FORM 2
THE PATENTS ACT 1970
(39 of 1970)
&
The Patents Rules, 2003
PROVISIONAL SPECIFICATION
(See section 10 and rule 13)
1. TITLE OF THE INVENTION:
"A Pharmaceutical composition comprising NSAIDs and Colchicine combination for use in acute and chronic painful conditions such as gout and osteoarthritis"
2. APPLICANT
(a) NAME. IPCA LABORATORIES LTD.
(b) NATIONALITY: Indian Company incorporated under the Indian Companies
ACT, 1956
(c) ADDRESS: 48, Kandivli Industrial Estate, Mumbai-400067,
Maharashtra, India
3. PREAMBLE TO THE DESCRIPTION
The following specification particularly describes the invention and its use thereof.

TECHNICAL FIELD OF THE INVENTION:
The present invention relates to a pharmaceutical composition comprising fixed dose combination of NSAIDs and Colchicine. In particular, it relates to a method of treating acute and chronic painful conditions, including gout and osteoarthritis using the said pharmaceutical composition.
BACKGROUND OF THE INVENTION:
Gout is a group of diseases characterized by arthritis and results from a disturbance of urate metabolism with the deposition of monosodium urate crystals in the joints and soft tissues. The serum urate levels are elevated as a result of overproduction or underexcretion of uric acid.
Gout is one of the most common rheumatic diseases worldwide. The commonly reported overall prevalence of gout is 6 per 1000 population for men and 1 per 1000 population for women. Gout is much more common in men than in women; it is rare before menopause and more common in old age. (BMJ 2006;332(7553):1315)
Non steroidal anti-inflammatory drugs are the treatment of choice for acute flares of gout arthritis. It is first line therapy for acute gout. Use of NSAIDs is associated with marked symptomatic relief within 24 hours. Although indomethacin is commonly used, there is no good evidence that one NSAID is more efficacious than another. Comparative studies have demonstrated that many nonsteroidal anti-inflammatory drugs are equivalent to indomethacin with respect to controlling acute gouty attacks. The similar efficacy of etoricoxib and indomethacin in a head-to-head comparison in patients with acute gout suggests that selective inhibitors of cyclooxygenase-2 provide an alternative for patients in whom nonselective cyclooxygenase inhibitors are contraindicated.


Osteoarthritis, the most common form of arthritis, is a debilitating progressive disease principally affecting the elderly. It has been a frustrating disease for both the patient and the physician. Its current impact on society is tremendous, and rivals that of ischemic heart disease in many regards. As the obesity epidemic rages on, OA will assume an even greater impact on society.
Current approaches to treating osteoarthritis includes medications; nonpharmacological modalities, such as physical therapy, exercise, weight management and orthotics; and (as a last resort) surgery—focus on reducing pain and improving (or at least maintaining) mobility. Drugs currently used to treat osteoarthritis fall into several categories: analgesics, NSAIDs, cyclo-oxygenase-2 (COX-2) inhibitors, corticosteroids, viscosupplementation, and symptomatic slow-acting drugs ('nutraceuticals'). The analgesics (paracetamol and opiates) have demonstrated less symptomatic efficacy than NSAIDs, while the latter have displayed mixed results in terms of joint space narrowing.
COX-2 inhibitors have been demonstrated to be equal to or superior to NSAIDs in effectiveness. Injectable therapies, such as corticosteroids and viscosupplementation have elicited favorable short-term response but no long-term structural modification.
The current OA armamentarium only reduces pain and perhaps improves function, and has no impact on the disease incidence or progression. Thus, the challenge for researchers to develop disease-modifying OA drugs becomes an issue of paramount importance. (Clin Geriatr Med. 2005 Aug;21(3):589-601, vii.)
Colchicine is an alkaloid prepared from the dried corns and seeds of Colchicum autumnale, the autumn crocus or meadow saffron.
Colchicine is an effective treatment for the reduction of pain and clinical symptoms in patients experiencing acute attacks of gout. Colchicine is the oldest available treatment for gout.


Colchicine is specifically indicated for treatment and relief of pain in attacks of acute gouty arthritis. It is also recommended for regular use between attacks as a prophylactic measure, and is often effective in aborting an attack when taken at the first sign of articular discomfort.
The exact mechanism of action of Colchicine in gout is not completely known, but it involves: (1) a reduction in lactic acid production by leukocytes, which results in a decrease in uric acid deposition, and (2) a reduction in phagocytosis, with abatement of the inflammatory response.
It reduces symptoms by inhibiting microtubule polymerization, thus disrupting chemotaxis and phagocytosis by inflammatory cells. It does not prevent the accumulation of monosodium urate deposits and joint damage in chronic gout.
Colchicine is not an analgesic, though it relieves pain in acute attacks of gout. It is not a uricosuric agent and will not prevent progression of gout to chronic gouty arthritis. It does have a prophylactic, suppressive effect that helps to reduce the incidence of acute attacks and to relieve the residual pain and mild discomfort that patients with gout occasionally feel.
Its usefulness for acute attacks is limited by its dose-dependent toxicity. Often patients experience gastrointestinal adverse effects, such as diarrhea, before relief of gout symptoms.
Colchicine is usually used at low doses, 0.5mg/0.6 mg once or twice daily, to prevent attacks or rebound flare-ups in patients in whom steroids are being tapered or urate-lowering therapy is being started.
The efficacy of NSAIDs in gout is well known. NSAIDs such as indomethacin, etoricoxib, piroxicam is already approved for gout. Treatment with NSAIDs such as indomethacin, etodolac is associated with decreases in serum uric acid levels. Two large


trials showed that clinical outcomes from indomethacin and etoricoxib, a cyclo-oxygenase-2 inhibitor, were similar. A double-blind, parallel group study carried out in 61 patients suffering from acute gouty arthritis to compare the effectiveness of etodolac and naproxen in the relief of symptoms showed significant improvement from baseline in all of the variables at each time point in both treatment groups. (Curr Med Res Opin 1991;12(7):423-9.)
Colchicine has well established efficacy in gout. A controlled study of Colchicine was conducted in acute gout, to determine its efficacy and toxicity. Two-thirds of Colchicine-treated patients improved after 48 hours, but only one-third of the patients receiving placebo demonstrated similar improvement. The Colchicine-treated patients responded earlier; significant differences from placebo were shown after 18-30 hours. (Aust N Z J Med, 1987 Jun;17(3):301-4)
The combination of NSAIDs with Colchicine will be an effective treatment for gout. The action of colchicine in gout will be augmented by NSAIDs. With its analgesic and antiinflammatory action, NSAIDs will relieve pain and reduce inflammation and will have synergistic action with colchicines. Some NSAIDs such as indomethacin, etodolac, by decreasing serum uric acid levels, will prevent the gout from progressing to chronic condition, which Colchicine monotherapy is unable to do. The dose of Colchicine will also be reduced and this will help in reduction of dose dependent side effects of Colchicine.
Even the EULAR recommends oral Colchicine and/or NSAIDs are first line agents for systemic treatment of acute gout.
NSAIDs have been used for acute and long term treatment of the signs and symptoms of osteoarthritis. Caution is required however, because NSAIDs therapy carries the risk of gastrointestinal side effects. However, with the availability of preferential COX-2 inhibitors such as etodolac, aceclofenac, nabumetone and selective COX-2 inhibitors such as celecoxib and etoricoxib, these adverse effects are reduced. The preferential


COX-2 inhibitors as well as selective COX-2 inhibitors have same efficacy as that of traditional NSAIDs but have improved gastrointestinal tolerability.
Osteoarthritis (OA) is traditionally considered to be an inherently non-inflammatory disease, but acute flares are accepted as a component in the course of advanced OA.
Inflammation in OA is frequently secondary to the presence of calcium-containing crystals, and leads to the production of interleukin-1 (IL-1), an important mediator of cartilage breakdown in OA. Crystal deposition in OA is probably not an "on-off' phenomenon as previously thought, and may not only contribute to acute flares of inflammation in OA, but may also contribute to chronic low-grade, persistent, clinically non-apparent inflammation.
Because calcium-containing crystals are frequently seen in severe OA and Colchicine has been shown to be beneficial in preventing calcium crystal-induced inflammation (pseudogout), it is hypothesized that Colchicine could have symptom-modifying or even disease-modifying effects in patients with OA.
A 12-week open clinical trial showed that a regimen consisting of colchicines + piroxicam + intraarticular steroid was better than piroxicam + intraarticular steroid alone in patients with knee OA exhibiting inflammation and calcium pyrophosphate dihydrate (CPPD) crystals in joint fluid. A randomized double-blind placebo controlled trial showed significantly better symptom-modifying effects when Colchicine was added to piroxicam plus intraarticular steroid over a 5-month period in patients with knee OA presenting with signs of inflammation irrespective of whether CPPD crystals were demonstrable. (Osteoarthritis Cartilage 2002 Apr;10(4):247-52.)
The addition of colchicine to nimesulide resulted in better symptom control in patients with moderately severe OA of the knee over a 5-month period. Significantly more patients in the Colchicine group showed a 30% or greater response rate in the primary assessment variables. Similarly, the comparison of mean between both the Colchicine


and the control group showed a statistically significant difference on univariate analysis. (Arthritis Rheum 2002 Jun 15;47(3):280-4.)
The hypothesis that Colchicine will be effective in OA is based on the potential to prevent crystal-induced acute inflammatory flares. However, in the present study, patients without inflammation at baseline were benefited by Colchicine. Hence, a different mechanism is possible. Interestingly, Colchicine has been shown to inhibit elastase, a matrix metalloproteinase (MMP) in patients with chronic obstructive pulmonary disease, and thereby prevents the progression of emphysema in those who have stopped smoking. Given the fact that MMPs play a pivotal role in the degenerative process of OA, the action of Colchicine on various MMPs may be the predominant mechanism that needs further evaluation. This may be responsible for the slowly progressive increase in the response observed with Colchicine
Fixed dose combination of NSAIDs with Colchicine will be safe and effective combination therapy for gout and osteoarthritis.
Thus it is an object of the present invention to provide a composition comprising fixed dose combination of NSAIDs and Colchicine thereby exhibiting synergistic action in acute and chronic painful conditions including gout and osteoarthritis; high response rates and quicker relief from pain; improved patient compliance due to co-formulation and better tolerability.
SUMMARY OF THE INVENTION
In one aspect, the present invention provides a composition comprising a fixed dose combination of NSAIDs and Colchicine for the treatment of acute and chronic painful conditions including gout and osteoarthritis.


In another aspect, the present invention provides a fixed dose combination tablet or capsule comprising NSAIDs and Colchicine useful for the treatment of acute and chronic painful condition.
DETAILED DESCRIPTION OF THE INVENTION
The composition of the present invention is in the form of fixed dose combination, of comprising of NSAIDs with Colchicine.
The said composition comprises therapeutically effective amount of Etodolac and Colchicine in the fixed dose combination for the treatment of acute and chronic painful conditions including gout and osteoarthritis.
The said composition is for oral administration in the solid dosage form preferably in the form of tablets or capsules. Wherein the said tablets can be conventional release tablets or extended release/ controlled release tablets.
The composition of the present invention has following advantages: 1. Synergistic action in acute and chronic painful conditions, including gout and osteoarthritis 2. High response rates and quicker relief from pain 3. Improved patient compliance due to co-formulation 4. Better tolerability.
The present invention also concerns an alternative method for treating acute and chronic painful conditions including gout and osteoarthritis.
The invention is further illustrated by following non-limiting examples.
EXAMPLES
Each tablet or capsule contains: (Can be conventional release or extended/controlled release)


1. Etodolac (200mg to 1200mg) + Colchicine (0.5mg to 6mg)
2. Aceclotenac (lOOmg to 200mg) + Colchicine (0.5mg to 6mg)
3. Indomethacin (25mg to 75mg) + Colchicine (0.5mg to 6mg)
4. Nabumetone (500mg to lgm) + Colchicine (0.5 to 6mg)
5. Etoricoxib (60mg to 120mg) + Colchicine (0.5 to 6mg)
6. Celecoxib (lOOmg to 400mg) + Colchicine (0.5 to 6mg)
7. Diclofenac (50 to 150mg) + Colchicine (0.5 to 6mg)
8. Piroxicam (lOmg to 40mg) + Colchicine (0.5 to 6mg)