FORM2
THE PATENTS ACT, 1970
(39 of 1970)
&
The Patents Rules, 2003
COMPLETE SPECIFICATION
(See section 10; rule 13)
1. Title of the invention - EXTENDED RELEASE PHARMACEUTICAL COMPOSITIONS
OF QUETIAPINE OR SALTS THEREOF
2. Applicant(s)
(a) NAME: ALEMBIC LIMITED
(b) NATIONALITY : An Indian Company
(C) ADDRESS: Alembic Campus, Alembic Road,
Vadodara-390 003, Gujarat, India
i
3. PREAMBLE TO THE DESCRIPTION
The following specification particularly describes the invention and the manner in which it is to be performed

EXTENDED RELEASE PHARMACEUTICAL COMPOSITIONS OF QUETIAPINE OR
SALTS THEREOF
FILED OF THE INVENTION
The present invention relates to an extended release pharmaceutical composition of micronized quetiapine or pharmaceutically acceptable salts thereof. The invention further relates to process of preparation of such compositions.
BACKGROUND OF THE INVENTION
The compound, ll-[4-[2-(2-hydroxyethoxy) ethyl]-l-piperazinyl]-dibenzo[b,f] [1,4] thiazepine (Quetiapine) [I],
[I] and its pharmaceutical^ acceptable salts exhibit useful antidopaminergic activity and may be used, for example, as an antipsychotic agent (for example, for the management of the manifestations of psychotic disorders) or as a treatment for hyperactivity (Seroquel® XR marketed by AstraZeneca as 50 mg , 150 mg, mg, 200 mg, 300mg and 400 Tablets).
The preparation and physical properties of ll-[4-[2-(2-hydroxyethoxy)ethyl]-l-piperazinyl] dibenzo[b,f][l,4]-thiazepine, and its pharmaceutically acceptable salts are described in published European Patents EP 240,228 and 282,236 as well as in U.S. Pat. No 4,879,288.
Various mechanisms of providing sustained, extended, controlled or modified release compositions of soluble as well as less soluble drugs are known in the art.

One of such mechanism involves particularly the use of gelling agents as matrix forming agents and hence also as the release rate controlling agent.
The use of gelling agents is generically preferred with less soluble drugs, as high soluble drug tend to generate a sustained release product which is susceptible to a phenomenon known as dose dumping .i.e. release of the active ingredient is delayed for a time but once release begins to occur, the rate of release are very high. Such fluctuations in release rate may lead to toxicity and therefore it has been difficult to provide such formulations with gelling agents having desired dissolution and pharmacokinetic profile.
Prior art also discloses extended release formulations of quetiapine or pharmaceutically acceptable salts thereof.
US 5,948,437 discloses a sustained release formulation comprising quetiapine and a matrices with a gelling agent, preferably hydroxypropylmethylcellulose (HPMC).
US 20070244093 disclose a sustained release formulation comprising quetiapine and a wax material.
WO 2007110878 discloses sustained release formulation of poorly soluble active agents with solubilizer and combination of acid soluble and pH dependent polymer.
WO 2008090569 relates to the modified release formulation of quetiapine, which comprises use of pH dependant rate controlling polymer and 2) release rate modifying system comprising gelling agent and gelling facilitating agent.
WO 2007086079 discloses once a day sustained release matrix tablets comprising phenothiazine derivative, a channelizer, a rate-controlling agent and suitable pharmaceutical excipients.
US 20080287418 disclose an extended release formulation of quetiapine together with HPMC of different viscosities.

US 200900099151 disclose modified release formulations of active agent with at least two swellable pH independent polymers, wherein at least one is hydrophilic.
US 20090220593 discloses a multiple unit extended release dosage forms of quetiapine for oral administration, wherein each unit comprises a core containing quetiapine and one or more of pharmaceutically acceptable excipients coated with a rate-controlling coating and process for the preparation thereof.
US 20090264408 discloses an extended release dosage form of quetiapine wherein the dosage form comprises quetiapine and rate-controlling polymer selected from polyethylene oxide, sodium alginate and natural gum and combinations thereof.
US 20090110728 disclose solid dosage form comprises a matrix core containing the pharmaceutical agent and a hydrophobic material, and a coating containing a hydrophilic pore-forming agent and a hydrophobic polymer.
Though several attempts have been made for the development of extended release formulations of quetiapine, the problems associated with said dosage forms like dose dumping, initial burst release, undesired release profile and more over physical instability still remains unsolved. In particular, there has been difficulty in achieving the consistency in desired dissolution and drug release rates.
Hence a need exists to develop an extended release formulation of quetiapine which overcome, or atleast alleviate, one or more of the above described difficulties while achieving the desired dissolution and pharmacokinetic profile.
Therefore, the principal object of the present invention is to provide an extended release composition of quetiapine or a pharmaceutically acceptable salt thereof ,which overcomes, or at least alleviate, one or more of the difficulties of prior art while achieving the desired dissolution and pharmacokinetic profile.

Another object of the present invention is to provide an extended release pharmaceutical composition of quetiapine or a pharmaceutically acceptable salt thereof, which maintains the required integrity to ensure consistency in dissolution and release of drug so as to achieve the desired dissolution and pharmacokinetic profile.
Another object of the present invention is to provide an extended release pharmaceutical composition of quetiapine or a pharmaceutically acceptable salt thereof, which is stable, has reduced side effects, easier to manufacture and involves a low formulation cost.
SUMMARY OF THE INVENTION
In one aspect, the present invention relates to an extended release pharmaceutical composition comprising; micronized quetiapine or pharmaceutically acceptable salts thereof along with one or more pharmaceutically acceptable release rate controlling agents.
Micronized quetiapine as used herein refers to quetiapine or salts thereof having D90 less than 50um or less.
In another aspect of the invention, there is provided a process for preparation of an extended release pharmaceutical composition, which process comprises the steps of; i) mixing micronized quetiapine or pharmaceutically acceptable salts thereof with one or more of pharmaceutically acceptable release rate controlling agents, optionally with wax and other pharmaceutically acceptable excipients; and ii) formulating the mixture of step (i) into suitable dosage form.
BRIEF DESCRIPTION OF THE DRAWINGS:
Fig 1 is a graph showing dissolution profile comparison of Innovator product (Seroquel® XR 200mg) and test, in-house product (Quetiapine Extended release tablets 200mg) in pH 0.01 N HCL solution (Apparatus II at speed of 50 rpm)
r

Fig 2 is a graph showing dissolution profile comparison of Innovator product (Seroquel XR 200mg) and test, in-house product (Quetiapine Extended Release Tablets 200mg) in 4.5 Acetate Buffer solutions (Apparatus II at speed of 50 rpm)
Fig 3 is a graph showing dissolution profile comparison of Innovator product (Seroquel XR 200mg) and test, in-house product (Quetiapine Extended Release Tablets 200mg) in 6.8 Phosphate Buffer solutions (Apparatus II at speed of 50 rpm)
DETAIL DESCRIPTION OF THE INVENTION
The present invention relates to an extended release pharmaceutical composition of quetiapine or a pharmaceutically acceptable salt thereof and to a process for preparation thereof.
The term "extended release" for the purposes of this invention refers to release of an active pharmaceutical agent over a prolonged period of time. The term 'extended release' as herein used includes sustained release, modified release, delayed release and controlled release.
The term 'pharmaceutically acceptable salt' includes but is not limited to salts such as chloride, maleate, fumarate, citrate, phosphate, methane sulphonate, sulphate and the like. Preferred salts include fumarates.
Micronization is the process of reducing the average diameter of a solid material's particles. For the said purpose, any of conventional methods, including but not limited to, such as milling, grinding, crushing, cutting or modern techniques such as RESS process (Rapid Expansion of Supercritical Solutions), the SAS method (Supercritical Anti-Solvent) and the PGSS method (Particles from Gas Saturated Solutions) can be employed.
A release rate controlling agents may comprises pharmaceutically acceptable hydrophobic or hydrophilic polymers or a mixture thereof which may include, but not limit to, acrylic polymers such as acrylic acid and methacrylic acid copolymers, methyl methacrylate copolymers, ethoxyethyl methacrylates, cyanoethyl methacrylate, poly(acrylic acid), poly(methacrylic acid), methacrylic acid alkylamide copolymer, poly(methyl methacrylate), polymethacrylate,

poly(methyl methacrylate) copolymer, polyacrylamide, aminoalkyl methacrylate copolymer, poly(methacrylic acid anhydride), glycidyl methacrylate copolymers, hydroxypropyl methyl cellulose, methyl cellulose, hydroxypropyl cellulose, sodium carboxymethyl cellulose, ethylcellulose, hydroxypropylcellulose/ethylcellulose mixture, macrogol, polyvinylpyrrolidone, polyvinyl alcohol, polysaccharide gums which are natural and modified (semi-synthetic) or synthetic or their combinations, such as xanthan gum, veegum, agar, guar gum, locust bean gum, gum arabic, okra gum, bentonite, arabinoglactin, pectin, tragacanth, scleroglucan, dextran, amylose, amylopectin, dextrin, alginic acid, alginic acid derivatives or mixture thereof.
A wax or a wax-like material is generally selected from netural or synthetic waxes which includes, but not limited to Glyceryl behenate, carnauba wax, beeswax, glycowax, castor wax, cetyl esters wax, cationic emulsifying wax, cetrimide emulsifying wax, an emulsifying wax, microcrystalline wax, a nonionic wax, a nonionic emulsifying wax, paraffin, petroleum wax, petroleum ceresin wax, spermaceti wax, white wax, or yellow wax, or mixture thereof.
In preferred embodiment, the present invention provides an extended release pharmaceutical composition comprising; micronized quetiapine or pharmaceutically acceptable salts thereof along with one or more pharmaceutically acceptable release rate controlling agents.
Micronized quetiapine as used herein refers to quetiapine or pharmaceutically acceptable salts thereof having a D90 particle size of 50um or less.
The dosage form of the invention comprises one or more of tablet, capsule, tablet in tablet, tablet in capsule, pellet, granules, powder, pellets in capsule, granules in capsule, spheroids, beads, pill and like other dosage forms suitable for administration.
For example, a tablet may contain, in addition to micronized quetiapine or pharmaceutically acceptable salts and release rate controlling polymers, a wax material and one or more other suitable excipients selected from the group comprising of diluents/fillers, lubricants, binders, disintegrants, glidants and like.

The term "fillers" used herein means the fillers which are used for ordinary pharmaceutical production, and includes excipients which facilitate the flow and compression of powdery materials and give the solid dosage forms strength.
The following are non-limiting examples of suitable fillers for use in present invention: microcrystalline cellulose, sodium citrate, dicalcium phosphate, colloidal silicon dioxide, starches, lactose, sucrose, glucose, mannitol, and silicic acid, alginates, gelatin, polyvinylpyrrolidinone, lactitol, dextrose, acacia, hypromellose, hydroxypropyl cellulose, hydroxyethyl cellulose, starch, and pregelatinized starch, with microcrystalline cellulose, such as PROSOLV.TM.
Binders include, but are not limited to, carbohydrates like starches such as potato starch, wheat starch, corn starch; liquid glucose, dextrin; celluloses such as hydroxypropyl celluloses and modified celluloses like hydroxyethyl cellulose, hydroxypropylmethyl cellulose, ethyl cellulose, sodium carboxy methyl cellulose; microcrystalline cellulose such as products known under the registered trade marks Avicel, Filtrak, Heweten or Pharmacel; natural gums like acacia, alginic acid, guar gum; povidone, syrup, polyethylene oxide, gelatin, amino acid derivatives and mixtures thereof.
The term "lubricant" as used herein includes excipients that reduce friction, heat and wear when applied as a surface coating to moving parts within the equipment used to make the matrices, such as dies and punches. Suitable lubricants include, either individually or in combination, a glyceride (e.g., glyceryl behenate (e.g., Compritol.TM. 888 ATO), glyceryl trimyristate, glyceryl trilaurate, glyceryl tristearate glyceryl monostearate, glyceryl palmitostearate, glyceryl triacetate); stearic acid and salts thereof, including magnesium, calcium, aluminum, zinc, and sodium stearates; hydrogenated vegetable oils (e.g., Sterotex.TM); colloidal silica; talc; waxes; boric acid; sodium benzoate; sodium acetate; sodium fumarate; DL-leucine; polyethylene glycol (e.g., Carbowax.TM. 4000 and Carbowax.TM. 6000); sodium oleate; sodium lauryl sulfate; and magnesium lauryl sulfate. The lubricant is more preferably selected from the group consisting of stearic acid salts such as calcium stearate and magnesium stearate, stearic acid, sodium stearyl fumarate, solid polyethylene glycols, sodium lauryl sulfate, and mixtures thereof. Magnesium stearate is a particularly preferred lubricant.

Glidants include, but are not limited to talc, starches, anhydrous colloidal silica, magnesium trisilicate and like.
The above listed excipients should be taken as merely exemplary and not limiting of the types of excipients that can be included in the formulations of the present invention. Also it has to be appreciated that there is considerable overlap between the above listed excipients in common usage since a given excipient is commonly used for any of several apparent functions. The amount of each excipient employed may vary within the ranges well known to those skilled in the art.
The composition of present invention may be prepared by conventional techniques well known to those skilled in the art such as wet granulation, direct compression, dry compaction (slugging) and like other as is suitable.
Micronized quetiapine or pharmaceutically acceptable salts thereof can be mixed with pharmaceutically acceptable excipients and can be granulated with aqueous solution/suspension of release rate controlling agents. Granules can be dried. Dried granules can be further mixed with other pharmaceutically acceptable excipients and formulated into suitable dosage forms.
The invention may be further illustrated by the following non-limiting example of 200 mg quetiapine fumarate extended release tablet.

Example Table: 1 ( 1:
'Quetiapine XR Tablets 200 mg)
S.No. Ingredients nig/Tab %w/w
Core
1 Quetiapine fumarate 230.27 57.57
2 Sodium Citrate 50.00 12.50
3 Polymethacrylates 30 7.50
4 Purified water
5 Lactose 40 10.00
6 Dibasic calcium phosphate 5.73 1.43
7 Glyceryl behenate 40 10.00
8 Magnesium stearate 4 01.00
Core weight 400.00 100
Procedure: Quetiapine fumarate, sodium citrate is mixed and granulated with polymethacrylates. Granules are dried and mixed with Lactose, DCP, Glyceryl behenate and then with magnesium stearate to form final blend. The resultant blend is compressed to form tablets. Tablets are optionally coated with film coats such as Opadry.
The extended release properties of the formulation of the present invention may be demonstrated by monitoring the dissolution of the active ingredient. The dissolution of the active ingredient may be monitored using standard procedures well known to those skilled in the art (e.g. the dissolution test procedures, such as the Rotating Basket Method (Apparatus I) or Paddle Method (Apparatus II), disclosed in the U.S. Pharmacopeia (USP). Such procedures include those in which the formulation is immersed in an aqueous medium such as water or hydrochloric acid and aliquots of the medium are withdrawn at various time points over a period of 24 hours. The aliquots are analyzed using high pressure liquid chromatography (HPLC) with UV detection to determine the concentration of dissolved active ingredient using standard methodology.
Dissolution profile is determined by using Apparatus II method at three different mediums particularly at I. 0.01 N HCL / 900ml, II. 4.5 Acetate Buffer / 900ml, III. 6.8 Phosphate Buffer/900 ml mediums, all at 50 rpm speed.
Dissolution Studies Data:
I. 0.01 N HCL / 900ml / USP II / 50 RPM

Following is the dissolution data obtained for example 1 in pH 0.01 N HCL Table: 2

Time Points (Hrs) %Re eased

Innovator (Seroqucl® XR) Test (Example I)
0 0 0
1 7 6
2 13 13
3 20 21
4 28 29
6 43 52
8 59 76
10 74 91
12 86 97
16 99 98
II. 4.5 Acetate Buffer / 900ml / USP II / 50 RPM
Following is the dissolution data obtained for example 1 in pH 4,5 Acetate Buffer Table: 3

Time Points (Hrs) %Re eased

Innovator (Seroquel® XR) Test (Example I)
0 0 0
1 6 7
2 13 10
4 29 22
6 46 41
8 63 69
10 75 85
12 86 90
16 96 96
20 100 98
24 101 98
III. 6.8 Phosphate Buffer / 900ml / USP II / 50 RPM
Following is the dissolution data obtained for example 1 in pH 6.8 Acetate Buffer

Table: 4
Time % Re eased
Points Innovator Test (Example I)
(Hrs) (Seroquel® XR)
0 0 0
1 2 4
2 4J> 6
4 11 13
6 19 21
8 28 32
10 36 42
12 45 50
16 62 61
20 1 73 1 70
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.

We claim:
1) An extended release pharmaceutical composition comprising micronized quetiapine or
pharmaceutically acceptable salts thereof along with one or more pharmaceutically acceptable
release rate controlling agents.
2) The composition of claim 1, wherein said micronized quetiapine has a D90 particle size of 50um or less.
3) The composition of claim 1, wherein said one or more pharmaceutically acceptable release rate controlling agents comprises one or more hydrophobic or hydrophilic polymers.
4) The composition of claim 3, wherein said hydrophobic polymers comprises acrylic acid and methacrylic acid copolymers, methyl methacrylate copolymers, ethoxyethyl methacrylates, cyanoethyl methacrylate, poly(acrylic acid), poly(methacrylic acid), methacrylic acid alkylamide copolymer, poly(methyl methacrylate), polymethacrylate, poly (methyl methacrylate) copolymer, polyacrylamide, aminoalkyl methacrylate copolymer, poly(methacrylic acid anhydride), glycidyl methacrylate copolymers or mixtures thereof.
5) The composition of claim 3, wherein said hydrophilic polymers comprises hydroxypropyl methyl cellulose, methyl cellulose, hydroxypropyl cellulose, sodium carboxymethyl cellulose, ethylcellulose, polyethylene glycol, polyvinylpyrrolidone, polyvinyl alcohol, polysaccharide gums such as xanthan gum, veegum, agar, guar gum, locust bean gum, gum arabic, okra gum, bentonite, arabinoglactin, pectin, tragacanth, scleroglucan, dextran, amylose, amylopectin, dextrin, alginic acid, alginic acid derivatives or mixtures thereof.
6) The composition of claim 1, which further comprises one or more of Glyceryl behenate, carnauba wax, beeswax, glycowax, castor wax, cetyl esters wax, cationic emulsifying wax, cetrimide emulsifying wax, an emulsifying wax, microcrystalline wax, a nonionic wax, a nonionic emulsifying wax, paraffin, petroleum wax, petroleum ceresin wax, spermaceti wax, white wax and yellow wax.

7) A process of preparation of an extended release pharmaceutical composition, which process comprises the steps of; i) mixing micronized quetiapine or pharmaceutically acceptable salts thereof with one or more pharmaceutically acceptable release rate controlling agents, optionally with wax and other pharmaceutically acceptable excipients; and ii) formulating the mixture of step (i) into suitable dosage form.
8) The composition of claim 1, wherein said composition comprises one or more of a tablet, mini tablet, capsule, tablet in tablet, tablet in capsule, pellet, granule, powder, pellets in capsule, granules in capsule, spheroids, beads and pill.