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:
DICLOFENAC AND MISOPROSTOL COMPOSITIONS
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 pharmaceutical composition comprising of coated minitablets of diclofenac or salts thereof along with other pharmaceutical^ acceptable excipients and beads of misoprostol or 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 pharmaceutical composition comprising of coated minitablets of diclofenac or salts thereof along with other pharmaceutically acceptable excipients and beads of misoprostol or 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 C14H1oCl2N02Na [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. G,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
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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 12005163847 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 a1 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 El 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 diclofenac is present in form of coated minitablets and misoprostol in form of beads, misoprostol is not exposed to diclofenac due to presence of intermediate seal coat and enteric coat between diclofenac and misoprostol, hence it is prevented from degradation resulting in stable formulation.
One of the aspects of the present invention provides a pharmaceutical composition comdrising of coated minitablets of diclofenac or salts thereof along with other pharmaceutically acceptable excipients and beads of misoprostol or salts thereof along with other pharmaceutically acceptable excipients.
The pharmaceutical composition comprising diclofenac or salt thereof wherein diclofenac is present as diclofenac sodium.
Coated minitablets of diclofenac or salt thereof can be prepared by
a) mixing diclofenac or salt thereof with other pharmaceutically acceptable excipients,
b) compressing the blend of step a) into minitablets,
c) coating minitablets of diclofenac or salt thereof of step b) with pharmaceutically acceptable seal coat polymer,
d) enteric-coating the seal coated minitablets of diclofenac or salt thereof of step c^ with pharmaceutically acceptable enteric coat polymer,
e) coating the enteric coated minitablets of diclofenac or salt thereof of step d) optionally with polyethylene glycol.
The weight of the uncoated diclofenac minitablets can be from about 10mg to about 50mg.
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.
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. The pharmaceutical 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.
During compression, pressure exerted on beads results in cracking of the beads. Coating of polyethylene glycol on enteric-coated diclofenac minitablets provides cushioning effect to minitablets 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.
Beads of misoprostol or salt thereof can be prepared by coating inert spherical beads with alcoholic solution of misoprostol-polymer dispersion.
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.
In misoprostol-polymer dispersion, polymer may be one or more of hydroxypropylmethylcellulose, hydroxypropylcellulose, polyvinylpyrrolidone and the like.
Alcohol used in preparation of alcoholic solution of misoprostol-polymer dispersion may be one or more of methanol, ethanol, propanol, isopropyl alcohol and the like.
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The pharmaceutical composition of the present invention can be prepared by mixing coated minitablets of diclofenac or salt thereof with beads of misoprostol or salt thereof j along with other pharmaceutically acceptable excipients and converting the final blend into suitable dosage form.
Suitable dosage form of the present invention can be in the form of tablet, caplet, capsule, disc or any other dosage form for oral administration.
In yet another aspect of the present invention there is provided a pharmaceutical composition comprising of coated minitablets of diclofenac or salts thereof and beads of misoprostol or salts thereof along with other pharmaceutically acceptable excipients, 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 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.
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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.
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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.
i 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 beads
1 Microcrystalline cellulose 15-95
Misoprostol: hypromellose (1:100)
2 Misoprostol 0.01-2.0
3 Hypromellose 10-99
4 Isopropyl alcohol q.s.
i Diclofenac sodium minitablets
Drug layering
5 Diclofenac sodium 5-80
6 Lactose s 10-90
7 Sodium starch glycolate 1-10
8 Magnesium stearate 0.1-3
Seal coating
9 Hypromellose + PEG 400 1-5
10 Purified water q.s.
Enteric coating
11 Methacrylic acid copolymer suspension(Methacrylic acid copolymer, sodium hydroxide! Talc, triethyl citrate, purified water) 8-25
12 PEG coating (PEG 6000, isopropyl alcohol) 1-10
Final Blend
Coated Diclofenac sodium minitabs
Misoprostol beads
13 Microcrystalline cellulose 10-90
14 Sodium starch glycolate 1-10
15 Colloidal silicon dioxide 1-5
15 Hydrogenated castor oil 0.1 to 3.0
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Procedure: Diclofenac sodium is mixed with lactose, sodium starch glycolate and lubricated with i magnesium stearate. Lubricated blend is compressed into minitablets with weight between 10mg to 50mg. Diclofenac sodium minitablets
are seal coated with hypromellose and polyethylene glycol 400 solution. Seal
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coated minitablets are enteric coated with coated with enteric polymer suspension prepared by mixing methacrylic acid polymer, sodium hydroxide, talc, triethyl citrate in water. Enteric-coated diclofenac sodium minitablets are further coated with polyethylene glycol 6000 solution prepared in isopropyl alcohol. Misoprostol-hypromellose dispersion is dissolved in isopropyl alcohol and coated on microcrystalline cellulose beads in fluidized bed processor. Coated diclofenac sodium minitablets are mixed with misoprostol beads along with microcrystalline cellulose, sodium starch glycollate, colloidal silicon dioxide and lubricated with hydrogenated castor oil. The final blend is compressed into tablets using suitable tooling. Compressed tablets are further coated with aqueous dispersion of Opadry.
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WE CLAIM:
1. A pharmaceutical composition comprising of coated minitablets of
diclofenac or salts thereof along with other pharmaceutically acceptable
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excipients and beads of misoprostol or salts thereof along with other pharmaceutically acceptable excipients.
2. The pharmaceutical composition of claim 1, wherein diclofenac or salts thereof is present in the form of diclofenac sodium.
3. The pharmaceutical composition of claim 1, wherein coated minitablets of diclofenac or salt thereof are prepared by:

a) mixing diclofenac or salt thereof with other pharmaceutically acceptable excipients,
b) compressing the blend of step a) into minitablets,
c) coating minitablets of diclofenac or salt thereof of step b) with pharmaceutically acceptable seal coat polymer,
d) enteric-coating the seal coated minitablets of diclofenac or salt thereof of step c) with pharmaceutically acceptable enteric coat polymer.
e) coating the enteric-coated minitablets of diclofenac or salt thereof of
step d) optionally with polyethylene glycol.
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4. The pharmaceutical composition of claim 3, wherein pharmaceutically
acceptable seal coat polymers comprises of one or more of hydroxypropyl
methy cellulose, hydroxypropyl cellulose and other suitable cellulose
ethers and the like.
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5. 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.
6. The pharmaceutical composition of claim 1, wherein beads of misoprostol or salt thereof are prepared by coating inert spherical beads with alcoholic solution of misoprostol-polymer dispersion.
7. The pharmaceutical composition of claim 6, 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.
8. The pharmaceutical composition of claim 6, wherein polymer in misoprostol-polymer dispersion comprises one or more of hydroxypropylmethylcellulose, hydroxypropylcellulose, polyvinyl pyrrolidone and the like.
9. A pharmaceutical composition comprising of coated minitablets of
diclofenac or salts thereof and beads of misoprostol or salts thereof along with other pharmaceutically acceptable excipients, 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 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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10. The pharmaceutical composition as per any preceding claims, wherein the pharmaceutically acceptable excipients comprises one or more of binders, fillers, lubricants, disintegrants, and glidants.
Dated this 30th day of March, 2007
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