and starch (part of the total quantity) were dry mixed in rapid mix
granulator.
b. Starch was dissolved in water.
c. Dry mix was granulated with the solution of step b in RMG.
d. The wet granules were then dried in a vacuum drier, passed through the sieve
and subjected to sizing.
e. Purified talc, microcrystalline cellulose (remaining quantity), crospovidone,
serratiopeptidase (enteric coated granules) and magnesium stearate were
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added to the granules of step d after passing it through the sieve, blended and compressed to get tablets. f. Finally the tablets were coated.
The said pharmaceutical composition have synergistic effects in such a way that the individual effects of the components of this composition would be enhanced by their combination; however, the exact dose of the combination drug to be administered to the patients to get the intended therapeutic effect may vary depending upon the weight, age, sex of the patient.
The said composition because of the above synergistic effect would also show other advantages like (1) employment of less amount of total drug; (2) minimization or elimination of local and/or systemic side effects; (3) improved efficiency and safety of treatment; and (4) better patient compliance.
Dated this the 04,h day of June, 2009
Di\ P. Aruna Sree Agent for the Applicant

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