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 tablet in tablet dosage form comprising a) an inner tablet comprising of duloxetine or salts thereof along with other pharmaceutically acceptable excipients b) an outer tablet comprising of 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 tablet in tablet dosage form comprising a) an inner tablet comprising of duloxetine or salts thereof along with other pharmaceutically acceptable excipients b) an outer tablet comprising of inert pharmaceutically acceptable excipients.
Duloxetine is a selective serotonin and norepinephrine reuptake inhibitor (SSNRI) for oral administration. The empirical formula of duloxetine is CisH^NOS, 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 when duloxetine or salt thereof is present as an inner tablet, duloxetine or salt thereof is not exposed to enteric polymer which is coated on outer tablet of inert pharmaceutically acceptable excipients, hence there is no reaction of duloxetine with enteric polymer resulting in compatible and stable formulation. 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 tablet in tablet dosage form comprising a) an inner tablet comprising of duloxetine or salts thereof along with other pharmaceutically acceptable excipients b) an outer tablet comprising of inert pharmaceutically acceptable excipients.
The tablet in tablet dosage form of the present invention comprises of duloxetine or salt thereof wherein duloxetine or salt thereof is present in the form of duloxetine hydrochloride.
Inner tablet of duloxetine or salt thereof can be prepared by mixing duloxetine or salt thereof optionally 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 tablets. Further this tablet may optionally be coated with seal coat polymer.
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.
Inner tablet of duloxetine can be present in the form of inlayed or pillowed tablet.
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The term "inlayed tablet" as used herein refers to a type of layered tablet in which instead the inner core tablet being completely surrounded by coating (outer tablet), top surface is completely exposed.
The term "pillowed tablet" as used herein refers to inner tablet tilted on the one side of the outer tablet surface, such that it looks like a pillow at the center.
The tablet in tablet dosage form comprises of inert 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.
The tablet in tablet dosage form 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 tablets. Duloxetine tablets are seal coated with seal coat polymer and seal coated duloxetine tablets are compressed with other excipients in such a way as to form tablet in tablet dosage form wherein inner tablet is of duloxetine or salt thereof and outer tablet is of inert pharmaceutically acceptable excipients. Tablet in tablet dosage form is further coated with pharmaceutically acceptable enteric polymer.
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
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derivatives such as carboxymethyl cellulose, cellulose acetate phthalate, hydroxypropylmethyl cellulose phthalate and other suitable polymers.
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 tablet in tablet dosage form

No Ingredients % Composition
1 Duloxetine hydrochloride 10-80
2 Lactose 10-90
3 Starch 10-90
4 Povidone 1-15
5 Purified water q.s.
6 Talc 0.5-10
7 Magnesium stearate 0.5-5
8 Colloidal silicon dioxide 0.5-5
9 Isopropyl alcohol q.s.
10 Purified water q.s.
Seal coating
11 Seal coat composition: (Sucrose, Hypromellose, Polyethylene glycol 6000, Talc, Purified water) 1-30
Enteric coating
12 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, and lubricated with magnesium stearate. Lubricated granules are compressed into tablets of suitable size using suitable tooling. Duloxetine tablets are seal coated by spraying hypromellose, sucrose, talc and polyethylene glycol 6000 dispersion in water. Seal coated tablets of duloxetine hydrochloride are compressed with talc, magnesium stearate and colloidal silicon dioxide in such a way so that duloxetine tablets are completely covered by other excipients to form a tablet in tablet dosage form 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 tablet in tablet dosage form comprising a) an inner tablet comprising of duloxetine or salts thereof along with other pharmaceutically acceptable excipients b) an outer tablet comprising of inert pharmaceutically acceptable excipients.
2. The tablet in tablet dosage form of claim 1, wherein duloxetine or salts thereof is present in the form of duloxetine hydrochloride.
3. The tablet in tablet dosage form of claim 1, wherein inner tablet of duloxetine or salt thereof is present in the form of inlayed tablet or pillowed tablet.
4. The tablet in tablet dosage form of claim 1, wherein inner tablet of duloxetine or salt thereof is prepared by mixing duloxetine or salt thereof optionally with other pharmaceutically acceptable excipients to form a premix, converting the premix into granules and compressing the granules into tablet.
5. The tablet in tablet dosage form of claim 1, wherein inner tablet of duloxetine or salt thereof is optionally coated with pharmaceutically acceptable seal coat polymer optionally along with other pharmaceutically acceptable excipients.
6. The tablet in tablet dosage form of claim 5, wherein pharmaceutically acceptable seal coat polymers comprises of one or more of hydroxypropyl methylcellulose, hydroxypropyl cellulose and other suitable cellulose ethers and the like.
7. The tablet in tablet dosage form of claim 1, wherein tablet in tablet is coated with pharmaceutically acceptable enteric coat polymer.
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8. The tablet in tablet dosage form of claim 7, wherein the 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.
9. The pharmaceutical composition of claim 1, wherein inert 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, hydrpgenated vegetable oil, colloidal silicon dioxide, talc, croscarmellose sodium, crospovidone, sodium starch glycolate and the like.
Dated this ^9m day of April, 2007 For Wockhardt Limited

(Mandar(Kodgule) Authorized Signatory
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