FORM 2
THE PATENTS ACT, 1970
(39 of 1970)
&
The Patent Rules, 2003
COMPLETE SPECIFICATION
[Section 10, and Rule 13]
TITLE OF THE INVENTION:
PHARMACEUTICAL COMPOSITIONS OF FLUVOXAMINE.
APPLICANT(S):
Name: Torrent Pharmaceuticals Limited
Nationality: Indian
Address: Torrent House, Off Ashram Road, Near Dinesh Hall, Ahmedabad 380 009,
Gujarat, India.
The following specification particularly describes the invention and the manner in which it is to be performed.

FIELD OF THE INVENTION
The present invention provides a pharmaceutical composition comprising fluvoxamine or pharmaceutically acceptable salt thereof, with pharmaceutically acceptable excipients.
Fluvoxamine maleate, which was first described in US Patent No. 4,085,225, is a selective serotonin (5-HT) reuptake inhibitor (SSRI) belonging to a new chemical series, the 2-aminoethyl oxime ethers of aralkylketones. Fluvoxamine maleate (Formula I) is chemically designated as 5-methoxy-4'-(trifluoromethyl) valerophenone-(E)-0-(2aminoethyl) oxime maleate (1:1).
LUVOX CR® (Fluvoxamine Maleate) Controlled-Release Capsules are available in 100 mg and 150 mg strengths for oral administration for the treatment of Obsessive compulsive disorder.

The marketed composition of fluvoxamine (LUVOX CR® Capsules) comprises talc, sugar spheres, ammonio methacrylate copolymer type B, dibutyl sebacate, red iron oxide, titanium dioxide and gelatin.
US Patent No. 7,465,462 discloses a multiparticulate controlled release formulation of fluvoxamine for oral administration, which comprises two different quantities of particles of fluvoxamine, wherein each of the particles comprises (i) an inert non-pareil core, (ii) a layer comprising fluvoxamine or a pharmaceutically-acceptable salt thereof disposed over the inert core, and (iii) a coating of a rate-controlling polymeric acrylate, methacrylate lacquer, or a mixture thereof disposed over the fluvoxamine layer, wherein the composition allows the controlled release of the fluvoxamine over a period of not less than about 12 hours following oral administration.

US Patent application No. 20080138411 describes a modified release pharmaceutical composition for oral administration, suitable for once daily dosing, comprising: (a) at least one selective serotonin re-uptake inhibitor (SSRI) and combinations thereof; (b) at least one release rate controlling polymer; (c) at least one diluent; (d) at least one binder; (e) at least one lubricant; (f) at least one surfactant; (g) at least one solubilizing agent; (h) at least one bioavailability enhancer; and (i) at least one acidifying agent.
US Patent application No. 20080213381 discloses an oral drug delivery system comprising: a core comprising at least one active ingredient and a pharmaceutically acceptable excipient and a composition selected from a swellable composition and a reactive composition located in an immediate vicinity of one or more preselected surfaces, and a coating surrounding the core, said coating comprising a water-insoluble polymer and a pH-dependent polymer.
US Patent application No. 20090220611 discloses coated microparticles containing at least one active and covered with at least two different coating films, characterized in that, in combination, the coating films are capable: of ensuring release of the active governed by two different triggering mechanisms, one based on a variation in pH and the other allowing the release of the active after a predetermined residence time in the stomach.
The present inventors while working on the fiuvoxamine compositions have surprisingly found that a single particle population comprising uniform coating of a rate controlling polymer is bioequivalent with the marketed LUVOX CR® Capsule formulation.
In one aspect of the present invention there is provided a controlled release pharmaceutical composition comprising a single particle population comprising fiuvoxamine or pharmaceutically acceptable salts thereof and at least one pharmaceutically acceptable excipient, wherein the composition is coated with a uniform coating of a rate controlling water-insoluble polymer.
In another aspect of the present invention there is provided a controlled release pharmaceutical composition comprising a single particle population comprising fiuvoxamine or

pharmaceutically acceptable salts thereof and at least one pharmaceutically acceptable excipient, wherein the composition is coated with a uniform coating comprising a mixture of a rate controlling water-insoluble polymer and a channelizer in a ratio of 10:1 to 1:1 parts by weight.
In another aspect of the present invention there is provided a controlled release pharmaceutical composition comprising a single particle population comprising:
(a) a core coated with a first layer of water-insoluble polymer;
(b) a second layer of fluvoxamine maleate over the first layer;
(c) a third layer of rate-controlling water-insoluble polymer over the second layer.
The term 'single particle population' means the composition comprising particles coated with only one amount of a rate-controlling water-insoluble polymer.
The pharmaceutically acceptable excipients include rate controlling water-insoluble polymers, inert sugar spheres, binders and channelizers.
Suitable rate controlling water-insoluble polymers include, but are not limited to ethyl cellulose, cellulose acetate, polyvinyl acetate; the waxes selected from hydrogenated castor oil, hydrogenated vegetable oil, bees wax, carnauba wax, microcrystalline wax, fatty acid esters such as glyceryl monostearate; glycerol monooleate, acetylated monoglycerides, tristearin, tripalmitin, cetyl esters wax, glyceryl palmitostearate, glyceryl behenate, and the like.
The amount of rate controlling water-insoluble polymer is based on the desired drug release profile. Normally the % weight gain achieved after coating of a rate controlling water-insoluble polymer is about 5 to 15 % by weight.
The preferred rate controlling water-insoluble polymer is ethyl cellulose. The desired % weight gain achieved after coating of a rate controlling water-insoluble polymer is about 10 to 15 % by weight.

The inert sugar spheres form the core of the composition. The preferred size range of the sugar spheres is between 25 # and 30 # (about 600 to 710 microns).
Suitable binders may include, but not limited to celluloses such as hydroxypropyl cellulose, hydroxy ethyl cellulose, hydroxypropyl methylcellulose, methylcellulose, povidone, starch, and other materials known to have cohesive and desirable binding properties.
The preferred binder is hydroxypropyl cellulose.
Suitable channelizers employed in the third layer of rate controlling polymer may include, but are not limited to inorganic salts such as sodium chloride and potassium chloride; sugars such as lactose, sucrose, mannitol and sorbitol; hydroxylated compounds, including polyvinyl alcohols and glycols, such as polyethylene glycol and propylene glycol; cellulose derived materials, such hydroxypropyl celluloses, hydroxypropyl methylcelluloses, and hydroxyethyl celluloses; water soluble polymers such as polyvinylpyrrolidone (povidone).
The ratio of rate controlling water-insoluble polymer to channelizer is based on the desired drug release profile. Normally the ratio is about 10:1 to 1:1 parts by weight. The amount of channelizer is directly proportional to the amount of drug released.
The preferred channelizer is hydroxypropyl cellulose. The preferred ratio of rate controlling water-insoluble polymer to channelizer is 4:1 parts by weight.
The pharmaceutical composition of the present invention is meant for oral administration and it can be prepared as powder, granules, pellets, beads, spheres, particulates, tablets, 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.

EXAMPLES

Example 1 Example 2 Example 3 Example 4
Component Amount (nig) / capsule Amount (mg) / capsule Amount (mg) / capsule Amount (mg) / capsule
Sugar Spheres (25/30) 76.49 76.49 76.49 231.750
Ethylcellulose 4.59 4.59 4.59 13.500
Talc 0.92 0.92 0.92 2.700
Methylene Chloride* q.s. q.s. q.s. q.s.
Methyl Alcohol* q.s. q.s. q.s. q.s.
Total theoretical weight 82.00 82.00 82.00 241.200
Sugar Spheres (Seal Coated) 82.000 82.000 82.000 82.000
Fluvoxamine Maleate 150.000 150.000 150.000 150.000
Hydroxy propylcellulose (Klucel LF) 12.000 12.000 12.000 12.000
Methyl alcohol* q.s. q.s. q.s. q.s.
Total theoretical weight 244.000 244.000 244.000 244.000
Fluvoxamine Maleate Pellets (Drug Coated) 244.000 244.000 244.000 244.000
Ethyl cellulose 1 Ocps 10.63 15.73 17.87 24.36
Hydroxy propylcellulose - 4.25 4.83 7.07
Triethyl Citrate 3.19 4.72 5.36 2.66
Ferric Oxide yellow - - - 0.07
Methyl Alcohol* q.s. q.s. q.s. q.s.
Methylene Chloride* q.s. q.s. q.s. q.s.
Total theoretical weight 257.82 268.70 272.06 278.16
% Weight Gain 5.66 % 8.20 % 11.5 % 14.00 %
Fluvoxamine Maleate Extended Release Pellets (Polymer Coated) 257.82 268.70 272.06 278.16
Hard Gelatin Capsule Shells (Size*l')# 76.00 76.00 76.00 76.00
Total theoretical weight 333.82 344.7 348.06 354.16
* Removed during process, does not remain in the finished product, except in traces.
# Weight varies as per actual Avg. weight of Empty Capsules shell
The composition of these examples can be prepared by the process comprising the steps of:
(a) Dispensing of sugar spheres of appropriate size;
(b) Seal Coating of the sugar spheres with a mixture of ethyl cellulose and talc;
(c) Fluvoxamine maleate drug layering over the seal coated spheres with hydroxy
propylcellulose as binder;

(d) Coating fluvoxamine maleate coated spheres with ethyl cellulose as rate-controlling water-
insoluble polymer and hydroxy propylcellulose as channelizer;
(e) Filling the coated spheres of step (d) into capsules.

The fluvoxamine composition remained stable after three months.

Claims:
1. A controlled release pharmaceutical composition comprising a single particle population comprising fluvoxamine or pharmaceutically acceptable salts thereof and at least one pharmaceutically acceptable excipient, wherein the composition is coated with a uniform coating of a rate controlling water-insoluble polymer.
2. The controlled release pharmaceutical composition according to claim 1, wherein the pharmaceutically acceptable excipients comprise a rate controlling water-insoluble polymer, inert sugar spheres, a binder and a channelizer.
3. The controlled release pharmaceutical composition according to claim 2, wherein the preferable rate controlling water-insoluble polymer is ethyl cellulose.
4. The controlled release pharmaceutical composition according to claim 3, wherein the % weight gain achieved by coating of ethyl cellulose is about 10 to 15 % by weight.
5. The controlled release pharmaceutical composition according to claim 2, wherein the size range of the sugar spheres is between 25 # and 30 #.
6. The controlled release pharmaceutical composition according to claim 2, wherein the preferable binder and/or channelizer is hydroxy propylcellulose.
7. A controlled release pharmaceutical composition comprising a single particle population comprising fluvoxamine or pharmaceutically acceptable salts thereof and at least one pharmaceutically acceptable excipient, wherein the composition is coated with a uniform coating comprising a mixture of a rate controlling water-insoluble polymer and a channelizer in a ratio of 10:1 to 1:1 parts by weight.
8. The controlled release pharmaceutical composition according to claim 7, wherein the ratio of a
rate controlling water-insoluble polymer to a channelizer is about 4:1 parts by weight

9. A controlled release pharmaceutical composition comprising a single particle population
comprising:
(a) a core coated with a first layer of water-insoluble polymer;
(b) a second layer of fluvoxamine maleate over the first layer;
(c) a third layer of rate-controlling water-insoluble polymer over the second layer.
10. A controlled release pharmaceutical composition of Fluvoxamine maleate as substantially
described and exemplified herein.