FORM 2
THE PATENTS ACT. 1970
(39 OF 1970)
&
THE PATENTS RULES, 2003
PROVISIONAL SPECIFICATION * (See section 10; rule 13)


SUSTAINED RELEASE ORAL COMPOSITION OF AN ANTIPSYCHOTIC AGENT
GENEPHARMS.A GENEPHARM INDIA PRIVATE LIMITED
A company incorporated under the laws of India having their office at
Regd. Off.: IB, Old Post Street, Kolkata-700001
The following specification describes the nature of this invention


A SUSTA1 NED RELEASE ORAL COMPOSITION OF AN ANTIPSYCHOTIC AGENT
The present invention relates to a sustained release oral pharmaceutical composition of an antipsychotic agent, -[2-(4-dibenzo (b,f}[l,4-thiazepin-l lyl -l-piperazinyl)ethoxy ethanol] or quetiapine (INN name) and its pharmaceutically acceptable salt. Antipsychotic agents are normarlly used to treat psychotropic disorders and other mental / emotional conditions including schizophrenia and acute manic episodes associated with bipolar 1 disorder.
Background of the invention
United Slates Patent No.4879288 (assigned to M/S 1CI, referred to herein as '288 patent) discloses compound ll-[4-[2-(2-hydroxyethoxy) ethyl]-l-piperazinyl}dibenzo [b,f][l,4]thiazepine as a novel antipsychotic c rug of the dibenzothiazepine class suitable for various psychotropic disorders and having le s side effects. The '288 patent exemplifies immediate release tablets of ll-[4-[2-(2-hydroxycihoxy) ethyl]-l-piperazinyl}dibenzo [b,f][l.4]thiazepine comprising lactose, pregelatinized starch. m.;ize starch, stearic acid, polyvinylpyrrolidone and magnesium stearate.
A sustained release oral dosage form of the phenothiazines derivatives is a desired approach in the treatment of psychotropic disorders. The sustained release formulation
(a) avoids frequent administration of the drug while maintaining uniform and constant release rate of the active pharmaceutical ingredient over an extended period of time and
(b) maintains effective plasma drug concentration and controlled release rate of medicament after a solid oral drug administration.
PCT Publication No.9745124 (assigned to M/s Zeneca) discloses a sustained release formulation comprising a galling agent and quetiapine or a pharmaceutically acceptable salt thereof, together with one or more pharmaceutically acceptable excipients. The gelling agent is hydroxypropvl methyl cellulose ..nd p.iarmaceutically acceptable excipient is selected from the group consisting of macrocrystalline cellulose, lactose, magnesium stearate, sodium citrate and povidone. Alternate formulations with non-gelling agents may provide sustained release at a steady rate.

PCT Publication No.0121179 (applicant M/s Astra Zeneca) discloses a granule formulation comprising quetiapine or a pharmaceutically acceptable salt thereof and a freely or very water-soluble biider. The granules are prepared by using fluid bed technology. The granules are dissolved or suspended in an aqueous medium and then administered to patients with central nervous system disorders.
PCT Publication No.20030395 16 (applicant M/s Piijisawa Phamaccuticla Co. Ltd.) discloses a method for improving dissolution of a poorly dispersible medicament like quetiapine. which comprises mixing the poorly dispersible active ingredient with a floating agent and/or a surfactant and granulating the mixture.
PCT Publication No.2005041935 (applicant M/S Alpharma) discloses a sustained release solid dosage fo. mulation comprising a matrix, wherein the matrix comprises a therapeutically effective amount of quetiapine or a pharmaceutically acceptable salt thereof, and a wax material. These formulations rray not provide sustained release at a steady rate and also incomplete drug release due to hydrophobic nature of wax.
We have now surprisingly found that by using lambda carrageenan in the dosage form with the active pharmaceutical ingredient, quetiapine or its pharmaceutically acceptable salt, provides a sustained release dissolution profile of quetiapine.
Object of the invention
The object of the present invention is to provide sustained release oral composition of an antipsychotic agent. 2-[2-(4-dibenzo {b.i"}[1.4-thiazepin-l lyl -l-piperazinyt)ethoxy ethanol] or its pharmaceutically acceptable salt with the use of lambda carrageenan.

Summary of the Invention
A sustained release oral composition of an antipsychotic agent comprising antipsychotic agent, -carrageenan and one or more pharmaceutically acceptable excipients; wherein the antipsychotic agent is 2-[2-(4-dibenzo {b,f}[l,4-thiazepin-l lyl -l-piperazinyl)ethoxy ethanol] or its pharmaceutically acceptable salt.
A process for the preparation of a sustained release oral composition of an antipsychotic agent comprising
(i) mixing 2-[2-(4-dibenzo {b,f}[l,4-thiazepin-l lyl -l-piperazinyl)ethoxy ethanol] or its pharmaceutically acceptable salt with .-carrageenan and one or more pharmaceutically acceptable excipients; (ii) compacting or granulating the mixture of (i) followed by milling; (iii) drying and optionally compressing; wherein the antipsychotic agent is 2-[2-(4-dibenzo {b,f}[ 1,4-thiazepin-1 lyl -l-piperazinyl)ethoxy ethanol] or its pharmaceutically acceptable salt.
Detailed Description of the Invention
According to one embodiment of the present invention is a sustained release oral composition of 2-[2-(4-dibcnzo{b,f}[l,4-thiazepin-I lyl -l-piperazinyl)ethoxy ethanol] or its pharmaceutically acceptabk- salt with lambda carrageenan and one or more pharmaceutically acceptable excipients.
The use of lambda - carrageenan reportedly provides distinct advantages such as
(a) zero order or steady release of2-[2-(4-dibenzo{b,f}[l,4-thiazepin-I lyl -l-piperazinyl)ethoxy ethanol]
(b) provides a steady release of 2-[2-(4-dibenzo {b,f}[1,4-thiazepin-l lyl -l-piperazinyl)ethox\ ethanol] in most organic solvents as lambda carrageenan is insoluble in them.
(c) As it is pH independent it provides a constant rate of release in the GIT.

The USPNF 23 describes carrageenan as hydrocolloid obtained by extraction with water or aqueous alkali from some members of the class Rhodophyceae(red seaweed). It consists chiefly of potassium. sodium, calcium magnesium and ammonium sulfate esters of galactose and 3,6- anhydrogalactose copolymers. These hexoses are alternatively linked at the a-1,3 and p-1,4 sites in the polymer.
The carrageenans are divided into three families according to the position of sulfate groups and the presence of anhydrogalactose.
X-Carragcenan (lambda - carrageenan) is a nongelling polymer containing about 35% ester sulfate by weight and no 3,6 anhydrogalactose.
i-Carrageenan (iota - carrageenan) is a gelling polymer containing about 32% ester sulfate by weight and approximately 30% 3,6 anhydrogalactose.
K-Carragi-onan (kappa - carrageenan) is a strongly gelling polymer which has a helical tertiary structure that allows geeling. It contains 25% ester sulfate by weight and approximately 34% 3:6 anhydrogalactose.
Among the three carrageenans we have found that the lambda (X-) carrageenan is the only nongelling polymer.
X-Carrageenan when formulated with 2-[2-(4-dibenzo{b,f}[l,4-thiazepin-l lyl -l-piperazinyl)ethoxv ethanol] or its pharmaceutically acceptable salt and optionally other pharmaceutical excipient(s) provides sustained or extended release of 2-[2-(4-dibenzo{b,f}[l,4-thiazepin-l lyl -1-piperazinyl)ethoxy ethanol].
The weight ratio of 2-[2-(4-dibenzo{b,f}[l,4-thiazepin-l lyl -l-piperazinyl)ethoxy ethanol] or its pharmaceutically acceptable salt to X-carrageenan may range from 1:0.1 to 1:10.
The sustained release oral composition of the present invention comprises one or more pharmaceutical excipient(s). The pharmaceutical excipient used in the oral composition of the

present invention must be compatible with 2-[2-(4-dibenzo{b,f}[l,4-thiazepin-l lyl -I-piperazinyl)ethoxy ethanol] or its pharmaceutically acceptable salt. The pharmaceutical excipient may be selected from diluents, binders lubricants, disintegrants, flavoring agents, coloring agents, stabilizers, surfactants, glidants, plasticizers, preservatives and sweeteners.
Diluents -nay be selected from calcium carbonate, calcium phosphate dibasic, calcium phosphate tribasic, calcium sulfate, microcrvstalline cellulose, microcrvstalline sificified cellulose, powdered cellulose, dextrates, dextrose, fructose, Inclilol, lactose anhydrous, lactose monohydratc.laciosc dihydraic. lactose trihydrate, mannitM, sorbitol, starch, pregelatinized starch sucrose, talc, xylitol. maltose maltodextrin, maltitol.
Binders may be selected from acacia, alginic acid, carbomer.carboxymethylcellulose calcium, carbomeihylceliulose sodium,microcryslalline cellulose,povvdered cellulose, ethyl cellulose, gelatin liquid glucose, guar gum, hydroxyethyl cellulose, hydroxypropyl cellulose, hydroxypropylmethyl cellulose. inaltodextrin,methylcellulose,ploydextrose; polyethtylene oxide, povidone, sodium alginate, starch paste, pregelatinized starch, sucrose, tragacanth, low-substituted hydroxypropyl cellulose.glucose, sorbitol. Suitable fillers are preferably selected from atleast one of starch derivative s.such as com starch, potato starch or rice starch. Polysaccharides such as dextrins. mallodcx rins, dextrates, microcrystalline cellulose, powdered cellulose, mixture of microcrvstalline cellulose and ;uiar gum, coprocessed blends of microcrystalline cellulose; and polyhydric alcohols, such as xylitol and sorbitol.
Disintegrants may be selected from alginic acid, carbon dioxide, carboxymethylcellulose calcium carboxymethylcellulose sodium, microcrystalline cellulose, powdered cellulose, croscarmelose sodium, crospovidone, sodium docusate, gaurgum, hydroxypropyl cellulose, methylcellulose, polacrilin potassium , poloxamer, povidone, sodium alginate, sodium glycine carbonate, sodium laulyl sulfate, sodium starch glycolate, starch, pregelatinized starch, low-substituted hydroxypropyl cellulose.
Glidants may be selected from calcium silicate, powdered cellulose, starch, talc, colloidal silicon dioxide.

Lubricants may be selected from magnesium stearate, stearic acid, sodium stearyl fumarate, magnesium iauryl sulphate, talc, polyethylene glycol, and glyceryl behenate.
Suitable sweeteners may be selected from sugars such as sucrose, lactose and glucose; cyclamate and salts thereof; saccharin and salts thereof; and aspartame.
Flavouring agents may be selected from natural or synthetic flavours such as strawberry flavour, wild cherry flavour, green apple flavour, spearmint flavour and peppermint flavour.
According to another embodiment of the present invention is provided a sustained release oral composition of 2-[2-(4-dibenzo{b,f}[l,4-thiazepin-l lyl -l-piperazinyl)ethoxy ethanol] or its pharmaceutical^ acceptable salt with lambda carrageenan and one or more pharmaceutically acceptable excipients wherein the dissolution profile of the oral composition releases 10 to 40% in 2 hrs and greater than 60% in more than 12 hrs of 2-[2~(4-dibenzo {b,f} [ 1,4-thiazepin-11 y 1 -1 -piperazinyl)ethoxy ethanol].
In yet another embodiment of the present invention is the process for the preparation of sustained release oral composition of 2-[2-(4-dibenzo{b,f}[l,4-thiazepin-Uyl -i-pjperazinyl)ethoxy ethanol] or its pharmaceutically acceptable salt comprising 2-[2-(4-dibenzo{b,f}[l,4-thiazepin-l lyl -piperazinyl)ethoxy ethanol] or its pharmaceutically acceptable salt, lambda carrageenan and one or more pharmaceutical excipient(s). 2-[2-(4-dibenzo{b,f}[l,4-thiazepin-l lyl -piperazinyl)ethoxy ethanol], lambda carrageenan and one or more pharmaceutical excipient(s) are mixed, compacted or granulated, milled, dried and optionally compressed.
The dosage form of the present invention may be prepared using conventional techniques employed in the art for mixing, compaction, granulation, milling, drying and compressing.
The oral composition may be selected from sprinkle granules or powder for reconstitution in a suspension, tablet, soluble tablet, rapidly disintegrating tablet, orally disintegrating tablet, rapidly disintegrating film, orally disintegrating powder for capsules, suspension or sachets, effervescent

tablet, a chewable tablet, water dispersible tablet, orodispersible tablet, a chewing gum and suspension.
The oral composition of the present invention was subjected to dissolution method (0. IN hydrochloric acid 750 ml, paddle 50 rpm. After 2 hrs addition of 250 ml of phosphate buffer to obtain pH 6.2)
The following examples illustrate preferred embodiments in accordance with the present invention without limiting the scope of the invention.
* EXAMPLES

Examples 1 2 3 4 5 6 7
Ingredients mg/tab mg/tab mg/lab mg/tab mg/tab mg/tab mg/tab
Queliapine Uemifumarate 230.5 230.5 230.5 230.5 230.5 230.5 230.5
st:;rn 209 (Lambda-ageciian) 250 250 250 250 200 200 150
.Vlicnicrystalline cellulose 64.5 — 64.5 113.5 113.5 99 99
Lactose SD — 64.5 --- — — ... ...
Glyceryl behenate — — — — — — 50
Povidone K30 — — ... — — 15 15
Mg S tea rate 5 5 5 6 6 5.5 5.5

Total weight 550 550 550 600 550 550 550


Process for the preparation of iinui .iles before compression into
-iiiili'tS Compaction and siting through 24
mesh Compaction and sizing through 24 mesh Wet
granulation with purified
water Wet
granulation with purified water Wet
granulation with purified water Wet
granulation with PVP binder solution Wet
granulation with PVP binder solution

Example 8 Dissolution profile of oral composition of the present invention

Dissolution profile Example 3 Example 4 Example 5 Example 6
TIME(h) 50rpm 50rpm 50rpm 50rpm lOOrpm 100 rpm
i 10.6 9.2 14.0 14.5 17.4 15.3
i 19.4 17.4 26.5 27.6 31.3 27.1
4 31.2 30.8 39.0 39.8 47.5 42.1
6 41.2 41.7 49.0 48.6 60.4 54.9
8 50.6 51.1 56.7 56.7 71.4 66.0
12 67.3 65.4 69.9 70.6 89.9 84.1
16 78.2 77.0 80.7 80.6 99.4 94.0
Example 9 Dissolution profile of innovator's tablets

T[(VIE(lirs) SEROQUEL
200mgNN0049
(CANADA) SEROQUEL 200mg FL076 (GREECE)
50rpm 50rpm lOOrpm
1 18.7 17.8 21.7
2 33.0 30.8 38.0
4 39.8 38.7 49.2
6 46.5 43.5 56.5
8 53.9 49.3 65.3
12 66.8 60.9 79.9
16 82.0 70.3 89.9

We herewith summarize the present invention
A. A sustained release oral composition of an antipsychotic agent comprising antipsychotic
agent, A-carrageenan and one or more pharmaceutically acceptable excipients; wherein the
antipsychotic agent is 2-[2-(4-dibenzo {b,f}[ 1.4-thiazepin-1 lyl -l-piperazinyl)ethoxy
ethanol] or its pharmaceutically acceptable salt.
B. A sustained release oral composition as summarized in A wherein the oral composition is
selected from sprinkle granules or powder for reconstitution in a suspension, tablet, soluble
tablet, rapidly disintegrating tablet, orally disintegrating tablet, rapidly disintegrating film,
orally disintegrating powder for capsules, suspension or sachets, effervescent tablet, a
chewable tablet, water dispersible tablet, orodispersibie tablet, a chewing gum and
suspension.
C. A sustained release oral composition as summarized in A wherein the pharmaceutical
excipient is selected from diluents, binders, lubricants, disintegrants, flavoring agents.
coloring agents, stabilizers, surfactants, glidants, plasticizers, preservatives and sweeteners.
D. A sustained release oral composition as summarized in A wherein the pharmaceutical
excipient is selected from lactose, povidone, glyceryl behenate, microcrystalline cellulose
and magnesium stearate.
E. A sustained release oral composition as summarized in A wherein the ratio of 2-[2-(4-
dibenzo {b,f}[l,4-thiazepin-l lyl -l-piperazinyl)ethoxy ethanol] or its pharmaceutically
acceptable salt to X-carrageenan is I: 0.1 to 1: 10.
F. A sustained release oral composition as summarized in B further comprising a coating.
G. A sustained release oral composition as summarized in A wherein the dissolution profile of
the oral composition releases 10 to 40% in 2 hrsand greater than 60% in more than 12 hrs of
2-[2-(4-dibeazo {b,f}[l,4-thiaxepin-l lyl -t-piperazmyl)ethoxy ethanol].

H. A process for the preparation of a sustained release oral composition of an antipsychotic agent comprising
(iv) mixing 2-[2-(4-dibenzo {b,f}[l,4-thiazepin-llyl -1-piperazinyl)ethoxy ethanol] or its pharmaceutically acceptable salt with X-carrageenan and one or more pharmaceutical! y acceptable excipients; (v) compacting or granulating the mixture of (i) followed by milling; (vi) drying and optionally compressing; wherein the antipsychotic agent is 2-[2-(4-dibenzo {b,f}[l,4-thiazepin-l lyl -1-piperazinyl)ethoxy ethanol] or its pharmaceutically acceptable salt.
Dated this 23rd day of March 2009.