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:
NOVEL ANALGESIC COMBINATION COMPRISING TRAMADOL AND DICLOFENAC
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 pharmaceutical analgesic composition comprising tramadol and diclofenac in admixture with pharmaceutically acceptable carrier and a method of treating moderate to severe pain by administering to a subject in need thereof, a therapeutically effective amount of said analgesic composition. The said pharmaceutical analgesic composition provides 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.
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4. DESCRIPTION
The present invention provides pharmaceutical analgesic composition comprising tramadol and diclofenac in admixture with pharmaceutically acceptable carrier and a method of treating moderate to severe pain by administering to a subject in need thereof, a therapeutically effective amount of said analgesic composition. The said pharmaceutical analgesic composition provides better pain management, reduced side effects and improved patient compliance.
Tramadol is a centrally acting synthetic opioid analgesic. It is chemically (±) cis-2-[(dimethylamino)methyl]-1-(3-methoxyphenyl) cyclohexanol hydrochloride. It is commercially available in form of its hydrochloride salt (Formula I) as Ultram tablets. Tramadol is indicated in the treatment of the management of moderate to moderately severe pain in adults.
r

n
..A )
HO .. |——'' OH-*
W' I /
CHg—N GH-S

.HCI

FORMULA I
Diclofenac, a non-steroidal anti-inflammatory, is a benzene-acetic acid derivative. Diclofenac sodium is chemically 2-[(2,6-dichlorophenyl)amino] benzeneacetic acid, monosodium salt (Formula II). Diclofenac is commercially available in two salt forms; one of them is sodium salt 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 II
Combination of opioids like tramadol with other drugs like non-opioid analgesic agents is well known in the prior art but with the limitations of shorter duration of action, frequent dosing, poor patient compliance and moreover increased side effects due to frequent dosing. Also, it is well known 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 tramadol with diclofenac is not known in the prior art.
There is a continuing need for analgesic medications that provide high efficacy pain relief and reduced possibility of undesirable effects. To overcome the problems exemplified in the prior art, the present inventors have come up with a novel analgesic combination comprising of 25-400 mg of tramadol or pharmaceutically acceptable salt or derivative thereof and 25-200 mg of diclofenac or pharmaceutically acceptable salt or derivative thereof in admixture with pharmaceutically acceptable carrier that provides -
1. Better pain management
2. Reduced dosing frequency
3. Improved patient compliance
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4. Reduced side effects when compared to chronic use of tramadol or diclofenac alone in the management of therapy.
In one of the aspects of present invention there is provided a method of treating moderate to severe pain by administering to a subject in need thereof, a pharmaceutical composition comprising 25-400 mg of tramadol or a pharmaceutically acceptable salt or derivative thereof and 25-200 mg of diclofenac or a pharmaceutically acceptable salt or derivative thereof in admixture with pharmaceutically acceptable carrier.
In yet another aspect of present invention there is provided a pharmaceutical composition comprising 25-400 mg of tramadol or pharmaceutically acceptable salt or derivative thereof and 25-200 mg of diclofenac sodium in admixture with pharmaceutically acceptable carrier wherein both tramadol hydrochloride and diclofenac sodium are present in an extended release form.
In yet another aspect of present invention there is provided a pharmaceutical composition comprising 100 mg of tramadol or pharmaceutically acceptable salt or derivative thereof and 100 mg of diclofenac sodium in admixture with pharmaceutically acceptable carrier wherein both tramadol hydrochloride and diclofenac sodium are present in an extended release form.
In yet another aspect of present invention there is provided a pharmaceutical composition comprising 200 mg of tramadol or pharmaceutically acceptable salt or derivative thereof and 100 mg of diclofenac sodium in admixture with pharmaceutically acceptable carrier wherein both tramadol hydrochloride and diclofenac sodium are present in an extended release form.
In yet another aspect of present invention there is provided a pharmaceutical composition comprising 300 mg of tramadol or pharmaceutically acceptable salt or derivative thereof and 100 mg of diclofenac sodium in admixture with
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pharmaceutical^ acceptable carrier wherein both tramadol hydrochloride and diclofenac sodium are present in an extended release form.
The pharmaceutical composition comprises of tramadol and diclofenac as active ingredients wherein tramadol and diclofenac can be present in an extended release form, delayed release form or immediate release form. Tramadol is present as tramadol hydrochloride and diclofenac as sodium or potassium salt. The pharmaceutical composition can be matrix or polymer coated composition.
The pharmaceutical composition comprises of tramadol and diclofenac, which can be formulated in parts or together by dry granulation, wet granulation or direct compression.
The pharmaceutical composition can be prepared in two parts. First part comprises of Intragranular and Extragranular material. The Intragranular material comprises of tramadol hydrochloride alongwith pharmaceutically acceptable carrier. Tramadol hydrochloride 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 lubricant, glidant, disintegrant, and the like.
Second part comprises of Intragranular and Extragranular material. The Intragranular material comprise of diclofenac sodium alongwith pharmaceutically acceptable carrier. Diclofenac sodium 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 lubricant, glidant, disintegrant and the like.
The first and second parts are compressed to form bilayer tablet that can be optionally coated using Opadry dispersion.
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The second part can also be compressed to form a tablet. The tablet can then be coated with seal coat, which is further coated with enteric polymers. The enteric-coated tablets of second part are compressed with a blend of first part to form tablet in tablet that can be optionally coated using Opadry dispersion.
The pharmaceutical composition can also be prepared in one part wherein tramadol and diclofenac alongwith pharmaceutically acceptable carrier are granulated using dry or wet granulation. The obtained granules are mixed with extragranular material that is selected from a group comprising one or more of lubricant, glidant, disintegrant, and the like. The resultant granules are compressed to form a bilayer tablet or given in a suitable dosage form.
The pharmaceutical composition can be granule, powder, sachet, pellet, suspension, capsule or compressed to form immediate release tablets, extended release tablets, controlled release tablet, delayed release tablet wherein the tablet can be bilayer tablet, multilayer tablet, tablet in tablet, effervescent tablet, mini tablet.
The pharmaceutical composition is meant for oral administration to subject in need and the said subject is mammal. The pharmaceutical composition is meant for once daily administration.
The pharmaceutically acceptable carrier can be selected from a group comprising of one or more of binder, filler, lubricant, glidant, disintegrant, pharmaceutically acceptable rate controlling polymer, enteric 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.
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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.
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 pharmaceutically 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
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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, 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
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EXAMPLES 1-3

SN Ingredients Example 1 mg/tab Example 2 mg/tab Example 3 mg/tab
PART1
Intragranular
1 Tramadol Hydrochloride 300 200 100.0
2 Ethyl cellulose FP 10 40 26.7 13.3
3 Xanthan Gum 50 33.3 16.7
4 Microcrystalline cellulose (Avicel 101) 68.5 45.7 22.8
Extragranular
5 Magnesium stearate 7 4.7 2.3
6 Talc 9.5 6.3 3.2
PART 2
Intragranular
7 Diclofenac sodium 100 100 100
8 Lactose monohydrate 40 40 40
9 Microcrystalline cellulose 20 20 20
10 Hypromellose [Methocel K 100 LV Premum CR] 50 50 50
11 Povidone K 30 4 4 4
Extragranular
12 Talc 5 5 5
13 Magnesium stearate 1 1 1
Procedure: The pharmaceutical analgesic compositions mentioned in examples 1 - 3 are prepared in two parts. The first part comprises of Intragranular material and Extragranular material. The Intragranular material is prepared by sifting individually and mixing specified quantities of tramadol hydrochloride, Ethyl cellulose FP 10, Xanthan Gum, Microcrystalline cellulose (Avicel 101) and then granulating using purified water. The obtained granules are sifted and mixed with pre-sifted extragranular material comprising talc and magnesium stearate.
The second part comprises of Intragranular material and Extragranular material. The Intragranular material is prepared by sifting individually and mixing specified quantities of diclofenac sodium, Lactose Monohydrate, Microcrystalline cellulose, Hypromellose [Methocel K 100 LV Premum CR], Povidone K -30 and then
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granulating using purified water. The obtained granules are sifted and mixed with pre-sifted extragranular material comprising talc and magnesium stearate.
The first and the second parts are compressed to form a bilayer tablet and can be optionally coated using Opadry dispersion.
EXAMPLES 4- 6

SN Ingredients Example 4 mg/tab Example 5 mg/tab Example 6 mg/tab
PART1
Intragranular
1 Tramadol Hydrochloride 100 200 300
2 Ethyl cellulose FP 10 136 126 110
3 Xanthan Gum 210 180 155
4 Microcrystalline cellulose (Avicel 101) 430 370 311
Extragranular
5 Magnesium stearate 9 9 9
6 Talc 15 15 15
PART 2
CORE TABLET
Intragranular
7 Diclofenac sodium 75 75 75
8 Lactose monohydrate 3.9 3.9 3.9
9 Avicel PH 101 3.9 3.9 3.9
10 Povidone K 30 1.8 1.8 1.8
Extragranular
11 Sodium Starch Glycolate 2.7 2.7 2.7
12 Talc 1.8 1.8 1.8
13 Magnesium stearate 0.9 0.9 0.9
Wt. Of core tablet 90 90 90
SEAL COATING
14 Opadry 1.8 1.8 1.8
ENTERIC COATING
15 Eudragit L-30-D 55 6 6 6
16 Triethyl citrate 0.6 0.6 0.6
17 Talc 0.75 0.75 0.75
Procedure: The pharmaceutical analgesic compositions mentioned in examples 4 - 6 are prepared in two parts. The first part comprises of Intragranular material
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and Extragranular material. The Intragranular material is prepared by sifting individually and mixing specified quantities of tramadol hydrochloride, Ethyl cellulose FP 10, Xanthan Gum, Microcrystalline cellulose (Avicel 101) and then granulating using purified water. The obtained granules are sifted and mixed with pre-sifted extragranular material comprising talc and magnesium stearate.
The second part comprises of Intragranular material and Extragranular material. The Intragranular material is prepared by sifting individually and mixing specified quantities of diclofenac sodium, Lactose Monohydrate, Microcrystalline cellulose (Avicel PH 101) and then granulating using Povidone K -30 solution in purified water. The obtained granules are sifted and mixed with pre-sifted extragranular material comprising sodium starch glycolate, talc and magnesium stearate. The resultant granules are compressed to form a tablet, which is further seal coated with opadry and then enteric-coated using enteric coating dispersion comprising of Eudragit L-30-D 55, Triethyl citrate and talc.
The enteric-coated tablets obtained from second part are compressed with a blend of first part to form tablet in tablet. The obtained tablets can be optionally coated using Opadry dispersion.
EXAMPLE 7

SN Ingredients mg/tab
PART1
Intragranular
1 Tramadol Hydrochloride 100
2 Ethyl cellulose FP 10 136
3 Xanthan Gum 210
4 Microcrystalline cellulose (Avicel 101) 430
Extragranular
5 Magnesium stearate 9
6 Talc 15
PART 2
Intragranular

7 Diclofenac Potassium 100
8 Lactose monohydrate 60
9 Microcrystalline cellulose 30
10 Hypromellose [Methocel K 100 LV Premum CR] 75
11 Povidone K 30 4
Extragranular
12 Talc 5
13 Magnesium stearate 1
Procedure: The pharmaceutical analgesic composition mentioned in example 4 is prepared in two parts. The first part comprises of Intragranular material and Extragranular material. The Intragranular material is prepared by sifting individually and mixing specified quantities of tramadol hydrochloride, Ethyl cellulose FP 10, Xanthan Gum, Microcrystalline cellulose (Avicel 101) and then granulating using purified water. The obtained granules are sifted and mixed with pre-sifted extragranular material comprising talc and magnesium stearate.
The second part comprises of Intragranular material and Extragranular material. The Intragranular material is prepared by sifting individually and mixing specified quantities of diclofenac potassium, Lactose Monohydrate, Microcrystalline cellulose (Avicel PH 101), Hypromellose [Methocel K 100 LV Premum CR] and then granulating using Povidone K -30 solution in purified water. The obtained granules are sifted and mixed with pre-sifted extragranular material comprising sodium starch glycolate, talc and magnesium stearate.
The blend of first and second part is compressed to form bilayer tablet and can be optionally coated using Opadry dispersion.
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EXAMPLE 8

SN Ingredients mg/tab
PART1
Intragranular
1 Tramadol Hydrochloride 100
2 Ethyl cellulose FP 10 136
3 Xanthan Gum 210
4 Microcrystalline cellulose (Avicel 101) 430
Extragranular
5 Magnesium stearate 9
6 Talc 15
PART 2
Intragranular
7 Diclofenac potassium 50
8 Lactose monohydrate 40
9 Dibasic Calcium Phosphate 50
10 Microcrystalline cellulose 84
11 Sodium starch glycolate 7.5
12 Povidone K 30 5
Extragranular
13 Sodium starch glycolate 7.5
14 Magnesium stearate 2
15 Talc 4
Procedure: The pharmaceutical analgesic composition mentioned in example 5 is prepared in two parts. The first part comprises of Intragranular material and Extragranular material. The Intragranular material is prepared by sifting individually and mixing specified quantities of tramadol hydrochloride, Ethyl cellulose FP 10, Xanthan Gum, Microcrystalline cellulose (Avicel 101) and then granulating using purified water. The obtained granules are sifted and mixed with pre-sifted extragranular material comprising talc and magnesium stearate.
The second part comprises of Intragranular material and Extragranular material. The Intragranular material is prepared by sifting individually and mixing specified quantities of diclofenac potassium, Lactose Monohydrate, Microcrystalline cellulose (Avicel PH 101), Sodium starch glycolate and then granulating using
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Povidone K -30 solution in purified water. The obtained granules are sifted and mixed with pre-sifted extragranular material comprising sodium starch glycolate, talc and magnesium stearate.
The blend of first and second part is compressed to form bilayer tablet and can be optionally coated using Opadry dispersion.
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WE CLAIM:
1. A method of treating moderate to severe pain by administering to a subject in need thereof, a pharmaceutical composition comprising 25-400 mg of tramadol or a pharmaceutically acceptable salt or derivative thereof and 25-200 mg of diclofenac or a pharmaceutically acceptable salt or derivative thereof in admixture with pharmaceutically acceptable carrier.
2. A method of claim 1 wherein Tramadol and diclofenac are present in an immediate release form, extended release form, delayed release form.
3. A pharmaceutical composition comprising 25-400 mg of tramadol or pharmaceutically acceptable salt or derivative thereof and 25-200 mg of diclofenac sodium in admixture with pharmaceutically acceptable carrier wherein both tramadol and diclofenac are present in an extended release form.
4. A pharmaceutical composition comprising 100 mg of tramadol or pharmaceutically acceptable salt or derivative thereof and 100 mg of diclofenac sodium in admixture with pharmaceutically acceptable carrier wherein both tramadol and diclofenac are present in an extended release form.
5. A pharmaceutical composition comprising 200 mg of tramadol or pharmaceutically acceptable salt or derivative thereof and 100 mg of diclofenac sodium in admixture with pharmaceutically acceptable carrier wherein both tramadol and diclofenac are present in an extended release form.
6. A pharmaceutical composition comprising 300 mg of tramadol or pharmaceutically acceptable salt or derivative thereof and 100 mg of
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diclofenac sodium in admixture with pharmaceutical^ acceptable carrier wherein both tramadol and diclofenac are present in an extended release form.
7. A pharmaceutical composition as per any preceding claims 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.
8. A pharmaceutical composition as per any preceding claims wherein pharmaceutical composition is tablet, pellet, sachet, capsule, granules, powder, suspension, bilayer tablet, multilayer tablet, tablet in tablet, effervescent tablet, mini tablet
9. A pharmaceutical composition as per any preceding claims wherein the pharmaceutical composition is administered by oral route.
10. A method as per claim 1 wherein the said subject is mammal
Dated this28th day of June, 2006
For Wockhardt Limited
(Mandar kodgule) Authorized Signatory
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