FORM 2
THE PATENT ACT 1970
(39 of 1970)
&
The Patents Rules, 2003
COMPLETE SPECIFICATION
(See section 10 and rule13)
1. TITLE OF THE INVENTION:
ONCE A DAY PHARMACEUTICAL COMPOSITION COMPRISING DICLOFENAC SODIUM IN AN EXTENDED RELEASE FORM AND MELOXICAM IN AN IMMEDIATE RELEASE FORM
2. APPLICANT (S)
(a) NAME: WOCKHARDT LTD.
(b) NATIONALITY: INDIAN
(c) ADDRESS: Wockhardt Towers, Bandra-Kurla Complex, Bandra
(East), Mumbai-400 051.
3. PREAMBLE TO THE DESCRIPTION
The present invention provides once a day pharmaceutical composition comprising diclofenac sodium in an extended release form and meloxicam in an immediate release form in admixture with pharmaceutically acceptable carrier so as to provide better pain management, reduced side effects and improved patient compliance.
The following specification particularly describes the invention and the manner in which it is to be performed.
4. DESCRIPTION
The present invention provides once a day pharmaceutical composition comprising diclofenac sodium in an extended release form and meloxicam in an immediate release form in admixture with pharmaceutically acceptable carrier so as to provide better pain management, reduced side effects and improved patient compliance.
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Diclofenac, a non-steroidal anti-inflammatory, is a benzene-acetic acid derivative. It is chemically 2-[(2,6-dichlorophenyl)amino] benzeneacetic acid, monosodium salt. Diclofenac is commercially available in two salt forms; one of them is sodium salt (Formula I) available as Voltaren-XR tablets and the other is potassium salt available as Cataflam tablets. Diclofenac is indicated for relief of signs and symptoms of osteoarthritis, rheumatoid arthritis and ankylosing spondylitis.
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FORMULA I
FORMULA II
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Meloxicam, an oxicam derivative, is a member of the enolic acid group of nonsteroidal anti-inflammatory drugs (NSAIDs). It is selective COX-2 inhibitor. Meloxicam is chemically 4-hydroxy-2-methyl-N-(5-methyl-2-thiazolyl)-2H-1,2-benzothiazine-3-carboxamide-1,1-dioxide (Formula II). It is commercially available under the trade name of MOBIC®. Meloxicam is indicated for relief of the signs and symptoms of osteoarthritis and rheumatoid arthritis, pauciarticular or polyarticular course Juvenile Rheumatoid Arthritis in patients 2 years of age and older.


Osteoarthritis and rheumatoid arthritis in the elderly is often treated with long-term NSAID therapy, to control pain, inflammation and to improve quality of life. Diclofenac is approved for the long-term symptomatic treatment of rheumatoid arthritis, osteoarthritis and ankylosing spondylitis. It is well known in the prior art that NSAIDs like diclofenac have the potential to cause gastrointestinal (Gl) bleeding and the abnormal elevation of liver enzymes. The said problem is associated when therapy is to be continued for a long period of time. Moreover, in such cases chronic use of single drug results in increased side effects and poor patient compliance. Combination of diclofenac with meloxicam is not known in the prior art.
To overcome the problems exemplified in the prior art, the present inventors while working on the analgesic combinations have surprisingly found that when 100 mg of diclofenac sodium in an extended release form is combined with either 7.5 mg or 15 mg of meloxicam in an immediate release form alongwith pharmaceutical^ acceptable carrier resulted in once a day formulation providing -
1. Better pain management associated with rheumatoid arthritis, osteoarthritis, ankylosing spondylitis and the like.
2. Improved patient compliance
3. Reduced side effects when compared to chronic use of diclofenac alone in the management of therapy.
In one of the aspects of present invention there is provided a pharmaceutical composition comprising 25-100 mg of diclofenac sodium in an extended release form and 5-20 mg of meloxicam in an immediate release form in admixture with pharmaceutically acceptable carrier.
In yet another aspect of the present invention there is provided a pharmaceutical composition comprising 100 mg of diclofenac sodium in an extended release form and 7.5 mg of meloxicam in an immediate release form in admixture with pharmaceutically acceptable carrier.
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In yet another aspect of the present invention there is provided a pharmaceutical composition comprising 100 mg of diclofenac sodium in an extended release form and 15 mg of meloxicam in an immediate release form in admixture with pharmaceutically acceptable carrier.
In yet another aspect of the present invention there is provided the method of treating moderate to severe pain by administering to a subject in need thereof a pharmaceutical composition comprising 25-100 mg of diclofenac sodium in an extended release form and 5-20 mg of meloxicam in an immediate release form in admixture with pharmaceutically acceptable carrier.
The pharmaceutical composition comprises of diclofenac sodium in an extended release form and meloxicam in an immediate release form as active ingredients alongwith pharmaceutically acceptable carrier. The pharmaceutical composition can be matrix or polymer coated composition.
The pharmaceutical composition comprises of preparing granules of one active ingredient, which is then compressed to form tablet, and then the formed tablet is coated with aqueous dispersion of second active ingredient in admixture with pharmaceutically acceptable carrier. The formulation can be prepared by dry granulation, wet granulation or direct compression. The pharmaceutical composition can be prepared in parts or in one single step.
The pharmaceutical composition can be prepared in two parts. First part comprises of Intragranular and Extragranular material. The Intragranular material comprises of diclofenac sodium alongwith pharmaceutically acceptable carrier. Diclofenac alongwith pharmaceutically acceptable carrier is granulated using wet granulation or dry granulation. The obtained granules are mixed with extragranular material that is selected from a group comprising of one or more of filler, lubricant, glidant, disintegrant, and the like.
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Second part comprises of meloxicam alongwith pharmaceutical^ acceptable carrier wherein meloxicam alongwith pharmaceutical^ acceptable carrier are sifted individually and then mixed. The obtained blend is lubricated.
The first and second parts are compressed to form bilayer tablet.
The pharmaceutical composition can be granule, powder, sachet, pellet, suspension, capsule or compressed to form immediate release tablets, extended release tablets, controlled release or delayed release tablet wherein the tablet can be bilayer tablet, multilayer tablet, tablet in tablet, effervescent tablet, mini tablet and the like.
The pharmaceutical composition is meant for oral administration to the subject and the said subject is mammal. The pharmaceutical composition is meant for once daily administration.
The pharmaceutical^ acceptable carrier can be selected from a group comprising of one or more of binder, filler, lubricant, glidant, disintegrant, pharmaceutically acceptable rate controlling polymer and the like.
Suitable binders may be one or more of starch, sugars, gums, low molecular weight hydroxypropylmethyl cellulose, polyvinyl pyrrolidone and hydroxypropyl cellulose.
Suitable fillers may be one or more of lactose, dicalcium phosphate, microcrystalline cellulose, mannitol and the like.
Suitable lubricants may be one or more talc, magnesium stearate, polyethylene glycol, hydrogenated vegetable oils, stearic acid, sodium stearyl fumarate and sodium benzoate.
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Suitable glidants may be one or both of colloidal silicon dioxide and talc or magnesium stearate.
Suitable disintegrant may be one or more of starch, croscarmellose sodium, crospovidone, sodium starch glycolate and the like
Suitable pharmaceutical^ acceptable rate controlling polymers to achieve delayed release, sustained release, controlled release or extended release can be hydrophilic or hydrophobic polymers.
Hydrophilic polymers can be selected from a group comprising of one or more of cellulose ethers, carbohydrate gum, polyuronic acid salts and mixtures, thereof. Suitable cellulose ethers include one or more of methylhydroxypropylcelluloses, hydroxyethylcelluloses, hydroxypropylcellulose, methylcelluloses, ethylcelluloses, and carboxymethylcelluloses and most particularly selected from the group consisting of methylhydroxypropylcelluloses, hydroxyethylcelluloses, and hydroxypropylcelluloses. Suitable carbohydrate gums include one or more of xanthan gum, tragacanth gum, gum karaya, guar gum, acacia, gellan, locust bean gum and other carbohydrate gums having similar properties. Suitable polyuronic acid salts include one or more of alkali metal salts of alginic acid or pectic acid and mixtures thereof.
Hydrophobic polymers can be selected from a group comprising of one or more of cellulose ethers, acrylic acid polymers, aliphatic alcohols and natural or synthetic wax or oil. Suitable acrylic acid polymers include any suitable acrylic acid and methacrylic acid copolymers, methyl methacrylate copolymers, ethoxyethyl methacrylates, cynaoethyl methacrylate, aminoalkyl methacrylate copolymer, poly(acrylic acid), poly(methacrylic acid), methacrylic acid alkylamide copolymer, poly(methyl methacrylate), poly(methacrylic acid) (anhydride), methyl methacrylate, polymethacrylate, poly(methyl methacrylate), poly(methyl methacrylate) copolymer, polyacrylamide, aminoalkyl methacrylate copolymer,
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poly(methacrylic acid anhydride), and glycidyl methacrylate copolymers. Suitable aliphatic alcohols can be selected from a group comprising of stearyl alcohol, cetostearyl alcohol, lauryl alcohol, myristyl alcohol and mixtures, thereof. Suitable natural or synthetic wax or oil can be selected from a group comprising of hydrogenated vegetable oil, hydrogenated castor oil, microcrystalline wax, Beeswax, Carnauba wax or glyceryl monostearate.
Suitable enteric polymers can be selected from a group comprising of one or more of cellulose acetate phthalate, shellac, Hydroxypropyl methylcellulose phthalate, and acrylic acid polymers like Eudragit.
While the present invention has been described in terms of its specific embodiments, certain modifications and equivalents will be apparent to those skilled in the art and are intended to be included within the scope of the present invention
EXAMPLES 1-2

SN Ingredients Example 1 mg/tab Example 2 mg/tab
PART1
Intragranular
1 Diclofenac sodium 100 100
2 Lactose mondnydrate 40 40
3 Microcrystalline cellulose 20 20
4 Hypromellose [Methocel K 100 LV Premum CR] 50 50
5 Povidone K 30 4 4
Extragranular
6 Talc 5 5
7 Magnesium stearate 1 1
PART 2
7 Meloxicam 7.5 15
8 Lactose Monohydrate 100 92.5
9 Microcrystalline cellulose 60 60
10 Sodium citrate dihydrate 10 10
11 Povidone K 30 8 8
12 Crospovidone 7.5 7.5
13 Magnesium stearate 2 2
14 Talc 5 5
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Procedure: The pharmaceutical analgesic compositions mentioned in examples 1 and 2 are prepared in two parts. The first part comprises of Intragranular material and Extragranular material. The Intragranular material is prepared by sifting individually and then mixing specified quantities of diclofenac sodium, lactose monohydrate, microcrystalline cellulose, Hypromellose [Methocel K 100 LV Premum CR] and then granulating using Povidone K 30 in purified water. The obtained granules are sifted and mixed with pre-sifted extragranular material comprising talc and magnesium stearate. The second part is prepared by sifting individually and then mixing specified quantities of Meloxicam, Lactose Monohydrate, Microcrystalline cellulose, Sodium citrate dihydrate, Povidone K -30 and Crospovidone. The blend is lubricated with talc and magnesium stearate. The first and the second parts are compressed to form a bilayer tablet and can be optionally coated with Opadry dispersion.
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WE CLAIM:
1. A pharmaceutical composition comprising 25-100 mg of diclofenac sodium in an extended release form and 5-20 mg of meloxicam in an immediate release form in admixture with pharmaceutically acceptable carrier.
2. A pharmaceutical composition comprising 100 mg of diclofenac sodium in an extended release form and 7.5 or 15 mg of meloxicam in an immediate release form in admixture with pharmaceutically acceptable carrier.
3. A pharmaceutical composition as per claim 1 and 2 wherein pharmaceutically acceptable carrier is selected from a group comprising of one or more of binder, filler, lubricant, glidant, disintegrant, pharmaceutically acceptable rate controlling polymer and the like.
4. A pharmaceutical composition as per claim 1 and 2 wherein pharmaceutical composition is tablet, pellet, sachet, capsule, granules, powder, suspension, bilayer tablet, multilayer tablet, tablet in tablet, effervescent tablet, mini tablet.
5. A pharmaceutical composition as per claim 1 and 2 wherein pharmaceutical composition is administered by oral route.
6. The method of treating moderate to severe pain by administering to a subject in need thereof a therapeutically effective amount of pharmaceutical composition comprising 100 mg of diclofenac sodium in an extended release form and 7.5 mg or 15 mg of meloxicam in an immediate release form in admixture with pharmaceutically acceptable carrier.
7. The method as per claim 6 wherein the daily dose of meloxicam is from about 7.5 mg to about 15 mg.
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8. The method of treating moderate to severe pain by administering to a subject in need thereof a therapeutically effective amount of pharmaceutical composition of claim 1 and claim 2.
9. The method as per claim 6 wherein the said subject is mammal.
Dated this 7nt day of June, 2006
For Wockhardt Limited

(Mandar Kodgule) Authorized Signatory
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