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:
BILAYERED 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 bilayered tablet dosage form comprising a) first layer, which further comprises of tablet of diclofenac or salts thereof optionally coated with enteric polymer, inlayed in said layer along with inert pharmaceutically acceptable excipients b) the second layer comprises of misoprostol or salts thereof optionally along with inert 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 bilayered tablet dosage form comprising a) first layer, which further comprises of tablet of diclofenac or salts thereof optionally coated with enteric polymer, inlayed in said layer along with inert pharmaceutically acceptable excipients b) the second layer comprises of misoprostol or salts thereof optionally along with inert 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 C14H10CI2NO2Na [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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HO
(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.
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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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.
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.
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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.
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 a NSAID is located in coated pellets and misoprostol, in a form of a solid dispersion in HPMC or PVP.
The present inventors while working on the diclofenac, misoprostol combination formulation have surprisingly found that when diclofenac tablet is inlayed in the first layer along with inert pharmaceutically acceptable excipients, it is not in
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direct contact with misoprostol which is present in second layer. Hence, misoprostol is prevented from degradation resulting in stable formulation.
One of the aspects of the present invention provides a bilayered tablet dosage form comprising a) first layer, which further comprises of tablet of diclofenac or salts thereof optionally coated with enteric polymer, inlayed in said layer along with inert pharmaceutically acceptable excipients b) the second layer comprises of misoprostol or salts thereof optionally along with inert pharmaceutically acceptable excipients.
The term "tablet of diclofenac or salts thereof optionally coated with enteric polymer, inlayed in said layer" as used herein refers to tablet of diclofenac or salts thereof optionally coated with enteric polymer being present at any position in the first layer.
The bilayered tablet dosage form of the present invention comprises of diclofenac or salt thereof wherein diclofenac or salts thereof is present in the form of diclofenac sodium.
Tablet of diclofenac or salt thereof can be prepared by mixing diclofenac or salt thereof optionally with other inert pharmaceutically acceptable excipients to form a premix, optionally converting the premix into granules by dry granulation or wet granulation and compressing the premix or granules into tablets. Further this tablet may optionally be coated with seal coat polymer followed by enteric coating with pharmaceutically acceptable enteric coating polymers.
The pharmaceutically acceptable seal coat polymers may be one or more of hydroxypropyl methylcellulose, hydroxypropyl cellulose and other suitable cellulose ethers.
The pharmaceutically acceptable enteric coating polymers may be one or more of methacrylic acid/methyl methacrylate copolymers such as Eudragits or
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cellulose derivatives such as carboxymethyl cellulose, cellulose acetate phthalate, hydroxypropylmethyl cellulose phthalate, hydroxypropyl methyl cellulose acetate succinate, polyvinyl acetate phtalate, cellulose acetate trimellitate, and other suitable polymers.
First layer of the bilayered tablet comprises of diclofenac tablet inlayed at any position in the said first layer along with inert pharmaceutically acceptable excipients and second layer comprises of misoprostol polymer dispersion in mixture with other inert pharmaceutically acceptable excipients.
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 tablets of diclofenac or salt thereof coated with enteric polymer with inert pharmaceutically acceptable excipients and the misoprostol blend in such a way that tablet of diclofenac or salt thereof is inlayed at any position in first layer along with inert pharmaceutically acceptable excipients and misoprostol blend being compressed as second layer resulting in bilayered tablet dosage form as shown in figure 2.
In yet another aspect of the present invention there is provided a bilayered 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 HCI at 37 °C ± 0.5°C and within first 30 minutes more than 75% 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 pH 6.8 phosphate buffer at 37 °C ± 0.5°C.
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The pharmaceutical composition comprises of inert 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.
Figure 1 shows the diclofenac misoprostol tablet dosage form of G.D. Searle (Arthrotec®) and Figure 2 shows some of the examples of diclofenac misoprostol bilayered tablet dosage form of the present invention.
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 bilayered tablet

No Ingredients % Composition
Misoprostol blend layer
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 tablets in inert excipients layer
7 Diclofenac sodium 5 to 70
8 Microcrystalline cellulose 10 to 90
9 Lactose 10 to 90
10 Sodium starch glycollate 1 to 10
11 Povidone 1 to 10
12 Magnesium stearate 0.1 to 5
Seal coating
13 Hypromellose + PEG 400 1 to 5
14 Purified water q.s.
Enteric coating
15 Methacrylic acid copolymer suspension (Methacrylic acid copolymer, sodium hydroxide, Talc, triethyl citrate, purified water) 8 to 25
Inert excipients
16 Crospovidone 1 to 10
10 Microcrystalline cellulose 10 to 80
11 Colloidal silicon dioxide 0.1 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 mixture is lubricated with pre-sifted hydrogenated castor oil in double cone blender to form misoprostol blend.
Diclofenac sodium is mixed with microcrystalline cellulose, lactose, povidone, and sodium starch glycollate in double cone blender to form a pre-mix. Pre-mix is further mixed with povidone and converted into flakes by compacting it through roll compactor. Flakes are sized into granules, which are then lubricated with magnesium stearate in double cone blender, and lubricated granules are compressed into tablets using suitable tooling. Compressed tablets are further seal coated with hypromellose polyethylene glycol solution in water. Seal coated diclofenac sodium tablets are coated with enteric polymer suspension prepared by mixing methacrylic acid polymer, sodium hydroxide, talc, triethyl citrate in water.
Inert excipients like crospovidone, colloidal silicon dioxide, sodium starch glycollate, microcrystalline cellulose and hydrogenated castor oil are mixed together in double cone blender.
Enteric coated diclofenac sodium tablets are compressed along with inert excipients and misoprostol blend in such a way that diclofenac sodium tablet is inlayed at any position in the first layer along with inert excipients and misoprostol blend being compressed as second layer to form bilayered tablet dosage form. Finally the bilayered tablet is further coated with aqueous dispersion of Opadry.
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WE CLAIM:
1. A bilayered tablet dosage form comprising a) first layer, which further
comprises of tablet of diclofenac or salts thereof optionally coated with
enteric polymer, inlayed in said layer along with inert pharmaceutically
acceptable excipients b) the second layer comprises of misoprostol or
salts thereof optionally along with inert pharmaceutically acceptable
excipients.
2. The bilayered tablet dosage form of claim 1, wherein diclofenac or salts thereof is present in the form of diclofenac sodium.
3. The bilayered tablet dosage form of claim 1, wherein enteric polymers comprises 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, hydroxypropylmethyl cellulose acetate succinate, polyvinyl acetate phtalate, cellulose acetate trimellitate, and other suitable polymers.
4. The bilayered tablet dosage form of claim 1, wherein tablet of diclofenac or salt thereof is prepared by mixing diclofenac or salt thereof optionally with other inert pharmaceutically acceptable excipients to form a premix, optionally converting the premix into granules by dry granulation or wet granulation and compressing the premix or granules into tablets.
5. The bilayered tablet dosage form of claim 3, wherein tablet of diclofenac or salts thereof is optionally coated with pharmaceutically acceptable seal coat polymers.
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6. The bilayered tablet dosage form of claim 4, wherein pharmaceutically acceptable seal coat polymers comprises of one or more of hydroxypropyl methylcellulose, hydroxypropyl cellulose, cellulose ethers and the like.
7. A bilayered 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 75% 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 pH 6.8 phosphate buffer at 37 °C ± 0.5°C.
8. The bilayered tablet dosage form of claim 1, wherein inert pharmaceutically acceptable excipients comprises one or more of binders, fillers, lubricants, disintegrants, and glidans.

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Abstract:
The present invention provides a bilayered tablet dosage form comprising a) first layer, which further comprises of tablet of diclofenac or salts thereof optionally coated with enteric polymer, inlayed in said layer along with inert pharmaceutically acceptable excipients b) the second layer comprises of misoprostol or salts thereof optionally along with inert pharmaceutically acceptable excipients. The invention also relates to processes for the preparation of such dosage form.
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