FORM 2
THE PATENT ACT 1970
(39 of 1970)
&
The Patents Rules, 2003
COMPLETE SPECIFICATION
(See section 10 arid 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 duloxetine or salts thereof along with polyethylene glycol and one or more pharmaceutically acceptable excipients. Granules of duloxetine or salt thereof and PEG are made by melt granulation process.
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 duloxetine or salts thereof along with polyethylene glycol 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 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.
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US Application No. 20060079569 disclose oral liquid compositions of duloxetine or its derivatives thereof.
The present inventors while working on the duloxetine formulation have surprisingly found that when duloxetine or salt thereof is melt granulated with PEG, PEG coats the duloxetine or salt thereof and hence prevents the exposure of duloxetine or salt thereof to 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. Further, formulations prepared by melt granulation method results in better bioavailability of duloxetine or salt thereof.
One of the aspects of the present invention provides a pharmaceutical composition comprising duloxetine or salts thereof along with polyethylene glycol (PEG) and one or more pharmaceutical^ acceptable excipients.
The pharmaceutical composition of the present invention comprises of duloxetine or salt thereof wherein duloxetine is present in the form of duloxetine hydrochloride.
The pharmaceutical composition comprises of polyethylene glycol (PEG) wherein a PEG may be selected from a group comprising one or more of PEG 1000, PEG 1450, PEG 1500, PEG 2000, PEG 3350, PEG 4000, PEG 6000, PEG 8000, PEG 20000 and the like.
In another aspect of the present invention there is provided a process of preparing pharmaceutical composition comprising
a) forming a molten mass by heating mixture of duloxetine or salt thereof with PEG optionally with other pharmaceutical^ acceptable excipients,
b) mixing the molten mass of step a) to obtain a homogenous mixture,
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c) cooling the molten mass of step b),
d) sizing the cooled mixture of step c) to form granules,
e) mixing granules of step d) with other pharmaceutical^ acceptable excipients,
f) converting the mixture of step e) into suitable pharmaceutical composition which is further optionally coated with pharmaceutical^ acceptable seal coat polymers followed by enteric coating with pharmaceutically acceptable enteric coating polymers.
The pharmaceutical composition of the present invention can be present in the form of granules, pellets, beads, spheroids, tablet, minitablet, microtablet, capsule, granules in capsule, pellets in capsule, minitablet in capsule or combinations thereof.
Any pharmaceutical composition as described above is further optionally coated with pharmaceutically acceptable seal coat polymers followed by enteric coating with pharmaceutically acceptable enteric coating polymers optionally along with other pharmaceutically acceptable excipients.
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.
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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.
The pharmaceutical composition of the present invention can be prepared in two parts. Duloxetine and a part of polyethylene glycol are mixed and heated along with fluidization where PEG melts and coats the duloxetine particles. This mix is then mixed with remaining part of PEG and heated where PEG melts and granulates duloxetine or salt thereof. Mixture is cooled and aggregates are sized into granules. Granules are mixed with other pharmaceutically acceptable excipients, coated with seal coat polymer followed by enteric coating the seal coated granules with enteric coat polymer and filling the enteric coated granules in hard gelatin capsules.
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 PEG 6000 0.5-30
3 Microcrystalline cellulose 10-90
5 Starch 10-90
7 Talc 0.5-10
8 Magnesium stearate 0.5-5
Seal coating
12 Seal coat composition: (Sucrose, Hypromellose, Polyethylene glycol 6000, Purified water) 1-30
Enteric coating
13 Methacrylic acid copolymer suspension (Methacrylic acid copolymer, sodium hydroxide, Talc, triethyl citrate, purified water) 5-25
Encapsulation
Hard gelatin capsules
Procedure: Duloxetine hydrochloride and a part of polyethylene glycol are mixed together and heated in fluidized bed, where PEG melts and coats duloxetine hydrochloride. This mix is then mixed with remaining part of polyethylene glycol, heated, where PEG melts and granulates duloxetine hydrochloride. Molten mass of duloxetine hydrochloride and PEG 6000 is cooled to room temperature, sized using multimill into granules. PEG coated granules of duloxetine hydrochloride are mixed with microcrystalline cellulose, starch, talc and magnesium stearate. Granules are coated with seal coat polymer in fluidized bed processor using Wurster's technique by spraying hypromellose, sucrose and polyethylene glycol 6000 solution in water. Seal coated granules are further coated with enteric polymer suspension prepared by mixing methacrylic acid polymer, sodium hydroxide, talc, triethyl citrate in water in fluidized bed processor using Wurster's
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technique. Enteric-coated granules of duloxetine hydrochloride are encapsulated in hard gelatin capsules of suitable size.

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WE CLAIM:
1. A pharmaceutical composition comprising duloxetine or salts thereof along with polyethylene glycol (PEG) 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 polyethylene glycol (PEG) may be selected from a group comprising one or more of PEG 1000, PEG 1450, PEG 1500, PEG 2000, PEG 3350, PEG 4000, PEG 6000, PEG 8000, PEG 20000 and the like.
4. The pharmaceutical composition of claim 1, wherein polyethylene glycol is PEG 6000.
5. A process of preparing pharmaceutical composition comprising

a) forming a molten mass by heating mixture of duloxetine or salt thereof with PEG optionally with other pharmaceutical^ acceptable excipients,
b) mixing the molten mass of step a) to obtain a homogenous mixture,
c) cooling the molten mass of step b),
d) sizing the cooled mixture of step c) to form granules,
e) mixing granules of step d) with other pharmaceutically acceptable excipients,
f) converting the mixture of step e) into suitable pharmaceutical composition which is further optionally coated with pharmaceutically acceptable seal coat polymers followed by enteric coating with pharmaceutically acceptable enteric polymers.
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6. The pharmaceutical composition of claim 1 comprises one or more of granules, pellets, beads, spheroids, tablet, minitablet, microtablet, capsule, granules in capsule, pellets in capsule, minitablet in capsule or combinations thereof.
7. The process 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.
8. The process of claim 5, 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 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.
For Wockhardt Limited

(Mandar Kodgule) Authorized Signatory
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