FORM2
THE PATENTS ACT, 1970 (39 of 1970)
&
The Patents Rules, 2003
PROVISIONAL SPECIFICATION
(See section 10; rule 13)
1. Title of the invention. - PHARMACEUTICAL FORMULATIONS OF
UETIAPINE

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 describes the invention


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

and its pharmaceutically 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.
The preparation and physical properties of 11-[4-[2-(2-hydroxyethoxy)ethyl]-1-piperazinyl] dibenzo[b,f][1,4]-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.
While there are numerous extended release formulations known in the art which utilize gelling agents, for example- hydroxypropyl methylcelluloses, it has been found to be difficult to formulate extended release formulations of soluble medicaments using gelling agents. The active ingredients which are soluble in water tend to generate an extended release product when gelling agents are used; which is
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susceptible to a phenomenon known as dose dumping. That is, release of the active ingredient is delayed for a time but once release begins to occur the rate of release is very high. Moreover, fluctuations tend to occur in the plasma concentrations of the active ingredient which increases the likelihood of toxicity. It has been found to be difficult to achieve the desired dissolution profiles or to control the rate of release of the soluble medicament. Therefore there is a need to develop new formulations without the use of gelling agents.
SUMMARY OF THE INVENTION
The present invention relates to an extended release formulation of quetiapine or a pharmaceutically acceptable salt 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, 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.
In one aspect, the invention relates to an extended release formulation comprising quetiapine or a pharmaceutically acceptable salt thereof and one or more non-gelling agents.
In another aspect, the invention relates to a process for preparing an extended release formulation comprising quetiapine or a pharmaceutically acceptable salt thereof and one or more non-gelling agents.
DETAILED DESCRIPTION OF THE INVENTION
The present invention provides for an extended release formulation comprising quetiapine or a pharmaceutically acceptable salt thereof and one or more non-gelling agents.
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The term 'pharmaceutically acceptable salts' includes but is not limited to salts such as chloride, maleate, fumarate, citrate, phosphate, methane sulphonate, sulphate and the like. Preferred salts include fumarates and a particularly preferred salt is the hemi-fumarate.
In addition to quetiapine the formulation contains one or more non-gelling agents. The term 'non-gelling agent' as used herein means any excipient, which does not form a gel when in contact with water and includes but is not limited to excipients like, for example polyvinyl acetate, polyethylene glycol and the like or mixtures thereof.
The amount of non-gelling agent, 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.
The formulation may be a solid dosage form such as a tablet, capsule, pellet, mini tablet, pill and the like.
In a 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, surfactants, colorants and the like.
Diluents include but are not limited to lactose, microcrystalline cellulose, dextrose, mannitol, sucrose, sorbitol and the like. Preferred diluents are lactose and microcrystalline cellulose. Lubricants include but are not limited to lubricants such as stearic acid, zinc, calcium or magnesium stearate and the like. Preferably magnesium stearate is used as a lubricant. Glidants include, but are not limited to talc, starches, anhydrous colloidal silica, magnesium trisilicate and the like. Binders
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include but are not limited to sucrose, polyethylene glycol, povidone (polyvinylpyrrolidone), corn or maize starch, pregelatinized starch and the like. Preferably povidone is used as a binder. Colorants include but are not limited to ferric oxides, FD & C dyes, lakes 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. Surfactants include but are not limited to surfactants such as non-ionic surfactants, anionic surfactants for example, sodium lauryl sulphate and the like.
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]-1-piperazinyl]-dibenzo[b,f]-[1,4]thiazepine, or a pharmaceutically acceptable salt thereof, the one or more non-gelling agent, such as for example polyethylene glycol, polyvinyl acetate 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. Polymers which may be suitable to provide an enteric coating include but are not limited to acrylic copolymer based pH dependent polymers and cellulose based pH dependent polymers. Examples of suitable acrylic polymers include but are not limited to methacrylic acid copolymers, ammonio methacrylate copolymers and the like.
Examples of suitable cellulose based pH dependent polymers include hydroxypropylmethylcellulose acetate succinate, hydroxypropylmethylcellulose phthalate, hydroxymethylethylcellulose phthalate, cellulose acetate phthalate, cellulose acetate succinate, cellulose acetate maleate, cellulose acetate trimelliate
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cellulose benzoate phthalate, cellulose propionate phthalate,. methylcellulose phthalate, carboxymethylethylcellulose, ethylhydroxyethylcellulose phthalate and the like.
The coating may include excipients like plasticizers. Plasticizers include but are not limited to triethyl citrate, triacetin, acetyl triethyl citrate, polyethylene glycol, diethyl phthalate, tributyl citrate, acetylated monoglycerides, glycerol, fatty acid esters, propylene glycol, dibutyl phthalate and the like. Colorants, detackifiers, surfactants, antifoaming agents, lubricants, stabilizers, acids, or bases may be added to the coatings in addition to plasticizers to solubilize or disperse the coating material and to improve coating performance. The coating preferably may contain for example, methacrylic acid co-polymer, lactose, polyethylene glycol and talc.
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 0 particular embodiment, the dissolution profile is determined by the Rotating Basket method by immersing a tablet in 750 ml of O.IN HCI for 2 hours at a speed of 100 rpm and then adding 250 ml of 0.2 M phosphate buffer to the dissolution media to afford a pH of 6.2.
As mentioned above, the compound 11-[4-[2-(2-hydroxyethoxy)ethyl]-l-piperazinyl]dibenzo[b,f]]1,4]-thiazepine, and its pharmaceutically acceptable salts, exhibit useful antidopaminergic activity and therefore the formulations of this
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invention may be used, for example, as antipsychotic agents or as a treatment for hyperactivity.
The invention may be further illustrated by the following non-limiting examples: Example 1

Sr No. Ingredients Strength

% w/w
Core material
1 Quetiapine Fumarate 462.500 54.23
2 Sodium Citrate 158.000 18.53
3 Microcrystalline Cellulose 102.500 12.02
4 Povidone 32.200 3.77
5 Polyvinyl Acetate 49.200 5.77
6 Sodium Lauryl Sulphate 0.600 0.07
7 Polyethylene Glycol 3.000 0.35
8 Magnesium Stearate 12.000 1.41
820.000
Enteric Coating
9 Methacrylic acid co polymer Type C 5.467 0.64

Lactose Monohydrate 11.389 1.34

Polyethylene Glycol 11.389 1.34

Talc 4.555 0.53
Total Weight(mg) 852.800 100.00
Procedure:
Quetiapine fumarate, sodium citrate and microcrystalline cellulose were blended. A binder solution was prepared by mixing povidone, polyvinyl acetate, polyethylene glycol and purified water. The dry mixture of quetiapine fumarate, sodium citrate and microcrystalline cellulose was wet granulated with the binder solution prepared above. The wet mass was dried until the loss on drying was less than 3.0% w/w. The dried granules were and passed through a suitable sieve. The sized granules were
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blended with magnesium stearate screened through a suitable sieve. The blended mixture was compressed into tablets. A coating dispersion was prepared by mixing methacrylic acid co polymer Type C, lactose monohydrate, polyethylene glycol, talc and purified water. The compressed tablets were coating using the coating dispersion.
Example 2

Sr No. ingredients Strength

% w/w
Core material
1 Quetiapine Fumarate 462.500 50.13
2 Sodium Citrate 190.000 20.59
3 Microcrystalline Cellulose 138.000 14.96
4 Povidone 35.300 3.83
5 Polyvinyl Acetate 54.000 5.85
6 Sodium Lauryl Sulphate 0.700 0.08
7 Polyethylene Glycol 6.000 0.65
8 Magnesium Stearate 13.500 1.46
900.000
Enteric Coating
9 Methacrylic acid co polymer Type C 3.750 0.41

Lactose Monohydrate 7.813 0.85

Polyethylene Glycol 7.813 0.85

Talc 3.124 0.34
Total Weight(mg) 922.5 100.00
Procedure:
Quetiapine fumarate, sodium citrate and microcrystalline cellulose were blended. A binder solution was prepared by mixing povidone, polyvinyl acetate, polyethylene glycol and purified water. The dry mixture of quetiapine fumarate, sodium citrate and microcrystalline cellulose was wet granulated with the binder solution prepared
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above. The wet mass was dried until the loss on drying was less than 3.0% w/w. The dried granules were sized and passed through a suitable sieve. The sized granules were blended with magnesium stearate screened through a suitable sieve. The blended mixture was compressed into tablets. A coating dispersion was prepared by mixing methacrylic acid co polymer Type C, lactose monohydrate, polyethylene glycol, talc and purified water. The compressed tablets were coated using the coating dispersion.
Example 3

Sr No. Ingredients Strength

% w/w
Core material
1 Quetiapine Fumarate 462.5 51.39
2 Sodium Citrate 190.0 21.11
3 Microcrystalline Cellulose 127.0 14.11
4 Povidone 35.3 3.92
5 Polyvinyl Acetate 54.0 6.00
6 Sodium Lauryl Sulphate 0.70 0.08
7 Polyethylene Glycol 6.0 0.67
8 Methacrylic acid co polymer Type C 11.0 1.22
9 Magnesium Stearate 13.5 1.5
900.0
Procedure:
Quetiapine fumarate, sodium citrate and microcrystalline cellulose were blended. A binder solution was prepared by mixing povidone, polyvinyl acetate, polyethylene glycol, methacrylic acid copolymer Type C and purified water. The dry mixture of quetiapine fumarate, sodium citrate and microcrystalline cellulose was wet granulated with the binder solution prepared above. The wet mass was dried until the loss on drying was less than 3.0% w/w. The dried granules were sized and passed through a suitable sieve. The sized granules were blended with magnesium
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stearate passed through a suitable sieve. ' he blended mixture was then compressed into tablets.
Dissolution studies data for Examples 1, 2 and 3:
Apparatus: USP Type I - Basket, 100 rpm

Time Points % Release (Quetiapine)
Example 1 Example 2 Example 3
1 18 18 27
2 28 27 41
3 31 31 43
4 34 34 46
6 40 45 50
8 49 55 56
10 57 64 62
12 64 73 67
14 69 78 72
16 74 82 77
20 81 89 85
24 86 93 92
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CLAIMS:
We claim:

Abhishek Sen Of S. Majumdar & Co.
1) An extended release formulation comprising quetiapine or a pharmaceutically acceptable salt thereof and one or more non-gelling agents. Dated this 2nd day of June 2008
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