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 pharmaceutical composition comprising duloxetine or salt thereof conjugated to ion exchange resin particles optionally along with other 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 duloxetine or salt thereof conjugated to ion exchange resin particles optionally along with other pharmaceutical^ 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 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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US Application No. 20070036851 disclose acid labile drug compositions of proton pump inhibitors wherein the proton pump inhibitors are conjugated to ion exchange resin particles.
The present inventors while working on the duloxetine formulation have surprisingly found that duloxetine can be stabilized against acid degradation by conjugating it with ion exchange resins. Conjugation between duloxetine and the ion exchange resin particles results from ionic bonds between oppositely charged species because of their mutual electrostatic attraction. The resulting stabilization is sufficient to prevent degradation of duloxetine in acidic pH.
One of the aspects of the present invention provides a pharmaceutical composition comprising duloxetine or salt thereof conjugated to ion exchange resin particles optionally along with other pharmaceutical^ acceptable excipients.
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.
Suitable ion-exchange resin particles may be anionic exchange resin particles which are commercially available as Duolite® resins, Purolite® resins, Amberlite® resins which are cholestyramines, a synthetic anionic exchange polymer in which quaternary ammonium groups are attached to a polystyrene-divinylbenzene copolymer. The resins may be sized to achieve a desired particle size.
For the present invention, the term duloxetine-resin conjugate as used herein refers to complexation between duloxetine and the ion exchange resin particles resulting from ionic bonds between oppositely charged species because of their mutual electrostatic attraction.
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The duloxetine resin conjugate contains duloxetine in an amount of about 1% to about 70% by weight and ion exchange resin from about 30% to about 99% by weight.
Another aspect of the invention provides a process of making duloxetine-resin conjugate comprising
a) slurrying anionic exchange resin particles in a solution containing duloxetine,
, b) washing the duloxetine resin conjugate,
c) drying the duloxetine resin conjugate.
Duloxetine resin conjugate may be sized to obtain a complex of desired size.
Duloxetine resin conjugate may be optionally coated with pharmaceutically acceptable seal coat polymers followed by enteric coating polymers.
In the duloxetine resin conjugate, duloxetine or salt thereof may optionally be coated with pharmaceutically acceptable seal coat polymers followed by pharmaceutically acceptable enteric coating polymers.
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 of the present invention can be prepared by slurrying duloxetine or salt thereof in a solution of anion exchange resin particles creating a duloxetine resin conjugate. Duloxetine resin conjugate is washed, dried and sized to a desirable particle size, which is then coated with enteric polymer. Duloxetine resin conjugate 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, suspension 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, 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 Amberlite 10-80
3 Purified water q.s.
Seal coating
Seal coat composition: (Sucrose, Hypromellose, Polyethylene glycol 6000, Purified water) 1-30
Enteric coating
Methacrylic acid copolymer suspension (Methacrylic acid copolymer, sodium hydroxide, Talc, triethyl citrate, purified water) 5-25
Encapsulation
Hard gelatin capsules
Procedure: Duloxetine hydrochloride and amberlite are dispersed in water by continuous mixing resulting in formation of duloxetine hydrochloride-amberlite conjugate. The conjugate is washed, dried and sized to a suitable size. Duloxetine-amberlite conjugate thus obtained is coated with seal coat polymer by spraying hypromellose, sucrose and polyethylene glycol 6000 solution in water. Seal coated complex is further coated with enteric polymer suspension prepared by mixing methacrylic acid polymer, sodium hydroxide, talc, triethyl citrate in water. Enteric-coated conjugate of duloxetine hydrochloride- amberlite is encapsulated in hard gelatin capsules of suitable size.
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WE CLAIM:
1. A pharmaceutical composition comprising duloxetine or salt thereof conjugated to ion exchange resin particles optionally along with other pharmaceutically 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 ion-exchange resin particles are anionic exchange resin particles.
4. The pharmaceutical composition of claim 3, wherein the anionic-exchange resin particle is Amberlite®.
5. The pharmaceutical composition of claim 1, wherein the duloxetine resin conjugate contains duloxetine in an amount of about 1% to about 70% by weight and ion exchange resin from about 30% to about 99% by weight.
6. A process of making duloxetine-resin conjugate comprising

a) slurrying anionic exchange resin particles in a solution containing duloxetine,
b) washing the duloxetine resin conjugate,
c) drying the duloxetine resin conjugate.

7. The pharmaceutical composition of claim 1, wherein the conjugated duloxetine resin particles are optionally coated with pharmaceutically acceptable seal coat polymer followed by coating with pharmaceutically acceptable enteric polymer.
8. The pharmaceutical composition of claim 7, wherein pharmaceutically acceptable seal coat polymers comprises of one or more of hydroxypropyl
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methylcellulose, hydroxypropyl cellulose, other suitable cellulose ethers and pharmaceutical^ acceptable enteric polymers comprises one or more of methacrylic acid/methyl methacrylate copolymers, carboxymethyl cellulose, cellulose acetate phthalate, hydroxypropyl methyl cellulose phthalate and the like.
9. The process of claim 6, wherein the duloxetine resin conjugate is sized to achieve a desired particle size.
10. 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.
Dated this£0™ day of April, 2007 For Wockhardt Limited
liUri
(Mandar Kbdgule) AuthorizecrSignatory
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