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:
PHARMACEUTICAL COMPOSITIONS OF PAROXETINE OR SALT THEREOF
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 granules of paroxetine or salt thereof along with hydroxypropyl alkylcellulose and hydroxyalkyl cellulose and one or more pharmaceutically acceptable excipients, wherein the granules of paroxetine or salt thereof are coated with pharmaceutically acceptable enteric coat polymer.
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 granules of paroxetine or salt thereof along with hydroxypropyl alkylcellulose and hydroxyalkyl cellulose and one or more pharmaceutically acceptable excipients, wherein the granules of paroxetine or salt thereof are coated with pharmaceutically acceptable enteric coat polymer.
Paroxetine hydrochloride is an orally administered psychotropic drug with a chemical structure unrelated to other selective serotonin reuptake inhibitors or to tricyclic, tetracyclic, or other available antidepressant or antipanic agents. It is the hydrochloride salt of a phenylpiperidine compound identified chemically as (-)-frans-4/:R-(4’-fluorophenyl)-3S-[(3’,4’-methylenedioxyphenoxy) methyl] piperidine hydrochloride hemihydrate and has the empirical formula of C19H20FNO3 HCI1/2H20. The molecular weight is 374.8 (329.4 as free base). Paroxetine hydrochloride is an odorless, off-white powder, having a melting point range of 120°C to 138°C and a solubility of 5.4 mg/ml in water. Its structural formula is:

Paroxetine hydrochloride is indicated for the treatment of major depressive disorder, panic disorder, with or without agoraphobia, social anxiety disorder, also known as social phobia, premenstrual dysphoric disorder (PMDD).
US Patent No. 4,721,723 disclose paroxetine hydrochloride hemihydrate, process of making it and its pharmaceutical compositions.
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US Patent No. 4,839,177, 5,422,123 and 6,548,084 discloses controlled release paroxetine compositions where elastic support of polymers is applied on to active core.
US Patent No. 6,113,944 and US Application 2004197403 disclose controlled release paroxetine compositions prepared by dry granulation.
US Patent No. 6,638,948 and 5,672,612 discloses amorphous paroxetine compositions.
US Patent No. 6,699,882 discloses compositions of paroxetine wherein paroxetine is adsorbed on a carrier.
US Patent No. 6,984,632 discloses inclusion complex of paroxetine with cyclodextrins.
US Patent No. 6,503,927 and 6,720,003 discloses solid dispersions of paroxetine.
US Patent No. 6,660,298 discloses compositions of paroxetine with acidulant.
US Patent No. 7,138,137 discloses compositions of paroxetine containing povidone and HCL free fillers.
US Application No. 2005191350, 2003144324 and 2005059701 disclose compositions of anhydrous paroxetine hydrochloride with povidone or co povidone as a binder.
US Application No. 2005266082 disclose compositions of paroxetine with lipid components.
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US Application No. 20060039975 disclose compositions of paroxetine with release retarding material wherein release-retarding material is not hydroxypropyl methylcellulose.
US Application No. 20060216345, PCT application No. WO2007012968 and WO2005034954 disclose compositions of paroxetine prepared by wet granulation method.
PCT Application No. WO2007011139 disclose sustained release paroxetine compositions with low viscous hydroxypropyl methylcellulose and high viscous hydroxypropyl methylcellulose.
PCT Application No. 2006059866 discloses sustained release paroxetine compositions with water-soluble erodable polymers and hydrogels.
The present inventors while working on the paroxetine formulation have surprisingly found that when both hydroxypropyl alkylcellulose and hydroxyalkyl cellulose are used together as matrix forming agents, it results in better control of near zero order sustained release of paroxetine over about 7 hours with little burst effect. Further combination of both hydroxypropyl alkylcellulose and hydroxyalkyl cellulose also leads to less dissolution variation.
The present inventors have further noticed when granules of paroxetine or salt thereof are coated with enteric polymer; enteric polymer prevents release of paroxetine in acidic environment such as stomach and releases paroxetine in basic environment, such as small intestine and hence prevents degradation of paroxetine.
One of the aspects of the present invention provides a pharmaceutical composition comprising granules of paroxetine or salt thereof along with hydroxypropyl alkylcellulose and hydroxyalkyl cellulose and one or more
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pharmaceutical acceptable excipients, wherein the granules of paroxetine or salt thereof are coated with pharmaceutical^' acceptable enteric coat polymer.
The pharmaceutical composition of the present invention comprises of paroxetine or salt thereof wherein paroxetine or salts thereof is present in the form of paroxetine hydrochloride hemihydrate.
Granules can be coated with enteric polymer using spray drier, glatt, fluidized bed processor or any other suitable technique known in the art.
The pharmaceutically acceptable enteric coating polymers 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, hydroxypropylmethyl cellulose acetate succinate, polyvinyl acetate phtalate, cellulose acetate trimellitate, and other suitable polymers.
In the present invention, the weight ratio of hydroxypropyl alkylcellulose to hydroxyalkyi cellulose may range from 1:10 to 10:1.
The hydroxypropyl alkyl cellulose may be one or more of hydroxypropyl methylcellulose, hydroxypropyl ethylcellulose, hydroxypropyl butylcellulose, hydroxypropyl pentylcellulose and the like.
The hydroxyalkyi cellulose may be one or more of hydroxymethyl cellulose, hydroxyethyl cellulose, hydroxypropyl cellulose, hydroxybutyl cellulose, hydroxypentyl cellulose and the like.
The pharmaceutical composition of the present invention, wherein hydroxypropyl alkyl cellulose is hydroxypropyl methylcellulose and hydroxyalkyi cellulose is hydroxypropyl cellulose.
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The pharmaceutical composition of the present invention may be prepared by mixing paroxetine or salts thereof with hydroxypropyl alkylcellulose and with other pharmaceutically acceptable excipients to form a pre-mix, granulating pre-mix to produce granules of desired size, blending the granules with hydroxyalkyl cellulose and other pharmaceutically acceptable excipients. Granules thus obtained are enteric coated with pharmaceutically acceptable enteric coating polymers. Enteric-coated granules of paroxetine or salt thereof are blended with other pharmaceutically acceptable excipients and mixture thus obtained is converted into suitable dosage form.
The pharmaceutical composition of the present invention 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.
When the pharmaceutical composition is present in the form of tablets, enteric-coated granules of paroxetine or salt thereof are blended additionally with polyethylene glycol. During compression, pressure exerted on granules results in cracking of the enteric coat. Presence of polyethylene glycol provides cushioning effect to granules and avoids cracking under compression pressure.
Polyethylene glycol may be selected from group comprising one or more of PEG 2000, PEG 4000, PEG 3350, PEG 6000, PEG 8000 and the like.
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
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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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EXAMPLIE1
Table 1: Composition of Paroxetine hydrochloride hemihydrate controlled release tablets

No Ingredients % Composition
1 Paroxetine hydrochloride hemihydrate 10-25
2 Lactose 10-90
3 Hydroxypropyl methyl cellulose 5-30
4 Colloidal silicon dioxide 0.1-5
5 Purified water q.s.
6 Hydroxypropyl cellulose-L 5-30
7 Talc 0.1-5
8 Magnesium stearate 0.1-5
9 PEG 6000 0.15-2.5
Enteric coating
9 Methacrylic acid copolymer suspension (Methacrylic acid copolymer, talc, triethyl citrate, purified water) 5-25
10 Film coating (Opadry) 1-8
Procedure: Paroxetine hydrochloride hemihydrate, part of lactose, hydroxypropyl methylcellulose and colloidal silicon dioxide are mixed and granulated with water to form a wet mass. Wet mass thus obtained is sized to form granules of desired size, which are dried and mixed with hydroxypropyl cellulose, talc and colloidal silicon dioxide. Granules thus obtained are enteric coated with enteric polymer suspension prepared by mixing methacrylic acid polymer, talc, triethyl citrate in water in fluidized bed processor. Enteric-coated granules of paroxetine or salt thereof are mixed with remaining part of lactose, Polyethylene glycol 6000 and lubricated with magnesium stearate and compressed into tablets usifig suitable tooling. Tablets of paroxetine hydrochloride hemihydrate are further film coated with aqueous dispersion of Opadry.
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WE CLAIM:
1. A pharmaceutical composition comprising granules of paroxetine or salt thereof along with hydroxypropyl alkylcellulose and hydroxyalkyi cellulose and one or more pharmaceutically acceptable excipients, wherein the granules of paroxetine or salt thereof are coated with pharmaceutically acceptable enteric coat polymer.
2. The pharmaceutical composition of claim 1, wherein paroxetine or salts thereof is present in the form of paroxetine hydrochloride hemihydrate.
3. The pharmaceutical composition of claim 1, wherein weight ratio of hydroxypropyl alkylcellulose to hydroxyalkyi cellulose ranges from 1:10 to 10:1.
4. The pharmaceutical composition of claim 1, wherein hydroxypropyl alkyl cellulose comprises one or more of hydroxypropyl methylcellulose, hydroxypropyl ethylcellulose, hydroxypropyl butylcellulose, hydroxypropyl pentylcellulose and the like.
5. The pharmaceutical composition of claim 1, hydroxyalkyi cellulose comprises one or more of hydroxymethyl cellulose, hydroxyethyl cellulose, hydroxypropyl cellulose, hydroxybutyl cellulose, hydroxypentyl cellulose and the like.
6. The pharmaceutical composition of claim 4, wherein hydroxypropyl alkyl cellulose is hydroxypropyl methylcellulose.
7. The pharmaceutical composition of claim 5, wherein hydroxyalkyi cellulose is hydroxypropyl cellulose.
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8. The pharmaceutical composition of claim 1, wherein the pharmaceutically acceptable enteric coating polymers comprises 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, hydroxypropylmethyl cellulose acetate succinate, polyvinyl acetate phthalate, cellulose acetate trimellitate, and 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 27™ day of April, 2007 For Wockhardt Limited

Authorized Signatory
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