FORM 2
The Patents Act, 1970
(39 of 1970)
&
The Patent Rutes, 2003
PROVISIONAL SPECIFICATION
[Section 10, and Rule 13]


SUSTAINED RELEASE
PHARMACEUTICAL COMPOSITION OF
QUETIAPINE AND PROCESS FOR
PREPARATION THEREOF
Applicant
Name: Torrent Pharmaceuticals Limited
Nationality: Indian
Address: Torrent House, Off Ashram Road, Near
Dinesh Hall, Ahmedabad 380 009,
Gujarat, India
The following specification describes the invention:

FIELD OF THE INVENTION
The present invention relates to sustained release pharmaceutical composition of quetiapine, and process for preparing such composition. More particularly, it relates to sustained release pharmaceutical composition of quetiapine comprising carrageenan and pharmaceutical^ acceptable excipients.
BACKGROUND OF THE INVENTION
US Patent No. 4,879,288 disclose 11-[4-[2^(2-hydroxyethoxy) ethyl] -1-piperazinyl] dibenzo [b, f] [1, 4] thiazepine as a novel antipsychotic drug of dibenzothiazepine class suitable for treatment of various psychotic disorders and having much reduced incidence of side effects. It is commonly known as quetiapine and is used for the treatment of schizophrenia and acute manic episodes associated with bipolar I disorder. Quetiapine is thought to exert its efficacy in schizophrenia through a combination of dopamine type 2 (D2) and serotonin type 2 (5HT2) antagonism. Quetiapine is marketed as its fumarate salt by AstraZeneca Pharmaceutical LP under the brand-name Seroquel®.
Due to high degree of bioavailability and rapid metabolism, quetiapine typically has to be administered multiple times. Such multiple administrations, however, may result in problems related to patient compliance. Accordingly, it may be advantageous to provide a composition which allows for sustained release of quetiapine. Such sustained release may provide a generally uniform and constant rate of release over an extended period of time which may achieve a stable and desired blood (plasma) level of quetiapine without the need for frequent administration. The art discloses some approaches for preparing sustained release pharmaceutical compositions of quetiapine.
US Patent no. 5,948,437 assigned to Zeneca Ltd. discloses a sustained release composition comprising quetiapine or a pharmaceutical^ acceptable salt thereof, and a gelling agent together with one or more pharmaceutically acceptable excipients. The gelling agent is described to a hydrophilic substance, which forms a gel when in contact with water. Preferably, the gelling agent is hydroxypropyl methylcellulose. Extended release tablets of quetiapine fumarate sold under the

tradename SEROQUEL XR by AstraZeneca are believed to be based on the teachings of US 5,948,437.
The WO 2005/41935 patent application assigned to Alpharma Inc. discloses dosage forms of quetiapine and its salts, including wax dosage forms, press-coat dosage forms, and sprinkle dosage forms. It also discloses pulsed release dosage forms of quetiapine and its salts. In one of its preferred embodiment, it discloses a sustained release solid dosage formulation comprising a matrix, wherein the matrix comprises a therapeutically effective amount of quetiapine or a pharmaceutically acceptable salt thereof, and a wax material.
The WO 2007/86079 patent application assigned to Astron Research Ltd. discloses once a day sustained release solid oral dosage form of quetiapine and their pharmaceutically acceptable salts comprising a channelizer, rate controlling polymer and suitable pharmaceutically acceptable excipients. The preferred channelizers are electrolytes and osmotic agents.
The WO 2007/110878 patent application assigned to Panacea Biotec Ltd. discloses a sustained release pharmaceutical composition comprising at least one poorly soluble active agent(s), at least one solubilizer, a release rate controlling polymer system consisting of an acid-soluble polymer and a pH-dependent polymer, and optionally other pharmaceutically acceptable excipients. The preferred solubilizers are hydrophilic surfactants, lipophilic surfactants, or mixtures thereof.
The WO 2007/00778 patent application assigned to Panacea Biotec Ltd. discloses a modified release pharmaceutical composition comprising at least one active agent(s); a polymer system comprising at least two swellable pH independent polymers wherein at least one is hydrophilic; and optionally other pharmaceutically acceptable excipients.
The WO 2007/133583 patent application assigned to Mallinckrodt Inc. discloses a modified release solid dosage form comprising a matrix core and a modified release coating. The matrix core comprises a hydrophobic material and a water

soluble pharmaceutical agent such as quetiapine. The modified release coating surrounds the matrix core, and comprises a hydrophobic polymer and a hydrophilic pore-forming agent. The dosage form exhibits a zero-order release profile upon dissolution. The hydrophilic pore-forming agent in modified release coating is described to be essential for zero-order release of drug from the dosage form.
The WO 2006/81347 patent application assigned to Elan Pharma discloses formulations that deliver quetiapine in a pulsed or bimodal manner. The formulations comprise an immediate release and a modified release component. The components are described to be selected from different populations of particles or mini-tablets.
The US 2008/221078 patent application discloses pharmaceutical composition of quetiapine, an intimate mixture of polyvinyl acetate and polyvinyl pyrrolidone (i.e. Kollidon SR®) and an acid.
There remains a need in the art for alternative sustained release pharmaceutical compositions of quetiapine. We have surprisingly found that sustained release compositions of quetiapine can be prepared by using carrageenan in the composition.
SUMMARY OF THE INVENTION One embodiment discloses a sustained release pharmaceutical composition comprising:
a) quetiapine,
b) carrageenan; and
c) at least one pharmaceutically acceptable excipient.
Another embodiment discloses a sustained release pharmaceutical composition comprising:
a) quetiapine,
b) carrageenan,
c) a hydrophobic release-modifying polymer; and
d) at least one pharmaceutically acceptable excipient.

Yet another embodiment discloses a process for preparing a sustained release pharmaceutical composition, wherein the process comprises: (i) mixing quetiapine, carrageenan and at least one pharmaceutically
acceptable excipient; (ii) granulating the mixture of step (i) with a solvent; (iii) drying the granules; (iv) optionally coating the granules obtained in step (iii) with a hydrophobic
release-modifying polymer; (v) mixing the granules of step (iii) or (iv) with at least one pharmaceutically
acceptable excipient; and (vi) compressing the mixture of step (v) into a tablet.
DETAILED DESCRIPTION OF THE INVENTION
The term "quetiapine" as described herein includes quetiapine free base, as well as pharmaceutically acceptable salts, prodrugs, metabolites thereof, or enantiomers thereof. It also includes hydrates, solvates and polymorphs of quetiapine free base or pharmaceutically acceptable salts thereof; or mixtures thereof, The preferred salt is quetiapine fumarate. Quetiapine may be present in an amount ranging from 1 % to 70 % by weight of the composition.
Carrageenan is a naturally occurring family of polysaccharides extracted from certain types of red seaweed belonging to the Rhodophyceae family. It is a high molecular weight polysaccharide made up of repeating galactose and 3, 6 anhydrogalactose units, both sulfated and nonsulfated. The units are joined by alternating ai.3 and pM glycosidic linkages. Carrageenan is basically of three types: lota, Kappa and Lambda. Preferably, carrageenan as used herein is the lambda grade of carrageenan, such as the grade marketed under the trade¬name Viscarin GP®. Carrageenan may be present in an amount ranging from 1 % to 50 % by weight of the composition.
The "hydrophobic release-modifying polymer" as described herein refers to any hydrophobic polymer which is capable of providing sustained release of quetiapine. The hydrophobic release-modifying polymer may be a pH-dependent

or a pH-independent pofymer or mixtures thereof. The hydrophobic refease-modifying polymer may be selected from polymethacrylates; phthalates like cellulose acetate phthalate, hydroxypropyl methyl cellulose phthalate, hydroxypropyi cellulose phthalate, polyvinyl acetate phthalate; hydroxypropyl methylcellulose acetate succinate, cellulose acetate, cellulose acetate butyrate, cellulose triacetate, polyethylene, polyvinylchloride, polyethylene vinyl acetate, polydimethyl siloxane, polyether urethane, zein, stearyl alcohol, and the like. Preferably, the hydrophobic release-modifying polymer may be selected from various pharmaceutically acceptable polymethacrylates sold under the brand name EUDRAGIT®. The hydrophobic release-modifying polymer and carrageenan may be added intragranularly or extragranularly or both.
The pharmaceutical compositions as described herein may comprise one or more pharmaceutically acceptable excipients selected from diluent, disintegrant, binder, buffering agent, glidant, lubricant, plasticizer, opacifying agent and anti-tacking agent.
Diluent may be selected from powdered cellulose, microcrystalline cellulose, starch, sugars such as lactose, sucrose, dextrose, dextrin, and the like; sugar alcohols such as mannitol, sorbitol or erythritol; calcium phosphate, calcium carbonate, calcium sulphate; and mixtures thereof. The diluent may be present in an amount ranging from 1 % to 90 % by weight of the composition.
Disintegrant may be selected from carboxymethylcellulose calcium, carboxymethylcellulose sodium, cross-linked carboxymethylcellulose sodium, cross-linked polyvinyl pyrrolidone, sodium starch glycolate, low-substituted hydroxypropyl cellulose, pregelatinized starch, sodium alginate; or mixtures thereof. The disintegrant may be present in an amount ranging from 1 % to 15 % by weight of the composition.
Buffering agent as described herein may be selected from organic acids and its salts, mineral acids, alkali metal phosphates, carbonates, hydroxides, oxides, base and the like; and mixtures thereof. Preferably, buffering agent is selected from benzoic acid, citric acid, tartaric acid, succinic acid, sodium carbonate,

sodium citrate, sodium or potassium hydroxide, dibasic sodium phosphate, disodium hydrogen ortho phosphate, and the like; or mixtures thereof. Preferably, the buffering agent is sodium citrate. The buffering agent may be present in an amount ranging from 0.1 % to 20 % by weight of the composition.
Lubricant or glidant may be selected from talc, metallic stearates such as magnesium stearate, calcium stearate, zinc stearate; colloidal silicon dioxide, finely divided silicon dioxide, stearic acid, hydrogenated vegetable oil, glyceryl palmitostearate, glyceryl monostearate, glyceryl behenate, sodium stearyl fumarate, magnesium trisilicate; or mixtures thereof. The lubricant or glidant may be present in an amount ranging from 0.1 % to 10 % by weight of the composition.
Plasticizer as described herein may be selected from propylene glycol, polyethylene glycol, triethyl citrate, acetyl triethyl citrate, diethyl phthalate, dibutyl phthalate, dibutyl sebacate; or mixtures thereof. Plasticizer is generally used in the coating to increase the flexibility and strength of the coat. The plasticizer may be present in an amount ranging from 0.1 % to 20 % by weight of the composition.
Anti-tacking agent as described herein may be selected from talc, finely divided silicon dioxide, glyceryl monostearate, and the like. The anti-tacking agent may be used in the coating to aid bulk build-up and form a smooth surface. The anti-tacking agent may be present in an amount ranging from 0.1 % to 20 % by weight of the composition.
Opacifying agent as described herein may be selected from titanium dioxide, iron oxides, and the like. The opacifying agent may be present in an amount ranging from 0.1 % to 10 % by weight of the composition.
The pharmaceutical compositions as described herein may be in the form of tablet, capsule, sachet, and the like. The compositions may be prepared by techniques such as wet granulation, dry granulation, drug layering, and the like. For example, quetiapine may be mixed with carrageenan and at least one

pharmaceutically acceptable excipient, and the mixture may be granulated with
water or an organic solvent in an apparatus, such as rapid mixer granulator or a
fluid bed processor to form granules. The organic solvent may be selected from
acetone, methanol, methylene chloride, isopropyl alcohol, and the like; or
mixtures thereof. The granules may optionally contain a hydrophobic release-
modifying polymer. Alternatively, the mixture of quetiapine, carrageenan and at
least one pharmaceutically acceptable excipient may be compacted in a roller
compacter and the compacts may be milled to obtain granules. The granules
may be coated with a solution or dispersion of the hydrophobic release-modifying
polymer and pharmaceutically acceptable excipients such as binder, plasticizer,
anti-tacking agent and opacifying agent. Alternatively, the granules devoid of any
coating may be compressed into a tablet which may further be coated with a
solution or dispersion of the hydrophobic release-modifying polymer or a film-
forming polymer and pharmaceutically acceptable excipients such as binder,
plasticizer, anti-tacking agent and opacifying agent. The film-forming polymer
may be selected from hydrophilic polymers like hydroxypropyl methylcellulose,
hydroxypropylcellulose, hydroxymethylcellulose, hydroxyethylcellulose,
methylcellulose, carboxyethylcellulose, sodium carboxymethylcellulose, polyvinylpyrrolidone, and the like; or mixtures thereof. Alternatively, the uncoated or coated granules may be filled in a capsule or a sachet.
In one embodiment, a sustained release tablet is prepared by: mixing quetiapine, carrageenan and at least one pharmaceutically acceptable excipient selected from diluent, disintegrant, buffering agent, or mixtures thereof;
granulating the mixture with a solvent; drying the granules;
mixing the granules with a lubricant or glidant; compressing the mixture into a tablet; and
optionally coating the tablet with a hydrophobic release-modifying polymer or a film-forming polymer.

In another embodiment, a sustained release tablet is prepared by: mixing quetiapine, carrageenan, a hydrophobic release-modifying polymer and at least one pharmaceutically acceptable excipient selected from diluent, disintegrant, buffering agent, or mixtures thereof; granulating the mixture with a solvent; drying the granules;
mixing the granules with a lubricant or glidant; and compressing the mixture into a tablet.
In further embodiment, a sustained release tablet is prepared by: mixing quetiapine, carrageenan and at least one pharmaceutically acceptable excipient selected from diluent, disintegrant, buffering agent, or mixtures thereof;
granulating the mixture with a solvent; drying the granules;
coating the granules with the hydrophobic release-modifying polymer; mixing the coated granules with a lubricant or glidant; and compressing the mixture into a tablet.
The pharmaceutical compositions as described herein may be illustrated by the following examples which are not to be construed as limiting the scope of the invention:
EXAMPLE 1

Ingredients Quantity
Quetiapine fumarate 10-60%
Lactose monohydrate 10-20%
Microcrystalline cellulose 10-20%
Sodium citrate 0-15%
Polyvinylpyrrolidone 4-10%
Carrageenan 10-25%
Methylene dichloride q.s.
Magnesium stearate 1-2%

PROCEDURE: Quetiapine fumarate, lactose, microcrystalline cellulose (Avicel PH 101), sodium citrate and carrageenan were mixed and granulated with a binder solution containing polyvinylpyrrolidone (PVP-K-30) in methylene dichloride. The granules were dried, lubricated with magnesium stearate and compressed into a tablet using appropriate tooling.
EXAMPLE 2

Ingredients Quantity (mg/tab)
Quetiapine fumarate 230.26
Lactose monohydrate 38.62
Microcrystalline cellulose 38.62
Sodium citrate 62.50
Polyvinylpyrrolidone 20.00
Carrageenan 100.00
Methylene dichloride q.s.
Magnesium stearate 10.00
PROCEDURE: Quetiapine fumarate, lactose, microcrystalline cellulose (Avicel PH 101), sodium citrate and carrageenan were mixed and granulated with a binder solution containing polyvinylpyrrolidone (PVP-K-30) in methylene dichloride. The granules were dried, lubricated with magnesium stearate and compressed into a tablet using appropriate tooling.

Table 1: Dissolution profile* of Example 2 in U5P Type I Apparatus (Basket) at 200 rpm, 37,0 ± 0.5 °C

Time (hr) % of drug dissolved
1 6.2
2 13
4 24.6
5 28.8
6 32.5
12 51.7
20 67.5
[*Dissolution Medium: 0- 5 hours: 900 ml of medium containing 0.05 M citric acid + 0.09 M sodium hydroxide to provide pH 4.7-4.9; 5-24 hours: addition of 100 ml of medium containing 0.05 M disodium phosphate + 0.46 M sodium hydroxide to provide the pH 6.4-6.8]
EXAMPLE 3

Ingredients Quantity (mg/tab)
Quetiapine fumarate 230.26
Methacrylic acid/methacrylate co-polymer 19.00
Lactose monohydrate 235.10
Carrageenan 49.74
Magnesium stearate 10.90
Acetone q.s.
PROCEDURE: Drug granules were prepared by granulating quetiapine fumarate with a binder solution containing methacrylic acid/methacrylate co-polymer (Eudragit L 100 55) in acetone. Base granules were prepared by granulating lactose monohydrate with a binder solution containing methacrylic acid/methacrylate co-polymer in acetone. The drug granules and the base granules were dried and mixed together. Carrageenan was mixed with mixture of

granules and lubricated with magnesium stearate and compressed into a tablet using appropriate tooling.