F0RM 2
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 FORMULATION OF
QUETIAPINE


2. Applicant(s)
(a) NAME :
(b) NATIONALITY:
(c) ADDRESS :
ALEMBIC LIMITED
An Indian Company.
Alembic Campus, Alembic Road, Vadodara - 390 003, Gujarat, India.
3. PREAMBLE TO THE DESCRIPTION

The following specification particularly describes the invention and the manner in which it is to be performed:


FIELD OF THE INVENTION
The present invention relates to an extended release formulation comprising 11-[4-[2-(2-hydroxyethoxy) ethyl]-1 -piperazinyl] dibenzo [b,f] [ 1,4]thiazepine or a pharmaceuticaliy acceptable salt thereof.
BACKGROUND OF THE INVENTION
The compound, ll-[4-[2-(2-hydroxyethoxy)ethyl]-l-piperazinyl]-dibenzo[b,f] [1,4] thiazepine (Quetiapine)fl]

[i]
and its pharmaceuticaliy 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).
The preparation and physical properties of ll-[4-[2-(2-hydroxyethoxy)ethyl]-l-piperazinyl] dibenzofb^l^J-thiazepine, and its pharmaceuticaliy 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.
Several attempts to provide dosage forms for delivery of active agents for extended periods of time have been described previously. However, there still exists a need to
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develop an extended release formulation particularly comprising drugs having pH dependent solubility with reduced side effects which can provide sustained delivery of active agent, that are easier to manufacture, and involves a low formulation cost.
W09745124 discloses a sustained release formulation comprising quetiapine and a gelling agent preferably hydroxypropylmethylcellulose.
WO 2005041935 provides for a sustained release formulation comprising quetiapine and a wax material.
WO2008/090569 relates to the modified release formulation of quetiapine, which hinges upon 1) use of pH dependant rate controlling polymer and 2) release rate modifying system.
WO03039516 discloses a method for improving dissolution of a poorly dispersible medicament like quetiapine, which comprises mixing the poorly dispersible medicament with a floating agent and/or a surfactant and granulating the mixture.
However, formulating the drugs having pH dependent solubility such as quetiapine into an extended release dosage form presents a number of problems. While these drugs have relatively good solubility at gastric pH, they have a relatively poor solubility at intestinal pH. The present invention provides an extended release composition formulation comprising quetiapine to address these problems
SUMMARY OF THE INVENTION
The present invention relates to an extended release formulation of quetiapine or a pharmaceutically acceptable salt thereof.
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In one aspect, the invention relates to an extended release formulation comprising quetiapine or a pharmaceutically acceptable salt thereof and a controlled release matrix comprising a mixture of hydrophilic polymers.
In another aspect, the invention relates to a process for preparing an extended release formulation comprising quetiapine or a pharmaceutically acceptable salt thereof and a controlled release matrix comprising a mixture of hydrophilic polymers.
DETAILED DESCRIPTION OF THE INVENTION
The present invention provides an extended release formulation comprising quetiapine or a pharmaceutically acceptable salt thereof and a controlled release matrix comprising a mixture of hydrophilic polymers.
The term "extended release" for the purposes of this invention refers to release of an active pharmaceutical agent over a prolonged period of time, such as for example over a period of 8, 12, 16 or 24 hours. 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.
In a preferred embodiment, the present invention comprises 20-80 % of quetiapine or a pharmaceutically acceptable salt thereof, preferably the present invention comprises 30-50 % of quetiapine or a pharmaceutically acceptable salt thereof.
According to the present invention, the formulation comprises a controlled release matrix comprises a mixture of hydrophilic polymers selected from but not limited to a
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group comprising polysaccharide gums which are natural and modified (semi¬synthetic) or synthetic or their combinations, including but not limited to xanthan gum, veegum, agar, guar gum, locust bean gum, gum arabic, okra gum, bentonite, arabinoglactin, pectin, tragacanth, scleroglucan, dextran, amylose, amylopectin, dextrin, alginic acid or other alginates such as alginic acid derivatives e.g. sodium alginate, propylene glycol alginate and the like or mixtures thereof.
In a preferred embodiment, the present invention comprises 10-40% by weight of the formulation, a controlled release matrix comprising a mixture of hydrophilic polymers. In a still preferred embodiment, the present invention comprises 15-30% by weight of the formulation, a controlled release matrix comprising a mixture of hydrophilic polymers.
In a still preferred embodiment of the present invention, The ratio of hydrophilic polymers in the controlled release matrix, is preferably selected such that the active ingredient is released from the formulation, in a controlled fashion, over a period of 4 hours or longer, preferably over a period of 8 hours or longer and in particular over a period of between 8 and 24 hours, that is so that at least 80 % of the active ingredient is released at the end of this period. Thus, the controlled release matrix comprises a mixture of hydrophilic polymers in a ratio of 1:10 to 10:1. More preferably the controlled release matrix comprises a mixture of xanthan gum and sodium alginate in a ratio of about 1:10 to about 1:10.
Thus, when xanthan gum is used along with sodium alginate to form a controlled release matrix, it reduces the initial bursting effect and in later stages acts as a channeling agent to increase the release rate of the active agent.
Xanthan gum when used as matrix forming agent in extended release tablets, may release the drug slightly faster in acidic media, due to more rapid initial surface
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erosion than at higher pH. After hydration of the gum the drug release is essentially pH independent.
Sodium alginate is a water soluble salt of alginic acid. Sodium alginate is insoluble below pH 3 and soluble above pH 3. The matrix formed by sodium alginate releases the drug slowly below pH 3 and shows a faster release rate above pH 3. Thus, when it is used along with xanthan gum to form the matrix it reduces the initial bursting effect and in the later stages, acts as channeling agent to increase the release rate of the drug. These two polymers when used in appropriate concentrations provide the desired release profile, when the delivery system travels through the GIT, having varying pH gradients.
In a further embodiment, the present invention optionally comprises a pH
independent rate controlling polymer. The pH independent rate controlling polymer
is selected from but not limited to the group comprising of alkyl celluloses,
hydroxyalkyl alkyl celluloses, hydroxy alkyl celluloses, polyethylene glycols,
copolymers of ethylene oxide with propylene oxide, gelatin, polyvinylpyrrolidones,
vinylpyrrolidones, vinyl acetates, polyvinylimidazoles, polyvinylpyridine N- oxides,
copolymers of vinylpyrrolidone with long-chained alpha-olefins, copolymers of
vinylpyrrolidone with vinylimidazole, poly(vinylpyrrolidone/dimethylaminoethyl
methacrylates), copolymers of vinylpyrrolidone/dimethylaminopropyl
methacrylamides, copolymers of vinylpyrrolidone/ dimethyl aminopropyl acrylamides, copolymer of polyvinyl acetate and polyvinylpyrrolidone, quaternised copolymers of vinylpyrrolidones and dimethylaminoethyl methacrylates, terpolymers of vinylcaprolactam/vinylpyrrolidone/ dimethylaminoethyl methacrylates, copolymers of vinylpyrrolidone and methacrylamidopropyl- trimethylammonium chloride, terpolymers of caprolactam/vinylpyrrolidone/dimethylaminoethyl methacrylates, copolymers of styrene and acrylic acid, polycarboxylic acids, polyvinyl alcohols, hydrolysed polyvinyl acetate, or mixtures thereof.
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In a still preferred embodiment, the pH independent rate controlling polymer is graft copolymer of polyvinyl acetate and polyvinylpyrrolidone mixed with sodium lauryl sulfate (such as marketed under the trade name of Kollicoat® SR).
The rate controlling polymer is present in an amount of 1-10% by weight of the formulation, more preferably the rate controlling polymer is present in an amount of 2-6% by weight of the formulation.
In a preferred embodiment, the present invention is formulated as a solid dosage form such as a tablet, capsule, pellet, mini tablet, pill and the like.
In a still preferred embodiment, the extended release formulation is a tablet. The tablet may contain, in addition to the active ingredient, one or more excipients selected from the group consisting of diluents, lubricants, binders, colorants, surfactants, pH modifiers, stabilizers and the like.
Diluents, which include, but are not limited to any modified or unmodified carbohydrates or their salts, esters; confectioner's sugar, compressible sugar, dextrates, dextrin, dextrose, fructose, lactitol, mannitol, sucrose, starch, lactose, xylitol, sorbitol, talc, celluloses or modified celluloses, micro crystal line cellulose, inorganic fillers such as group I and II metal salts like carbonates, silicates, borates, sulphates, phosphates and mixtures thereof.
Lubricants may be selected from, but are not limited to, those conventionally known in the art such as Mg, Al or Ca or Zn stearate, polyethylene glycol, glyceryl behenate, mineral oil, sodium stearyl fumarate, stearic acid, hydrogenated vegetable oil and talc
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Glidants include, but are not limited to talc, starches, anhydrous colloidal silica, magnesium trisilicate and the like.
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.
Colorants include but are not limited to ferric oxides, FD & C dyes, lakes and the like. Surfactants include but are not limited to surfactants such as non-ionic surfactants, anionic surfactants for example, sodium lauryl sulphate and the like.
pH modifiers include but are not limited to suitable organic acids such as benzoic acid, citric acid, tartaric acid, succinic acid, adipic acid and the like or the corresponding alkali metal salts thereof, preferably the alkali metal salts of such acids. In particular the sodium salt of citric acid (i.e. sodium citrate) can be used.
Suitable stabilizers include but not limited to calcium sulfate, calcium chloride, aluminium chloride, magnesium chloride, calcium lactate, calcium citrate, magnesium citrate and magnesium sulfate.
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
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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 formulations of the present invention may be prepared by conventional technique
well known to those skilled in the art wet granulation, direct compression, dry
compaction (slugging) and the like. Thus, for example, the active ingredient 11-[4-[2-
(2-hydroxyethoxy)ethyl]-l-piperazinyl]-dibenzo[b,f]-[l,4]thiazepine, or a
pharmaceutically acceptable salt thereof, hydrophilic polymers, such as for example alginates, xanthan gum and the like, and optionally other excipients are mixed. The mixed components are wet granulated, the granules are dried and milled, the mixture is blended with a lubricant such as magnesium stearate and the blended mixture is compressed to form tablets or filled into capsules. The tablets can be optionally coated.
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. In a particular embodiment, the dissolution profile is determined by the Rotating Basket method by immersing a tablet in 1000 ml of pH 4.5 acetate buffer at a speed of 100 rpm.
As mentioned above, the compound ll-[4-[2-(2-hydroxyethoxy)ethyl]-l-piperazinyl]dibenzo[b,f]]l,4]-thiazepine, and its pharmaceutically acceptable salts,
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exhibit useful antidopaminergic activity and therefore the formulations of this invention may be used, for example, as antipsychotic agents or as a treatment for hyperactivity.
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. The invention may be further illustrated by the following non-limiting examples:
Examples

Sr.
No. Ingredients Example 1 Example 2 Example 3

mg/tab %
w/w mg/tab %
w/w mg/tab /o
w/w
1. Quetiapine fiimarate 200.00 40.00 200.00 39.22 200.00 38.46
2. Microcrystalline cellulose (AvicelPHlOl) 123.00 24.60 103.00 20.20 123.00 23.65
3. Sodium Alginate (Protanal LF240D) 100.00 20.00 120.00 23.53 100.00 19.23
4. Xanthan gum (Xantural 75) 40.00 8.00 40.00 7.84 40.00 7.69
5. Povidone K-30 30.00 6.00 30.00 5.88 30.00 5.77
6. Kollicoat SR 30 D ~ — ~ ~ 20.00 3.85
7. Purified water q.s. — q.s. ~ q.s. -
8. Magnesium stearate 7.00 1.40 7.00 1.37 7.00 1,35
9. Opadry — ~ 10.00 1.96 — -
Total 500.00 100.00 510.00 100.00 520.00 100.00
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Procedure:
Sift Quetiapine Fumarate, microcrystalline Cellulose, Sodium Alginate and Xanthan gum together through suitable sieve. Mix sifted raw materials using suitable equipment. Disperse Povidone K-30/ Kollicoat SR 30 D in purified water. Granulate the dry mix mass with binder using suitable equipments. Dry the wet mass till the required LOD is obtained. Sift the dried granules through suitable sieve. To the above blend add the sifted quantity of lubricant as per mentioned in formula and continue the mixing for few minutes so as to form the lubricated blend. Compress the above lubricated blend by using suitable compression machine. Coat the compress tablets by Opadry in suitable coating machine.
Dissolution studies data:
Apparatus: USP Type I - Basket, 100 rpm

Time Points (Bra) % Release (Quetiapine)
Seroquel XR Example 1 Example 2 Example 3
1 7 5 5 . 5
2 15 15 14 14
4 34 33 33 33
6 53 50 52 51
8 71 71 72 69
10 86 87 87 86
12 96 95 94 93
14 102 100 99 97
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We claim:
1) An extended release formulation comprising quetiapine or a pharmaceutical^ acceptable salt thereof, and a controlled release matrix comprising a mixture of hydrophilic polymers.
2) An extended release formulation according to claim 1, wherein the formulation comprises 20-80% by weight of the formulation of quetiapine or a pharmaceutical^ acceptable salt thereof.
3) An extended release formulation according to claim 1, wherein the formulation comprises 30-50% by weight of the formulation of quetiapine or a pharmaceutically acceptable salt thereof.
4) An extended release formulation according to claim 1, wherein the hydrophilic polymers are selected from the group comprising polysaccharide gums which are natural and modified (semi-synthetic) or synthetic or their combinations, including but not limited to xanthan gum, veegum, agar, guar gum, locust bean gum, gum arabic, okra gum, bentonite, arabinoglactin, pectin, tragacanth, scleroglucan, dextran, amylose, amylopectin, dextrin, alginic acid or other alginates such as alginic acid derivatives e.g. sodium alginate, propylene glycol alginate and the like or mixtures thereof.
5) An extended release formulation according to claim 1, wherein the formulation comprises 10-40% by weight of the formulation of a controlled release matrix comprising a mixture of hydrophilic polymers.
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6) An extended release formulation according to claim 1, wherein the formulation comprises 15-30% by weight of the formulation of a controlled release matrix comprising a mixture of hydrophilic polymers.
7) An extended release formulation according to claim 1, wherein the controlled release matrix comprises the mixture of hydrophilic polymers in a ratio of about 1:10 to 10:1.
8) An extended release formulation according to claim 7, wherein the ratio of xanthan gum to sodium alginate is about 1:10 to 10:1.
9) An extended release formulation according to claim 8, wherein the ratio of xanthan gum to sodium alginate is about 1:3.
10) An extended release formulation according to claim 1, which optionally
comprises a pH independent rate controlling polymer.
11) An extended release formulation according to claim 10, wherein the formulation comprises 1-10% by weight of the formulation, a pH independent rate controlling polymer.
12) An extended release formulation according to claim 11, wherein the formulation comprises 2-6% by weight of the formulation of a pH independent rate controlling polymer.
13) An extended release formulation according to claim 10, wherein the pH
independent rate controlling polymer is selected from alkyl celluloses, hydroxyalkyl
alkyl celluloses, hydroxy alkyl celluloses, polyethylene glycols, copolymers of
ethylene oxide with propylene oxide, gelatin, polyvinylpyrrolidones,
vinylpyrrolidones, vinyl acetates, polyvinyl imidazoles, polyvinylpyridine N- oxides,
copolymers of vinylpyrrolidone with long-chained alpha-olefins, copolymers of
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vinylpyrrolidone with vinylimidazole, poly(vinylpyrrolidone/dimethylaminoethyl
methacrylates), copolymers of vinylpytrolidone/dimethylaminopropyl
methacrylamides, copolymers of vinylpyrrolidone/ dimethylaminopropyl acrylamides, copolymer of polyvinyl acetate and polyvinylpyrrolidone, quaternised copolymers of vinylpyrrolidones and dimethylaminoethyl methacrylates, terpolymers of vinylcaprolactam/vinylpyrrolidone/ dimethylaminoethyl methacrylates, copolymers of vinylpyrrolidone and methacrylamidopropyl- trimethylammonium chloride, terpolymers of caprolactam/vinylpyrrolidone/dimethylaminoethyl methacrylates, copolymers of styrene and acrylic acid, polycarboxylic acids, polyvinyl alcohols, hydrolysed polyvinyl acetate, or mixtures thereof.
14) An extended release formulation according to claim 10, wherein the pH independent rate controlling polymer is a graft copolymer of polyvinyl acetate and polyvinylpyrrolidone mixed with sodium lauryl sulfate (such as marketed under the trade name of Kollicoat SR).
15) An extended release formulation according to claim 1, further comprises pharmaceutically acceptable additives selected from the group comprising diluents, binders, lubricants, glidants, pH modifiers, stabilizers.
16) A process of preparation of an extended release formulation according to claim 1,
which comprises of the following steps:
i) mixing the active agent, hydrophilic polymers and optionally one or more
excipients.
ii) granulationg the mix of step (i) with a binder solution,
iii) optionally adding one or more excipient(s) including a pH independent polymer,
and
iv) formulating the mixture into a suitable dosage form.
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17) An extended release formulation substantially as herein described and illustrated with respect to the examples.
18) The process for the preparation of an extended release formulation substantially as herein described and illustrated with respect to the examples.

Abhishek Sen
OfS. Majumdar&Co.
Applicant's Agent
Dated this 12th day of January 2009
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