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:
ENTERIC COATED DULOXETINE 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 capsule dosage form comprising duloxetine or salt thereof along with other pharmaceutically acceptable excipients wherein capsule is coated with pharmaceutically acceptable enteric coat.
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 capsule dosage form comprising duloxetine or salt thereof along with other pharmaceutically acceptable excipients wherein capsule is coated with pharmaceutically acceptable enteric coat.
Duloxetine is a selective serotonin and norepinephrine reuptake inhibitor (SSNRI) for oral administration. The empirical formula of duloxetine is C18H19NOS, which corresponds to a molecular weight of 297.42. Duloxetine is a white to slightly brownish white solid, which is soluble in water. Its structural formula is:

Duloxetine is (+)-N-methyl-3-(1-naphthalenyloxy)-2-thiophenepropanamine, and is commonly used as its hydrochloride salt. Eli Lilly markets duloxetine, under the trade name of Cymbalta®, as a delayed release capsule comprising enteric-coated pellets of the drug. It is indicated for the treatment of major depressive disorder and for the treatment of diabetic peripheral neuropathic pain. These enteric-coated pellets are designed to prevent degradation of the drug in the acidic environment of the stomach.
Duloxetine is acid labile, and acid hydrolysis of its ether linkage results in a thienyl alcohol and 1-naphthol. 50% of a dosage is hydrolyzed to 1-naphthol within one hour at pH of 1.0, which is achieved under fasting conditions. At a pH of 2.0, 10% of the dosage degrades to 1-Naphthol in one hour and at a pH of 4.0, 10% degradation would take up to 63 hours. Typically such acid sensitive
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compounds are formulated as enteric-coated pellets to protect them from degradation.
The enteric dosage forms have been employed to protect the duloxetine from degradation because it is very important that duloxetine should not be exposed to gastric acid prior to absorption. Although it is stable at alkaline pH, it gets destroyed rapidly as pH falls. Therefore, if the micro encapsulation or the enteric coating is disrupted (e.g., by trituration of the compound or chewing the capsule), duloxetine would be exposed to degradation by the gastric acid in the stomach. Duloxetine was also found to react with many enteric coatings to form a slowly-or even insoluble coating.
US Patent No. 5,023,269 disclose process of making duloxetine or its derivatives and the pharmaceutically acceptable acid additions salts thereof and its pharmaceutical compositions.
US Patent No. 5,508,276 discloses' duloxetine, in the form of enteric pellets of which the enteric layer comprises hydroxypropylmethylcellulose acetate succinate.
US Application No. 20060165776 discloses compositions containing a core consisting of a duloxetine or its derivatives, the said core comprised of pharmaceutically inert nuclei and the duloxetine or its derivatives compressed together, an intermediate and an enteric layer, wherein the composition is free of alkaline reacting compounds.
US Application No. 20070004795 disclose compositions of duloxetine with buffering agents.
US Application No. 20060079569 disclose oral liquid compositions of duloxetine or its derivatives thereof.
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The present inventors while working on the duloxetine formulation have surprisingly found that a compatible and stable formulation of duloxetine or salt thereof can be made by encapsulating duloxetine or salt thereof in a capsule which is then coated with enteric coat polymer. Enteric coating of the present invention is insoluble in acid environment, such as stomach, and releases duloxetine in basic environment, such as small intestine. This prevents duloxetine from degradation and provides stable formulation.
One of the aspects of the present invention provides a capsule dosage form comprising duloxetine or salt thereof along with other pharmaceutically acceptable excipients, wherein capsule is coated with pharmaceutically acceptable enteric coat.
In another aspect of the present invention there is provided a capsule dosage form comprising granules of duloxetine or salt thereof along with other pharmaceutically acceptable excipients, wherein capsule is coated with pharmaceutically acceptable enteric coat.
In another aspect of the present invention there is provided a capsule dosage form comprising pellets or beads of duloxetine or salt thereof along with other pharmaceutically acceptable excipients, wherein capsule is coated with pharmaceutically acceptable enteric coat.
In yet another aspect of the present invention there is provided a capsule dosage form comprising minitablets of duloxetine or salt thereof along with other pharmaceutically acceptable excipients, wherein capsule is coated with pharmaceutically acceptable enteric coat.
The pharmaceutical composition of the present invention comprises of duloxetine or salt thereof wherein duloxetine or salts thereof is present in the form of duloxetine hydrochloride.
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Granules of duloxetine or salt thereof can be prepared by dry granulation method or wet granulation method or any other granulation techniques well known in the art.
Pellets or beads of duloxetine or salt thereof can be made by spraying drug on inactive cores or by extrusion-spheronization/marumerization or a similar technique. Pellets or beads of duloxetine or salt thereof may also be prepared by adsorbing duloxetine or salt thereof on pharmaceutically acceptable adsorbent, processing the adsorbate into beads or pellets of duloxetine or salt thereof.
Minitablets can be prepared by mixing duloxetine or salt thereof with other pharmaceutically acceptable excipients to form a premix, converting the premix into granules by dry granulation or wet granulation and compressing the granules into minitablets or alternatively by layering duloxetine on inert core minitablets.
Spraying or adsorption can be carried out by fluidized bed processor, glatt, spray dryer or by any other suitable coating techniques known in the art.
Inactive cores 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, vegetable gums, waxes, and the like.
The term adsorbate as used herein refers to a physical mixture and/or a complex in which duloxetine is adhered to or adsorbed on a surface of a pharmaceutically acceptable absorbent.
Adsorbate of duloxetine or salt thereof can be processed in to beads of duloxetine or salt thereof by extrusion- spheronization or marumerization or any other suitable technique known in the art.
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Pharmaceutically acceptable adsorbents may be one or more of colloidal silicon dioxide, calcium silicate, magnesium aluminum silicate, porous ceramics, polypropylene foams, cellulose, cellulose derivatives, polyols, starches, pre-gelatinized starches, starch derivatives, modified starches, dextrins, maltodextrins, polydextroses, dextroses, calcium carbonate, calcium phosphate, calcium sulfate.
Inert core minitablets can be prepared by mixing inert pharmaceutically acceptable excipients to form a premix or optionally converting premix into granules by dry granulation or wet granulation and compressing premix or granules into minitablets.
The pharmaceutically acceptable enteric coating polymers for coating the capsule are polymers which are insoluble in acidic environment and do not release duloxetine or salt there of for at least 2 hours. Enteric polymers of the present invention are selected from the 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.
The pharmaceutical composition of the present invention can be prepared by mixing duloxetine or salt thereof with pharmaceutically acceptable excipients and granulating the premix with binder solution, drying the granules and mixing with other pharmaceutically acceptable excipients. Dried granules are either lubricated and compressed in to minitablets or sized into beads or pellets by extrusion-spheronization.
Granules of duloxetine or minitablets of duloxetine or beads/pellets of duloxetine are filled into hard gelatin capsule, which is then coated with enteric polymer.
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The pharmaceutical composition comprises of pharmaceutically acceptable excipients wherein excipients are selected from a group comprising one or more of povidone, starch, polyethylene glycol, stearic acid, gums, hydroxypropylmethyl cellulose, polyethylene glycol, microcrystalline cellulose, lactose, mannitol, calcium phosphate, calcium sulfate, kaolin, powdered sugar, magnesium stearate, zinc stearate, calcium stearate, stearic acid, sodium stearyl fumarate, hydrogenated vegetable oil, colloidal silicon dioxide, talc, 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 Duloxetine hydrochloride delayed release capsules

No Ingredients % Composition
1 Duloxetine hydrochloride 10-80
2 Lactose 10-90
3 Starch 10-90
4 Povidone 1-15
5 Isopropyl alcohol q.s.
6 Purified water q.s.
7 Talc 0.5-10
8 Magnesium stearate 0.5-5
9 Colloidal silicon dioxide 0.5-5
Encapsulation
Hard gelatin capsules
Enteric coating of hard gelatin capsules
10 Methacrylic acid copolymer suspension (Methacrylic acid copolymer, sodium hydroxide, Talc, triethyl citrate, purified water) 5-25
Procedure: Duloxetine hydrochloride is mixed with lactose, starch and granulated with povidone solution in isopropyl alcohol water mixture. Granules are dried, mixed with colloidal silicon dioxide. Granules are either lubricated with magnesium stearate and lubricated granules are compressed into minitablets of suitable size using suitable tooling or sized into beads or pellets by extrusion-spheronization.
Granules as such or minitablets or pellets/beads of duloxetine or salt thereof are filled into hard gelatin capsules which is further coated with enteric polymer suspension prepared by mixing methacrylic acid polymer, sodium hydroxide, talc, triethyl citrate in water.
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WE CLAIM:
1. A capsule dosage form comprising duloxetine or salt thereof along with other pharmaceutically acceptable excipients, wherein capsule is coated with pharmaceutically acceptable enteric coat.
2. A capsule dosage form comprising granules of duloxetine or salt thereof along with other pharmaceutically acceptable excipients, wherein capsule is coated with pharmaceutically acceptable enteric coat.
3. A capsule dosage form comprising pellets or beads of duloxetine or salt thereof along with other pharmaceutically acceptable excipients, wherein capsule is coated with pharmaceutically acceptable enteric coat.
4. A capsule dosage form comprising minitablets of duloxetine or salt thereof along with other pharmaceutically acceptable excipients, wherein capsule is coated with pharmaceutically acceptable enteric coat.
5. The capsule dosage form as per any preceding claims, wherein duloxetine or salts thereof is present in the form of duloxetine hydrochloride.
6. The capsule dosage form as per any preceding claims, 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.
7. The capsule dosage form of claim 1,2,3 and 4 wherein pharmaceutically acceptable excipients comprises one or more of povidone, starch, polyethylene glycol, stearic acid, gums, hydroxypropylmethyl cellulose, polyethylene glycol, microcrystalline cellulose, lactose, mannitol, calcium phosphate, calcium sulfate, kaolin, powdered sugar, magnesium stearate, zinc stearate, calcium stearate, stearic acid, sodium stearyl fumarate,
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hydrogenated vegetable oil, colloidal silicon dioxide, talc, croscarmellose sodium, crospovidone, sodium starch glycolate and the like.
For Wockhardt Limited

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