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:
PHARMACEUTICAL COMPOSITION COMPRISING DICLOFENAC AND MISOPROSTOL
2. APPLICANT (S)
(a) NAME: WOCKHARDT LTD.
(b) NATIONALITY: INDIAN
(c) ADDRESS: Wockhardt Towers, Bandra-Kurla Complex, Bandra
(East), Mumbai- 400051.

3. PREAMBLE TO THE DESCRIPTION
The present invention provides a pharmaceutical composition comprising coated beads of diclofenac or salt thereof along with pharmaceutically acceptable excipients and a coating comprising misoprostol or salt there of along with pharmaceutical acceptable excipients characterized in that said misoprostol coating covers not more than 90% of the coated beads of diclofenac or salt thereof.
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 a pharmaceutical composition comprising coated beads of diclofenac or salt thereof along with pharmaceutically acceptable excipients and a coating comprising misoprostol or salt there of along with pharmaceutical acceptable excipients characterized in that said misoprostol coating covers not more than 90% of the coated beads of diclofenac or salt thereof.
Diclofenac sodium is a phenylacetic acid derivative that is a white to off-white, virtually odorless, crystalline powder. Diclofenac sodium is freely soluble in methanol; soluble in ethanol and practically insoluble in chloroform and in dilute acid. Diclofenac sodium is sparingly soluble in water. Its chemical formula is C14H10Cl2NO2Na [M.W. = 318.14] and name is 2-[(2,6-dichlorophenyl) amino] benzeneacetic acid, monosodium salt. Its structural formula is:

Misoprostol is a water soluble, viscous liquid that contains approximately equal amounts of two diastereomers. Its chemical formula is C22H38O5 [M.W. = 382.54]
and name is (±) methyl 11a, 16-dihydroxy-16-methyl-9-oxoprost-13E-en-1-oate.
Its structural formula is :

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(11R, 16S)-Form
Arthrotec (diclofenac sodium/misoprostol) is a combination product containing diclofenac sodium, a non-steroidal anti-inflammatory drug (NSAID) with analgesic properties, and misoprostol, a gastrointestinal (Gl) mucosal protective prostaglandin E1 analog. Arthrotec oral tablets are white to off-white, round, biconvex and approximately 11mm in diameter. Each tablet consists of an enteric-coated core containing 50mg or 75mg diclofenac sodium surrounded by an outer mantle containing 200mcg misoprostol. Inactive ingredients in Arthrotec include: colloidal silicon dioxide; crospovidone; hydrogenated castor oil; hypromellose; lactose; magnesium stearate; methacrylic acid copolymer; microcrystalline cellulose; povidone (polyvidone) K-30; sodium hydroxide; starch (corn); talc; triethyl citrate.
US Patent No. 5,601,843 and 5,698,225 discloses a tablet having a core of a NSAID selected from diclofenac and piroxicam which core is surrounded by a mantle coating of a prostaglandin such as misoprostol, wherein an intermediate coating can be present between the NSAID core and prostaglandin mantle coating.
US Patent No. 5,015,481 discloses a pharmaceutical composition comprising an admixture of an NSAID selected from diclofenac and piroxicam, a prostaglandin such as misoprostol, and a stabilizer, preferably HPMC.
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US Patent No 6,740,340 discloses a pharmaceutical tablet that incorporates two smaller tablets, one of which comprises an NSAID and the other of which comprises misoprostol, preferably in a form of a dispersion in HPMC.
US Patent No. 6,511,680 and 6,319,519 discloses a dosage form wherein an NSAID is located in coated pellets and misoprostol, for example in a form of a solid dispersion in HPMC or PVP, is located outside the pellets.
US Patent No. 6,183,779 and 6,287,600 discloses a dosage form wherein an NSAID is located in enteric coated granules or particles and misoprostol, for example in a form of a solid dispersion in HPMC or PVP, is located outside the pellets. U.S. Pat. No. 6,387,410, 6,514,525, 6,537,582 and 6,787,155 discloses a similar dosage form except that the NSAID containing pellets are said to be in a delayed release formulation.
US Patent No 6,656,503 discloses a pharmaceutical tablet comprising a core and a film coating wherein the core comprises an NSAID and the film coating comprises a polymer and misoprostol.
US Patent No 5,232,704 disclose a capsule dosage form containing one layer comprising a drug release layer comprising misoprostol and the other a buoyant or floating layer.
US Application 2005163847 discloses a solid dosage form comprising a first portion comprising NSAID; and a coating comprising an antiulcerative compound, said coating at least partially surrounding the NSAID portion.
US Application 20040185100 disclose a dual release dosage form comprising an extended release NSAID and an immediate release stabilized prostaglandin.
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US Application 2005031690 discloses a dosage form comprising a plurality of zones, at least one of which comprises an NSAID and another of which comprises a solid dispersion of a prostaglandin type compound in HPMC.
European Patent Application No. 1020182A3 discloses a two-layer tablet having an NSAID and misoprostol located in separate layers. Again the misoprostol can be in a form of a solid dispersion in HPMC.
European Patent Application No. EP1216030A1 discloses a dosage form including a mixture of a delay release formulation of NSAID and a mixture containing a prostaglandin and one or more excipients.
European Patent Application No. EP1091731 discloses a dosage form wherein an NSAID is located in coated pellets and misoprostol, in a form of a solid dispersion in HPMC or PVP.
NSAIDs present great therapeutic benefit in treatment of inflammatory conditions such as arthritis, but have an ulcerogenic effect in the upper gastrointestinal tract, which can seriously limit their usefulness, especially for chronic treatment. Certain prostaglandin type compounds, especially prostaglandin E1 derivatives and more particularly misoprostol, have been found to mitigate or provide protection against such ulcerogenic effects when co-administered with an NSAID.
Chemical degradation of certain prostaglandin type compounds, particularly prostaglandin E1 derivatives such as misoprostol, is accelerated in presence of water, and the primary pathway of degradation is believed to be dehydration to the corresponding prostaglandin A derivative. The problem of chemical instability becomes more acute when the prostaglandin type compound is coformulated with certain NSAIDs such as diclofenac or piroxicam.
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The present inventors while working on the diclofenac, misoprostol combination formulation have surprisingly found that even when misoprostol coats 90% of the enteric coated beads of diclofenac or salt thereof, misoprostol is not in direct contact with diclofenac due to presence of intermediate seal coat and enteric coat and hence it is prevented from degradation resulting in stable formulation.
One of the aspects of the present invention provides a pharmaceutical composition comprising coated beads of diclofenac or salt thereof along with pharmaceutically acceptable excipients and a coating comprising misoprostol or salt there of along with pharmaceutical acceptable excipients characterized in that said misoprostol coating covers not more than 90% of the coated beads of diclofenac or salt thereof.
The pharmaceutical composition comprising coated beads of diclofenac or salt thereof wherein diclofenac is present as diclofenac sodium.
Coated beads of diclofenac or salt thereof can be prepared by:
a) coating inert spherical beads with suspension of diclofenac or salt thereof
b) overcoating the diclofenac loaded beads of step a) by a pharmaceutically acceptable seal coat polymer
c) enteric-coating the seal coated diclofenac beads of step b) with pharmaceutically acceptable enteric polymer.
d) enteric -coated beads of diclofenac or salt thereof of step c) are mixed with polyethylene glycol optionally along with other pharmaceutically acceptable excipients.
During compression, pressure exerted on beads results in cracking of the beads. Presence of polyethylene glycol in enteric-coated diclofenac beads provides cushioning effect to beads and avoids cracking under compression pressure.
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Polyethylene glycol may be selected from group comprising one or more of PEG 2000, PEG 4000, PEG 3350, PEG 6000, PEG 8000 and the like.
Inert spherical beads can be made up of one or more of saccharides or derivatives thereof such as polysaccharides, sugars such as mannitol, sorbitol, lactose, sucrose, maltodextrin, starches such as maize starch, rice starch, celluloses such as microcrystalline cellulose, sodium carboxymethyl cellulose and the like.
Suspension of diclofenac or salt thereof can be made up of diclofenac or salt thereof along with one or more hydrophilic polymers, water and pharmaceutically acceptable excipients.
The hydrophilic polymers . comprises one or more of hydroxypropyl methylcellulose, hydroxypropyl cellulose, polyvinyl pyrrolidone, methacrylates and the like.
The pharmaceutically acceptable seal coat polymers can be selected from a group comprising of one or more of hydroxypropyl methylcellulose, hydroxypropyl cellulose and other suitable cellulose ethers.
The pharmaceutically acceptable enteric coating polymers can be selected from a group comprising one or more of methacrylic acid/methyl methacrylate copolymers such as Eudragits or cellulose derivatives such as carboxymethyl cellulose, cellulose acetate phthalate, hydroxypropylmethyl cellulose phthalate and other suitable polymers.
In misoprostol-polymer dispersion, polymer may be one or more of hydroxypropylmethylcellulose, hydroxypropylcellulose, polyvinylpyrrolidone and the like.
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In misoprostol-polymer dispersion, polymer may be one or more of hydroxypropylmethylcellulose, hydroxypropylcellulose, polyvinylpyrrolidone and the like.
The pharmaceutical composition of the present invention can be made by mixing diclofenac loaded enteric-coated beads with other pharmaceutically acceptable excipients. Diclofenac loaded enteric coated beads blend is divided into two parts in such a way that first part contains 90% of the enteric-coated beads of diclofenac and other second part contains the remaining 10% of the enteric-coated beads of diclofenac. First part containing 90% of the enteric-coated beads of diclofenac is mixed with misoprostol-hypromellose dispersion. Enteric-coated diclofenac beads coated with misoprostol-hypromellose dispersion and second part containing the remaining 10% of the enteric-coated beads of diclofenac are processed into suitable dosage form.
Suitable dosage form of the present invention can be in the form of bilayered tablet, trilayered tablet, tablet in capsule, or any other dosage form suitable for oral administration.
In yet another aspect of the present invention there is provided a pharmaceutical composition comprising coated beads of diclofenac or salt thereof and coating of misoprostol or salt thereof wherein the said coating covers not more than 90% of the coated beads of diclofenac and wherein the formulation exhibits a dissolution profile such that within first 2 hours less than 2% of diclofenac or salt thereof is released wherein the release rate is measured in Apparatus 2 (USP, Dissolution, paddle, 50 rpm) using 1000 ml of 0.1N HCI at 37 °C ± 0.5°C and within first 30 minutes more than 80% of diclofenac or salt thereof is released, wherein the release rate is measured in Apparatus 2 (USP, Dissolution, paddle, 50 rpm) using 1000 ml of pH 6.8 phosphate buffer at 37 °C ± 0.5°C.
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The pharmaceutical composition comprises of pharmaceutically acceptable excipients wherein excipients may include binders, fillers, lubricants, disintegrants, and glidants.
Suitable binder may be selected from a group comprising one or more of, povidone, starch, stearic acid, gums, hydroxypropylmethyl cellulose and the like.
Suitable filler may be selected from a group comprising one or more of, microcrystalline cellulose, lactose, mannitol, calcium phosphate, calcium sulfate, kaolin, dry starch, powdered sugar and the like.
Suitable lubricants may be selected from a group comprising one or more of magnesium stearate, zinc stearate, calcium stearate, stearic acid, sodium stearyl fumarate, hydrogenated vegetable oil and the like.
Suitable glidants may be one or more of colloidal silicon dioxide, talc or cornstarch and the like.
Suitable disintegrant may be one or more of starch, croscarmellose sodium, crospovidone, sodium starch glycolate and the like.
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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EXAMPLE 1
Table 1: Composition of Diclofenac-misoprostol tablets

No Ingredients % Composition
Misoprostol coating
Misoprostol: hypromellose (1:100)
1 Misoprostol 0.01 to 2.0
2 Hypromellose 10 to 99
Diclofenac sodium enteric coated beads
Beads
1 Microcrystalline cellulose 30 to 95
Drug layering
2 Diclofenac sodium 5 to 70
3 Hypromellose 3 to 25
4 Polyethylene glycol 0.15 to 2.5
5 Purified water q.s.
Seal coating
6 Hypromellose + PEG 400 1 to 5
7 Purified water
Enteric coating
8 Methacrylic acid copolymer suspension (Methacrylic acid copolymer, sodium hydroxide, Talc, triethyl citrate, purified water) 8 to 25
Blend for beads compression
9 PEG 6000 0.5 to 5
10 Microcrystalline cellulose 10 to 80
11 Sodium starch glycolate 1 to 10
12 Hydrogenated castor oil 0.1 to 2.0
Procedure: Diclofenac sodium suspension is prepared in water along with hypromellose and polyethylene glycol under stirring. Microcrystalline cellulose beads are coated with diclofenac sodium suspension in fluidized bed processor. Drug loaded beads thus obtained are seal coated with hypromellose and
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polyethylene glycol 400 solution. Seal coated drug loaded beads are coated with enteric polymer suspension prepared by mixing methacrylic acid polymer, sodium hydroxide, talc, triethyl citrate in water. Enteric-coated beads are lubricated with polyethylene glycol 6000 in double cone blender and further mixed with microcrystalline cellulose, sodium starch glycollate. Above blend is lubricated with hydrogenated vegetable oil.
Diclofenac loaded enteric-coated beads blend is divided into two parts in such a way that first part contains 90% of the enteric-coated beads of diclofenac and other second part contains the remaining 10% of the enteric-coated beads of diclofenac. First part containing 90% of the enteric-coated beads of diclofenac is blended with misoprostol-hypromellose dispersion in double cone blender. This blend of enteric-coated beads of diclofenac coated with misoprostol-hypromellose is compressed with second part containing remaining 10% diclofenac loaded enteric-coated beads into bilayered tablets using suitable tooling. Finally the tablet is further coated aqueous dispersion of Opadry.
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WE CLAIM:
1. A pharmaceutical composition comprising coated beads of diclofenac or
salt thereof along with pharmaceutically acceptable excipients and a
coating comprising misoprostol or salt there of along with pharmaceutical
acceptable excipients characterized in that said misoprostol coating
covers not more than 90% of the coated beads of diclofenac or salt
thereof.
2. The pharmaceutical composition of claim 1, wherein diclofenac or salt
thereof is present in the form of diclofenac sodium.
3. The pharmaceutical composition of claim 1, wherein coated beads of
diclofenac or salt thereof are prepared by:
a) coating inert spherical beads with suspension of diclofenac or salt thereof
b) surrounding the diclofenac loaded beads of step a) by a pharmaceutically acceptable seal coat polymer
c) enteric-coating the seal coated diclofenac beads of step b) with suitable enteric polymer.
d) enteric -coated beads of diclofenac or salt thereof of step c) are mixed with polyethylene glycol optionally along with other pharmaceutically acceptable excipients.
4. The pharmaceutical composition of claim 3, wherein inert spherical beads
comprises one or more of saccharides or derivatives thereof such as
polysaccharides, sugars such as mannitol, sorbitol, lactose, sucrose,
maltodextrin, starches such as maize starch, rice starch, celluloses such
as microcrystalline cellulose, sodium carboxymethyl cellulose and the like.
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5. The pharmaceutical composition of claim 3, wherein suspension of diclofenac or salt thereof is made up of diclofenac or salt thereof along with one or more hydrophilic polymers comprising one or more of hydroxypropyl methylcellulose, hydroxypropyl cellulose, polyvinyl pyrrolidone, methacrylates, water and other pharmaceutically acceptable excipients.
6. The pharmaceutical composition of claim 3, wherein pharmaceutically acceptable seal coat polymers comprises of one or more of hydroxypropyl methylcellulose, hydroxypropyl cellulose, cellulose ethers and the like.
7. The pharmaceutical composition of claim 3, wherein pharmaceutically acceptable enteric coating polymers comprises one or more of methacrylic acid/methyl methacrylate copolymers, carboxymethyl cellulose, cellulose acetate phthalate, hydroxypropylmethyl cellulose phthalate and the like.
8. A pharmaceutical composition comprising coated beads of diclofenac or salt thereof and coating of misoprostol or salt thereof characterized in that
. the said : coating covers not more than 90% of the coated beads of diclofenac and wherein the formulation exhibits a dissolution profile such that within first 2 hours less than 2% of diclofenac or salt thereof is released wherein the release rate is measured in Apparatus 2 (USP, Dissolution, paddle, 50 rpm) using 1000 ml of 0.1 N Hcl at 37 °C ± 0.5°C and within first 30 minutes more than 80% of diclofenac or salt thereof is released, wherein the release rate is measured in Apparatus 2 (USP, Dissolution, paddle, 50 rpm) using 1000 ml of pH 6.8 phosphate buffer at 37 °C ± 0.5°C.
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9. The pharmaceutical composition as per any preceding claims, wherein the pharmaceutically acceptable excipients comprises one or more of binders, fillers, lubricants, disintegrants, and glidants.
10. The pharmaceutical composition of the claim 1, wherein the pharmaceutical composition is a bilayered tablet, trilayered tablet, tablet in capsule or any other suitable dosage form for oral administration.
Dated this 30TH day of March, 2007 For Wockhardt Limited
(Mandar Kodgule) Authorized Signatory
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