FORM 2
THE PATENT ACT 1970
(39 of 1970)
&
The Patents Rules, 2.003
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 pharmaceutical composition comprising coated minitablets of duloxetine or salt thereof along with pharmaceutically acceptable excipients, wherein duloxetine or salt thereof is not in the form of beads or pellets.
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 minitablets of duloxetine or salt thereof along with pharmaceutically acceptable excipients, wherein duloxetine or salt thereof is not in the form of beads or pellets.
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 were 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 duloxetine or salt thereof is simply mixed with other pharmaceutically excipients and processed into minitablets (without making beads or pellets of duloxetine or salt thereof), which are further coated with enteric polymer, 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.
One of the aspects of the present invention provides a pharmaceutical composition comprising coated minitablets of duloxetine or salt thereof along with pharmaceutically acceptable excipients, wherein duloxetine or salt thereof is not in the form of beads or pellets.
The pharmaceutical composition of the present invention comprises of duloxetine or salt thereof wherein duloxetine is present in the form of duloxetine hydrochloride.
The term "coated minitablets of duloxetine or salt thereof as used herein comprises of minitablets of duloxetine or salt thereof optionally coated with pharmaceutically acceptable seal coat polymer followed by enteric coating with pharmaceutically acceptable enteric polymer.
Coated minitablets of duloxetine or salt thereof can be prepared by mixing duloxetine or salt thereof with other 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 minitablets. Minitablets thus obtained are further optionally coated with pharmaceutically acceptable seal coat polymer followed by pharmaceutically acceptable enteric polymer.
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Alternatively coated minitablets of duloxetine or salt thereof can also be made by spraying or adsorbing the slurry or solution of duloxetine or salt thereof on the inert core minitablets which are further optionally coated with pharmaceutically acceptable seal coat polymer followed by pharmaceutically acceptable enteric polymer.
Inert core minitablets can be prepared by mixing inert pharmaceutically acceptable excipients, optionally converting the premix into granules by dry granulation or wet granulation and compressing the premix or granules into minitablets.
Slurry or solution of duloxetine or salt thereof comprises 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. Such slurry may be milled through a machine adapted for grinding suspensions in order to reduce the particle size of duloxetine.
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, hydroxypropyl methyl cellulose phthalate and other suitable polymers.
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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, lubricating the granules and compressing the lubricated granules into minitablets. Minitablets are further coated with seal coat polymer along with polyethylene glycol followed by enteric coating the seal coated minitablets with enteric coat polymer. Minitablets thus obtained can be present in the form of minitablet, minitablet in tablet, inlay tablet, pillow tablet, granules in capsule, minitablets in capsule or any other dosage form suitable for oral administration.
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
Core minitablets of Duloxetine hydrochloride
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
Seal coating
10 Seal coat composition: (Sucrose, Hypromellose, Polyethylene glycol 6000, Talc, Purified water) 1-30
Enteric coating
11 Methacrylic acid copolymer suspension (Methacrylic acid copolymer, sodium hydroxide, Talc, triethyl citrate, purified water) 5-25
Encapsulation
Hard gelatin capsules
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 and lubricated with magnesium stearate. Lubricated granules are compressed into minitablets of suitable size using suitable tooling. Minitablets of duloxetine or salt thereof are seal coated by spraying hypromellose, sucrose, talc and polyethylene glycol 6000 dispersion in water. Seal coated minitablets are further coated with enteric polymer suspension prepared by mixing methacrylic acid polymer, sodium hydroxide, talc,
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triethyl citrate in water. Enteric-coated minitablets of duloxetine hydrochloride are encapsulated in hard gelatin capsules of suitable size.

WE CLAIM:
1. A pharmaceutical composition comprising comprising coated minitablets of duloxetine or salt thereof along with pharmaceutically acceptable excipients, wherein duloxetine or salt thereof is not in the form of beads or pellets.
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 coated minitablets of duloxetine or salt thereof are prepared by mixing duloxetine or salt thereof with other pharmaceutically acceptable excipients to form a premix, converting the premix into granules and compressing the granules into minitablets which are further optionally coated with pharmaceutically acceptable seal coat polymer followed by pharmaceutically acceptable enteric polymer.
4. The pharmaceutical composition of claim 3, wherein pharmaceutically acceptable seal coat polymers comprises of one or more of hydroxypropyl methylcellulose, hydroxypropyl cellulose and other suitable cellulose ethers and the like.
5. The pharmaceutical composition of claim 3, pharmaceutically acceptable enteric coating polymers comprises one or more of methacrylic acid/methyl methacrylate copolymers, carboxymethyl cellulose, cellulose acetate phthalate, hydroxypropyl methyl cellulose phthalate and the like.
6. The pharmaceutical composition of claim 1 comprises one or more of minitablet, minitablet in tablet, inlay tablet, pillow tablet, granules in capsule, minitablets in capsule.
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7. The pharmaceutical composition of claim 1, 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, hydrogenated vegetable oil, colloidal silicon dioxide, talc, croscarmellose sodium, crospovidone, sodium starch glycolate and the like.
Dated this &0™ day of April, 2007 For Wockhardt Limited
UiUUk
(Mandar Kpdgule) Authorized Signatory
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