FORM 2
THE PATENT ACT 11970
(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-Kuirla Complex, Bandra
(East), Mumbai-400 051.
3. PREAMBLE TO THE DESCRIPTION
The present invention provides a pharmaceutical composition comprising coated beads of duloxetine or salt thereof along with stabilizer and one or more 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 coated beads of duloxetine or salt thereof along with stabilizer and one or more pharmaceutically acceptable excipients.
Duloxetine is a selective serotonin and norepinephrine reuptake inhibitor (SSNRI) for oral administration. The empirical formula of duloxetine is C-isH-igNOS, 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 even when beads of duloxetine are coated with enteric polymer other than hydroxypropylmethylcellulose acetate succinate, duloxetine does not react with enteric 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.
The present inventors have further noticed that addition of stabilizer provides a stable pharmaceutical composition of duloxetine or salt thereof. The stabilizer in the pharmaceutical composition comprising duloxetine or salts thereof is capable of preventing degradation of duloxetine by imparting an alkaline pH around the duloxetine particle when the said composition is dissolved or dispersed in an aqueous solution. The stabilizer neutralizes the acidic groups in the composition and surrounding media thereby maintaining an alkaline pH around duloxetine particle. This prevents degradation of duloxetine or salt thereof in acidic environment and provides stable formulation.
The term "stabilizer" as used herein refers to one or more pharmaceutically acceptable substances capable of preventing degradation of duloxetine by imparting an alkaline pH. The stabilizer creates an alkaline pH around the particles of duloxetine or salt thereof when water is adsorbed thereon or when water is added. The stabilizer may be present from 0 to 90% by weight of the total composition. The pH may be determined by taking a unit dosage of the composition containing e.g. 20 mg of duloxetine and dispersing or dissolving the composition in 10 to 100 ml of water.
One of the aspects of the present invention provides a pharmaceutical composition comprising coated beads of duloxetine or salt thereof along with stabilizer and one or more pharmaceutically acceptable excipients.
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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.
The stabilizer may be selected from the group comprising one or more of salts of organic acid or base and salts of an inorganic acid or base and inorganic or organic bases. Suitable salts of inorganic acids include alkali metal salts of carbonates, phosphates, oxides like calcium carbonate, magnesium carbonate, potassium carbonate, sodium bicarbonate, potassium hydrogen carbonate, anhydrous sodium, potassium or calcium dibasic phosphate, or trisodium phosphate, magnesium oxide. The organic base may be one or more of amino acids like glycine, alanine, asparginine, cysteine, glutamine, leucine, isoleucine, proline, phenylalanine and the like. The salts of organic acid include sodium citrate, sodium acetate, sodium tartrate and the like. Glucosamine, meglumine, tromethamine, ammonia and the like are also covered within the meaning of stabilizer.
The term "coated beads of duloxetine or salt thereof as used herein comprises of beads of duloxetine or salt thereof optionally coated with pharmaceutical^ acceptable seal coat polymer followed by enteric coating with pharmaceutically acceptable enteric polymer.
Coated beads of duloxetine or salt thereof may be prepared by spraying inactive cores with slurry or solution of duloxetine or salt thereof optionally along with other pharmaceutically acceptable excipients and optionally coating the beads of duloxetine or salt thereof thus obtained with pharmaceutically acceptable seal coat polymer followed by enteric coating with pharmaceutically acceptable enteric polymer.
Alternatively, coated beads of duloxetine or salt thereof may also be prepared by process of extrusion-spheronization or marumerization and optionally coating the
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beads of duloxetine or salt thereof thus obtained with pharmaceutically acceptable seal coat polymer followed by enteric coating with pharmaceutically acceptable enteric polymer.
Further, coated 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 of duloxetine or salt thereof and optionally coating the beads of duloxetine or salt thereof thus obtained with pharmaceutically acceptable seal coat polymer followed by enteric coating with pharmaceutically acceptable enteric polymer.
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.
Slurry or solution of duloxetine or salt thereof comprises of duloxetine or salt thereof suspended or dissolved in water along with one or more polymers such as hydroxypropyl methylcellulose, hydroxypropyl cellulose, polyvinyl pyrrolidone, methacrylates and the like, and optionally with other pharmaceutically acceptable excipients. Slurry of duloxetine or salt thereof may be milled through a machine adapted for grinding suspensions in order to reduce the particle size of duloxetine.
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.
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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.
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.
The pharmaceutically acceptable seal coat polymers may 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 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 layering duloxetine or salt thereof on inactive core along with stabilizer and other pharmaceutically acceptable excipients, and coating the beads of duloxetine or salt thereof thus obtained with seal coat polymer followed by enteric coating with enteric polymer. Coated beads of duloxetine or salt thereof thus obtained can be present in the form of tablet, capsule, beads, caplet, disc, pills, spheroids, minitablets, granules in capsule, beads in capsule, minitablets in capsule or any other dosage form suitable for oral administration.
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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, 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
Enteric coated beads of Duloxetine hydrochloride
Inactive core
1 Sugar spheres 10-90
Drug layering
2 Duloxetine hydrochloride 10-80
3 Magnesium oxide 0.1-10
4 Hypromellose 5-90
5 Polyethylene glycol 6000 0.5-10
6 Talc 0:5-10
7 Purified water q.s.
Seal coating
8 Seal coat composition: (Sucrose, Hypromellose, Polyethylene glycol 6000, Purified water) 1-30
Enteric coating
9 Methacrylic acid copolymer suspension (Methacrylic acid copolymer, sodium hydroxide, Talc, triethyl citrate, purified water) 5-25
Encapsulation
Hard gelatin capsules
Procedure: Hypromellose solution is prepared in water and duloxetine hydrochloride along with PEG 6000 is added to hypromellose solution. Talc and magnesium oxide are dispersed in above solution using a stirrer. Slurry thus obtained is sprayed on inactive sugar sphere cores in fluidized bed processor by Wurster technique. Duloxetine beads thus obtained are seal coated by spraying hypromellose, sucrose and polyethylene glycol 6000 solution in water. Seal coated beads are further coated with enteric polymer suspension prepared by mixing methacrylic acid polymer, sodium hydroxide, talc, triethyl citrate in water.
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Enteric-coated beads of duloxetine hydrochloride are encapsulated in hard gelatin capsules of suitable size.

WE CLAIM:
1. A pharmaceutical composition comprising coated beads of duloxetine or salt thereof along with stabilizer and one or more pharmaceutical^ acceptable excipients.
2. The pharmaceutical composition of claim 1, wherein duloxetine or salts thereof is present in the form of duloxetine hydrochloride.
3. The pharmaceutical composition of claim 1, wherein stabilizer comprises one or more of salts of organic acid or base and salts of an inorganic acid or base and inorganic or organic bases.
4. The pharmaceutical composition of claim 1, wherein coated beads of duloxetine or salt thereof are prepared by spraying inactive cores with slurry or solution of duloxetine or salt thereof optionally along with other pharmaceutically acceptable excipients and optionally coating the beads of duloxetine or salt thereof thus obtained with pharmaceutically acceptable seal coat polymer followed by enteric coating with pharmaceutically acceptable enteric polymer.
5. The pharmaceutical composition of claim 4, wherein inactive cores comprises one or more of polysaccharides, mannitol, sorbitol, lactose, sucrose, maltodextrin, maize starch, rice starch, microcrystalline cellulose, sodium carboxymethyl cellulose, vegetable gums, waxes and the like.
6. The pharmaceutical composition of claim 4, wherein slurry or solution of duloxetine or salt thereof comprises duloxetine or salt thereof suspended in water along with polymers comprising one or more of hydroxypropyl methylcellulose, hydroxypropyl cellulose, polyvinyl pyrrolidone,
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methacrylates, and optionally other pharmaceutically acceptable excipients.
7. The pharmaceutical composition of claim 4, wherein pharmaceutically acceptable seal coat polymers comprises of one or more of hydroxypropyl methylcellulose, hydroxypropyl cellulose and other suitable cellulose ethers and the like.
8. The pharmaceutical composition of claim 4, 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 the like
9. The pharmaceutical composition of claim 1 comprises one or more of tablet, capsule, caplet, disc, pills, spheroids, minitablets, granules in capsule, pellets in capsule, minitablets in capsule.
10. The pharmaceutical composition of claim 1, wherein pharmaceutically acceptable excipients comprises one or more of povidone, starch, stearic acid, gums, hydroxypropylmethyl cellulose, polyethylene glycol, microcrystalline cellulose, lactose, mannitol, kaolin, magnesium stearate, stearic acid, sodium stearyl fumarate, colloidal silicon dioxide, talc, croscarmellose sodium, crospovidone, and the like.
Dated this ^o.1 M day of April, 2007 For Wockhardt Limited
(Mandar Kodgule) Authorized Signatory
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