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:
A PILLOW TABLET DOSAGE FORM OF DICLOFENAC AND MISOPROSTOL
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 a pillow tablet dosage form comprising a) an inner pillowed tablet comprising of misoprostol or pharmaceutically acceptable salts thereof along with other pharmaceutically acceptable excipients b) an outer tablet comprising of coated beads of diclofenac or pharmaceutically acceptable salts thereof along with other pharmaceutically acceptable excipients.
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 pillow tablet dosage form comprising a) an inner pillowed tablet comprising of misoprostol or pharmaceutically acceptable salts thereof along with other pharmaceutically acceptable excipients b) an outer tablet comprising of coated beads of diclofenac or pharmaceutically acceptable salts thereof along with other pharmaceutically acceptable excipients.
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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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 when misoprostol is present as a inner pillowed tablet within the outer diclofenac tablet where diclofenac is present in form of coated beads, misoprostol is not exposed to both diclofenac and outer environmental conditions, hence it is prevented from degradation resulting in stable formulation.
The term "inner pillowed tablet" as used herein refers to inner tablet of misoprostol tilted on the one side of the diclofenac tablet surface, such that it looks like a pillow at the center.
One of the aspects of the present invention provides a pillow tablet dosage form of diclofenac-misoprostol comprising:
a) an inner pillowed tablet comprising of misoprostol or pharmaceutically acceptable salts thereof along with other pharmaceutically acceptable excipients
b) an outer tablet comprising of coated beads of diclofenac or pharmaceutically acceptable salts thereof along with other pharmaceutically acceptable excipients.
The pillow tablet dosage form comprising 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 coat polymer.
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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.
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
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copolymers such as Eudragits or cellulose derivatives such as carboxymethyl cellulose, cellulose acetate phthalate, hydroxypropylmethyl cellulose phthalate and other suitable polymers.
Misoprostol tablets of the present invention can be prepared by mixing misoprostol-polymer dispersion with other pharmaceutically acceptable excipients and compressing the blend in to tablets.
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 compressing blend of enteric-coated beads of diclofenac or salt thereof with misoprostol tablet along with other pharmaceutically acceptable excipients into pillow tablet dosage form in such a way that misoprostol tablet is tilted on the one side of diclofenac tablet surface, such that it looks like a pillow at the center.
In yet another aspect of the present invention there is provided a pillow tablet dosage form of diclofenac-misoprostol, 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 900 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.
The pharmaceutical composition comprises of pharmaceutically acceptable excipients wherein excipients may include binders, fillers, lubricants, disintegrants, and glidants.
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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 tablet
Misoprostol: hypromellose (1:100)
1 Misoprostol 0.01 to 2.0
2 Hypromellose 10 to 99
3 Crospovidone 1 to 10
4 Colloidal silicon dioxide 0.1 to 10
5 Microcrystalline cellulose 10 to 90
6 Hydrogenated castor oil 0.1 to 2.0
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 q.s.
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
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Procedure: Misoprostol-hypromellose dispersion is mixed with microcrystalline cellulose, crospovidone, and colloidal silicon dioxide in double cone blender. Above blend is lubricated with pre-sifted hydrogenated castor oil in double cone blender and compressed into tablets using suitable tooling.
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 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 compressed along with misoprostol tablet in such a way that misoprostol tablet is tilted on the one side of diclofenac tablet surface, such that it looks like a pillow at the center.
Finally the pillow tablet is further coated aqueous dispersion of Opadry.
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WE CLAIM:
1. A pillow tablet dosage form of diclofenac-misoprostol comprising:
b) an inner pillowed tablet comprising of misoprostol or pharmaceutically acceptable salts thereof along with other pharmaceutical^ acceptable excipients
c) an outer tablet comprising of coated beads of diclofenac or pharmaceutically acceptable salts thereof along with other pharmaceutically acceptable excipients.

2. The pillow tablet dosage form of claim 1, wherein diclofenac is present in the form of diclofenac sodium.
3. The pillow tablet dosage form 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) 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.
4. The pillow tablet dosage form of claim 3, wherein inert spherical beads
comprises one or more of polysaccharides, mannitol, sorbitol, lactose,
sucrose, maltodextrin, maize starch, rice starch, microcrystalline cellulose,
sodium carboxymethyl cellulose and the like.
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5. The pillow tablet dosage form 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 pillow tablet dosage form 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 pillow tablet dosage form 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. The pillow tablet dosage form of claim 1, wherein misoprostol or salt thereof tablets are prepared by mixing misoprostol-polymer dispersion with other pharmaceutically acceptable excipients and compressing the blend in to tablets.
9. The pillow tablet dosage form of claim 8, wherein polymer in misoprostol-polymer dispersion comprises one or more of hydroxypropylmethylcellulose, hydroxypropylcellulose, polyvinyl pyrrolidone and the like.
10. A pillow tablet dosage form of diclofenac-misoprostol, 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 900
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
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measured in Apparatus 2 (USP, Dissolution, paddle, 50 rpm) using 1000 ml of pH 6.8 phosphate buffer at 37 °C ± 0.5°C.

Dated this 30TH day of March, 2007 For Wockhardt Limited

(Mandar Kodgule) Authorized Signatory
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