Technical Field of the Invention
The present invention relates to extended release dosage forms for oral administration comprising quetiapine and the process for the preparation thereof.
Background of the invention
Quetiapine is a psychotropic drug belonging to a chemical class, the dibenzothiazepine derivatives and is chemically designated as 11-[4-[2-(2-hydroxyethoxy) ethyl]-1-piperazinyl] dibenzo[b,f][1,4] thiazepine. Quetiapine acts as an antagonist at several neurotransmitter receptors including dopamine D1 and D2 receptors, serotonin 5HTA1 and 5HT2 receptors, histamine H1 receptor and adrenergic α1 and a2 receptors. Quetiapine is thought to exert its antipsychotic effects primarily via antagonism of dopamine D2 receptor and serotonin 5HT2 receptors.
Currently, quetiapine is commercially available as conventional immediate release tablets in 25, 50, 100, 200, 300 and 400 mg strengths marketed by Astra Zeneca, under the brand name Seroquel®, requiring two or three times a day dosing. It is also available as extended release tablets in 50,150, 200, 300 and 400mg strengths under the brand name Seroquel® XR. These tablets contain quetiapine as a hemifumarate salt, lactose monohydrate, microcrystalline cellulose, sodium citrate, hypromellose, magnesium stearate and hypromellose, polyethylene glycol 400, titanium dioxide, yellow iron oxide (200 and 300mg tablets) in the film coat.
It is desirable in the treatment of diseases both therapeutically and prophylactically to provide the active pharmaceutical ingredient in extended release form. Advantages of extended release systems over conventional dosage forms are well known. Extended release dosage forms increase patient compliance due to reduction in frequency of dosing. They also reduce the severity and frequency of side effects, as they maintain substantially constant plasma levels. This is especially important in the treatment of schizophrenia and bipolar mania, for the alleviation of psychosis, where blood levels of medicament must be maintained at a therapeutically effective level to provide symptomatic relief.

Quetiapine and its pharmaceutically acceptable salts, its preparation, physical properties and beneficial pharmacological properties are disclosed in US Patent No. 4,879,288 and European Patents EP 240,228 and 282,236.
PCT application 2007/000778 exemplifies modified release matrix tablets comprising quetiapine fumarate, a polymer system in an amount of less than about 80% w/w of the composition comprising atleast two swellable pH independent polymers wherein atleast one is hydrophilic and additionally, atleast one pH dependent hydrophilic release controlling polymer; and other pharmaceutically acceptable excipients.
PCT application 2007/110878 exemplifies hard gelatin capsules containing sustained release granules comprising quetiapine fumarate, atleast one solubilizer (e.g. propylene glycol caprylate/caprate, Labrafac®), a release rate-controlling polymer system comprising hydrophilic polyethylene oxide and hydroxyethylcellulose, and other pharmaceutical^ acceptable excipients.
PCT application 2007/086079 discloses once a day sustained release matrix tablets comprising phenothiazine derivative, a channelizer, a rate controlling agent and suitable pharmaceutical excipients. Examples cited therein disclose sustained release formulations of quetiapine fumarate with water-soluble polymer i.e. hydroxypropyl methylcellulose and other excipients.
US application 2005/0158383 discloses sustained release dosage forms of quetiapine in a waxy matrix. In the formulations described therein, the coating composition comprising a hydrophilic polymer may be press coated onto the core.
PCT application 2001/21179 discloses a granule formulation comprising quetiapine or a pharmaceutically acceptable salt thereof and freely or very water-soluble binder.
PCT application 2003/39516 discloses a method for improving dissolution of poorly dispersible medicament like quetiapine, which comprises mixing the poorly dispersible medicament with a floating agent and/or a surfactant and granulating the mixture.
A typical sustained release formulation of quetiapine is described in US Patent No. 5,948,437. It discloses matrix formulations of quetiapine wherein the matrix is comprised of gelling agents, particularly, hydroxypropyl methylcellulose for sustained release. The patent further discloses that it is difficult to formulate sustained release formulations of soluble medicaments like quetiapine fumarate and gelling agents like hydroxypropyl methylcellulose for reasons of dose dumping. That is, release of the active ingredient is delayed for a time but once the release begins to occur, the rate of release is very high. Further some degree of diurnal variation in plasma concentration of the active ingredient has also been observed and lastly, it has been found to be difficult to achieve the desired dissolution profiles or to control the rate of release of the soluble medicament. The sustained release tablets of quetiapine have been prepared with hydroxypropyl methylcellulose as the sole rate controlling polymer.
We, hereby, disclose extended release dosage forms of quetiapine, which would provide the desired pharmacokinetic profile wherein the dosage form comprises a matrix containing quetiapine and a rate-controlling polymer and one or more of pharmaceutically acceptable excipients as well as process for the preparation thereof. The rate controlling polymer may be a polymer selected from polyethylene oxide, sodium alginate and natural gums such as xanthan gum or locusts gum. It may additionally comprise atleast one water-insoluble polymer.
Summary of the Invention
In one general aspect, it relates to an extended release dosage form of quetiapine wherein the dosage form comprises quetiapine and a rate controlling polymer selected from polyethylene oxide, sodium alginate and natural gum and combinations thereof.
In another general aspect, it relates to an extended release dosage form of quetiapine wherein the dosage form comprises quetiapine and a rate controlling polymer selected from polyethylene oxide, sodium alginate and natural gum and combinations thereof; wherein the dosage form provides therapeutically effective plasma levels of quetiapine for a period of upto about 24 hours.

In another general aspect it relates to a process for preparing an extended release dosage form of quetiapine wherein the process comprises mixing quetiapine and a rate controlling polymer selected from polyethylene oxide, sodium alginate and natural gum and combinations thereof and processing into solid dosage form.
In another general aspect it relates to a process for preparing an extended release dosage form of quetiapine wherein the process comprises mixing quetiapine and a rate controlling polymer selected from polyethylene oxide, sodium alginate and natural gum and combinations thereof and one or more of other pharmaceutical excipients; granulating the blend with a granulating liquid; drying the granules; lubricating the granules with a lubricant; and compressing the granules into a tablet.
In another general aspect, it relates to an extended release dosage form of quetiapine wherein the dosage form comprises quetiapine and a rate controlling polymer selected from polyethylene oxide, sodium alginate and natural gum and combinations thereof and atleast one water-insoluble polymer.
In another general aspect, it relates to an extended release dosage form of quetiapine wherein the dosage form comprises quetiapine and a rate controlling polymer selected from polyethylene oxide, sodium alginate and natural gum and combinations thereof; and atleast one water-insoluble polymer, wherein the dosage form provides therapeutically effective plasma levels of quetiapine for a period of upto about 24 hours.
In another general aspect, it relates to an extended release dosage form of quetiapine wherein the dosage form comprises quetiapine and a rate controlling polymer selected from polyethylene oxide, sodium alginate and natural gum and combinations thereof and atleast one water-insoluble polymer, wherein the water-insoluble polymer is selected from ammonio-methacrylate copolymers, methacrylic acid copolymers, ethyl cellulose and combinations thereof.
In another general aspect it relates to a process for preparing an extended release dosage form of quetiapine wherein the process comprises mixing quetiapine and a rate controlling polymer selected from polyethylene oxide, sodium alginate and natural gum and combinations thereof and atleast one water-insoluble polymer and processing into solid dosage form.

In another general aspect it relates to a process for preparing an extended release dosage form of quetiapine wherein the process comprises mixing quetiapine and a rate controlling polymer selected from polyethylene oxide, sodium alginate and natural gum and combinations thereof and one or more of other pharmaceutical excipients; granulating the blend with a solution/dispersion of water-insoluble polymer; drying the granules; lubricating the granules with a lubricant; and compressing the granules into a tablet.
In another general aspect it relates to a process for preparing an extended release dosage form of quetiapine wherein the process comprises mixing quetiapine and one or more of other pharmaceutical excipients; granulating the blend with a solution/dispersion of water-insoluble polymer; mixing the granules with a rate controlling polymer selected from polyethylene oxide, sodium alginate and natural gum and combinations thereof and one or more of other pharmaceutical excipients; and compressing the resultant blend into a tablet.
Detailed Description of the Invention
"Quetiapine", as recited herein means quetiapine or a pharmaceutical^ acceptable form of quetiapine, including without limitation, its free base form, and all pharmaceutically acceptable salts, complexes, enantiomer, solvates, hydrates, and polymorphs. The preferred quetiapine salt is quetiapine hemifumarate.
The rate controlling polymers may be selected from polyethylene oxide, sodium alginate or natural gums. Polyethylene oxide may be of different viscosity grades such as Polyox WSR 303, Polyox WSR 301, Polyox WSR N-60K, Polyox WSR Coagulant available from Colorcon. Natural gums may be selected from gum tragacanth, locust bean gum, guar gum, karaya gum or xanthan gum. The dosage forms as described herein may additionally comprise atleast one water-insoluble polymer. Examples of suitable water-insoluble polymers include acrylates such as methacrylates, polymethacrylic acid-based polymers and copolymers such as those sold under the trade name Eudragit™; cellulose derivatives such as ethyl cellulose, cellulose acetate, cellulose acylate, cellulose diacylate, cellulose triacylate, cellulose diacetate, cellulose triacetate, mono-, di- and tri-cellulose alkanylates, mono-, di-, and tri-cellulose arylates,

mono-, di- and tri-cellulose adenylates; polyethylene; polyvinyl chloride; vinyl acetate/vinyl chloride copolymer; vinylidene chloride/acrylonitrile copolymer; high molecular weight polyvinylalcohols and mixtures thereof. Particularly preferred are Eudragit RL/RS and ethyl cellulose. The total amount of rate controlling polymers in the tablet relative to quetiapine depends upon the rate of drug release required and also upon the type and molecular weight of the polymers and other excipients present in the formulation and may vary from about 5% to about 95% by weight of the composition. The dosage forms may also comprise other rate controlling polymers such as crosslinked polyacrylic acids (Carbopols), polyvinylpyrrolidone and the like.
The term "dosage form" as recited herein includes dosage forms such as tablets, granules, capsules filled with granules or tablets.
The other pharmaceutical excipients may be one or more of diluents, binders, pH modifiers, anti-oxidants, disintegrants, glidants/lubricants and plasticizers.
Suitable diluents may be selected from one or more of any conventional diluents such as microcrystalline cellulose, silicified microcrystalline cellulose, lactose, mannitol, sorbitol, calcium phosphate, calcium sulfate, calcium carbonate, starch, starch pregelatinized and the like.
Suitable binders may be selected from one or more of polyvinylpyrrolidone, cross-linked polyvinylpyrrolidone, polyvinyl alcohol, carboxymethyl cellulose, hydroxypropyl methylcellulose, hydroxypropyl cellulose, microcrystalline cellulose, silicified microcrystalline cellulose, starch pregelatinized, and the like.
Suitable pH modifiers may be selected from benzoic acid, citric acid, tartaric acid and metal salts thereof.
Suitable anti-oxidants may be selected from butylated hydroxytoluene, butylated hydroxyanisole, Vitamin E, tocopherol and the like. Particularly preferred is butylated hydroxytoluene.
Suitable disintegrants may be selected from carboxymethyl cellulose, sodium carboxymethyl cellulose, cross-linked sodium carboxymethyl cellulose, sodium starch

glycolate, starch, pregelatinized starch, hydroxypropyl starch and the like.
Suitable glidants/lubricants may include one or more of magnesium stearate, calcium stearate, zinc stearate, stearic acid, talc, colloidal silicon dioxide, hydrogenated vegetable oil, polyethylene glycol, sodium stearyl fumarate and the like.
Suitable granulating liquid may be a solvent such as water, isopropyl alcohol, acetone, methanol, ethanol, dichloromethane or mixtures thereof or a solution/dispersion of a polymer, for example polyvinylpyrrolidone.
The rate-controlling polymers may be provided as solutions/dispersions in organic solvent/water or mixture of organic solvent and water and may comprise suitable plasticizers. Examples of plasticizers include citrate esters, phthalate esters, triacetin, castor oil, polyethylene glycols, propylene glycol and the like.
Tablets can additionally be coated with non-rate-controlling polymer compositions like Opadry® sold by Colorcon to impart aesthetic appeal.
The compositions described herein may be prepared by conventional processes using commonly available equipments. The process may comprise involving wet granulation, dry granulation or direct compression processes.
Preferred pharmaceutical compositions of the present invention may take form of several different embodiments.
In one embodiment, the extended release dosage form is a tablet comprising quetiapine and a rate controlling polymer selected from polyethylene oxide, sodium alginate and natural gums or combination thereof and one or more of other pharmaceutical excipients.
In another embodiment, the extended release dosage form is a tablet comprising quetiapine and a rate controlling polymer selected from polyethylene oxide, sodium alginate and natural gums or combination thereof; pH modifier; and one or more of other pharmaceutical excipients.

In another embodiment, the extended release dosage form is a tablet and is prepared by the process comprising mixing quetiapine, diluents, pH modifier, rate controlling polymer; granulating with a granulating liquid; drying the granules; mixing the dried granules with lubricant and glidant and compressing into tablet using appropriate tooling.
In another embodiment, the extended release dosage form is a tablet comprising quetiapine and a rate controlling polymer selected from polyethylene oxide, sodium alginate and natural gums or combination thereof and atleast one water-insoluble polymer and one or more other pharmaceutical excipients.
In the above embodiment, the water-insoluble polymer may be selected from ethyl cellulose or Eudragit.
In another embodiment, the extended release dosage form is a tablet and is prepared by the process comprising mixing quetiapine and a rate controlling polymer selected from polyethylene oxide, sodium alginate and natural gums and combinations thereof and one or more of other pharmaceutical excipients; granulating with a solution/dispersion of atleast one water-insoluble polymer; drying the granules; mixing the dried granules with lubricant and glidant and compressing into tablet using appropriate tooling.
In another embodiment, the extended release tablet is prepared by the process comprising mixing quetiapine and one or more of other pharmaceutical excipients; granulating the blend with a solution/dispersion of water-insoluble polymer; mixing the granules with a rate controlling polymer selected from polyethylene oxide, sodium alginate and natural gum and combinations thereof and one or more of other pharmaceutical excipients; and compressing the resultant blend into a tablet.
The following examples are given for purpose of illustrating the present invention and not intended to limit the scope in any way.

Example 1 (1a-1c): Extended release tablets of quetiapine comprising Polyox as the rate controlling polymer
(Table Removed)

Procedure for Example 1:
1. Accurately weighted quantities of quetiapine fumarate, lactose monohydrate, microcrystalline cellulose, sodium citrate and polyox were mixed in a suitable blender.
2. The above blend was transferred to rapid mixer granulator and granulated with Isopropyl alcohol and purified water.
3. The granules were dried in a fluidized bed dryer.
4. The dried granules were mixed with magnesium stearate and colloidal silicon dioxide and butylated hydroxytoluene (if present).
5. The blend of step 4 was compressed into tablets using appropriate tooling and the resultant tablets were optionally coated with Opadry.

Table 1: Dissolution profile of tablets prepared as per Examples 1a-1c in 900ml_ of 0.1 N HCI in USP Dissolution Apparatus Type I at 100rpm
(Table Removed)

Example 2: Extended release tablets of quetiapine comprising Polyox and xanthan gum as the rate controlling polymers
(Table Removed)

Procedure for Example 2:
1. Accurately weighted quantities of quetiapine fumarate, lactose monohydrate, microcrystalline cellulose, sodium citrate, xanthan gum and polyethylene oxide were mixed in a suitable blender.
2. The above blend was transferred to rapid mixer granulator and granulated with Isopropyl alcohol and purified water.
3. The granules were dried in a fluidized bed dryer.
4. The dried granules were mixed with magnesium stearate and colloidal silicon dioxide.
5. The blend of step 4 was compressed into tablets using appropriate tooling and the resultant tablets were coated with Opadry.
Table 2: Dissolution profile of tablets prepared as per Example 2 in 900mL of 0.1 N HCI in USP dissolution Apparatus Type I at 100rpm
(Table Removed)

Example 3: Extended release tablets of quetiapine comprising sodium alginate as the rate controlling polymer
(Table Removed)

Procedure for Example 3:
1. Accurately weighted quantities of quetiapine fumarate, lactose monohydrate, microcrystalline cellulose, sodium citrate and sodium alginate were mixed in a suitable blender.
2. The above blend was transferred to rapid mixer granulator and granulated with purified water.
3. The granules were dried in a fluidized bed dryer.
4. The dried granules were mixed with magnesium stearate and colloidal silicon dioxide.
5. The blend of step 4 was compressed into tablets using appropriate tooling and the resultant tablets were coated with Opadry.

Table 3: Dissolution profile of tablets prepared as per Example 3 in 900mL of 0.1N HCI in USP Dissolution Apparatus Type I at 100rpm
(Table Removed)

Example 4 (4a-4b): Extended release tablets of quetiapine comprising Polyox and ethyl cellulose as the rate controlling polymers
(Table Removed)

Procedure for Example 4:
1. Accurately weighted quantities of quetiapine fumarate, lactose monohydrate, microcrystalline cellulose, sodium citrate and Polyox were mixed in a suitable blender.
2. The above blend was transferred to a rapid mixer granulator and granulated with ethyl cellulose binder solution in isopropyl alcohol and dichloromethane.
3. The granules were dried in a fluidized bed dryer.
4. The dried granules were mixed with butylated hydroxytoluene (if present), magnesium stearate and colloidal silicon dioxide.
5. The blend of Step 4 was compressed into tablets using appropriate tooling.
Table 4: Dissolution profile of tablets prepared as per Examples 4a-4b in 900mL of 0.1 N HCI in USP Dissolution Apparatus Type I at 100rpm
(Table Removed)

Example 5 (5a-5d): Extended release tablets of quetiapine comprising Polyox and Eudragit as rate controlling polymers
(Table Removed)

Procedure for Example 5:
1. Quetiapine fumarate and colloidal silicon dioxide were mixed together and loaded in Glatt.
2. Dispersion of talc was prepared in water and triethyl citrate was added to it and stirred.
3. Dispersion of step 2 was added in Eudragit dispersion and stirred for 45 minutes.
4. Blend of step 1 was granulated with dispersion of step 3.
5. The resultant granules were mixed with lactose monohydrate, microcrystalline cellulose and Polyox.
6. Blend of step 5 was mixed with butylated hydroxytoluene, magnesium stearate and colloidal silicon dioxide.
7. The above blend was compressed into tablets using appropriate tooling.

Table 5: Dissolution profile of tablets prepared as per Examples 5a-5d in 900ml of 0.1 N HCI in USP Dissolution Apparatus Type I at 100rpm
(Table Removed)

Example 6 (6a-6d): Extended release tablets of quetiapine comprising Polyox and Eudragit as the rate controlling polymers
(Table Removed)

Procedure for Example 6:
Same as described above for Example 5.
Table 6: Dissolution profile of tablets prepared as per Examples 6a-6d in 900ml of pH 6.8 phosphate buffer in USP Dissolution Apparatus Type I at 100rpm
(Table Removed)

Example 7 (7a-7b): Extended release tablets of quetiapine comprising Polyox, xanthan gum and Eudragit as the rate controlling polymers
(Table Removed)

Procedure for Example 7:
1. Quetiapine fumarate and colloidal silicon dioxide were mixed together and loaded in Glatt.
2. Dispersion of talc was prepared in water and to it triethyl citrate was added.
3. Dispersion of step 2 was added in Eudragit dispersion and stirred for 45 min.
4. Blend of step 1 was granulated with dispersion of step 3.
5. The resultant granules were mixed with lactose monohydrate, microcrystalline cellulose, Polyox and xanthan gum.
6. Blend of step 5 was mixed with butylated hydroxytoluene, magnesium stearate and colloidal silicon dioxide.
7. The above blend was compressed into tablets using appropriate tooling.
Table 7: Dissolution profile of tablets prepared as per Examples 7a-7b in 900ml of 0.1 N HCI in USP Dissolution Apparatus Type I at 100rpm
(Table Removed)

WE CLAIM:
1) An extended release dosage form comprising quetiapine and a rate controlling polymer selected from polyethylene oxide, sodium alginate and natural gum and combinations thereof and other pharmaceutically acceptable excipients.
2) The extended release dosage form according to Claim 1, wherein other pharmaceutically acceptable excipients comprise one or more of plasticizers, solvents, binders, diluents, disintegrants, pH modifiers, antioxidants, lubricants, glidants or mixtures thereof.
3) A process for the preparation of extended release dosage form according to Claim 1, wherein the process comprises mixing quetiapine and a rate controlling polymer selected from polyethylene oxide, sodium alginate and natural gum and combinations thereof and compressing the blend into a tablet.
4) A process for the preparation of extended release dosage form according to Claim 1, wherein the process comprises mixing quetiapine and a rate controlling polymer selected from polyethylene oxide, sodium alginate and natural gum and combinations thereof and one or more of other pharmaceutically acceptable excipients; granulating the blend with a granulating liquid; drying the granules; lubricating the granules with a lubricant; and compressing the granules into a tablet.
5) The extended release dosage form according to Claim 1, further comprising atleast one water-insoluble polymer.
6) The extended release dosage form according to Claim 5, wherein the water-insoluble polymer is selected from ammonio-methacrylate copolymers, methacrylic acid copolymers, ethyl cellulose and combinations thereof.

7) A process for the preparation of extended release dosage form according to Claim 5, wherein the process comprises mixing quetiapine and a rate controlling polymer selected from polyethylene oxide, sodium alginate and natural gum and combinations thereof and atleast one water-insoluble polymer and compressing the blend into a tablet.
8) A process for the preparation of extended release dosage form according to Claim 5, wherein the process comprises mixing quetiapine and a rate controlling polymer selected from polyethylene oxide, sodium alginate and natural gum and combinations thereof and one or more of other pharmaceutically acceptable excipients; granulating the blend with a solution/dispersion of water-insoluble polymer; drying the granules; lubricating the granules with a lubricant; and compressing the granules into a tablet.
9) A process for the preparation of extended release dosage form according to Claim 5, wherein the process comprises mixing quetiapine and one or more of other pharmaceutically acceptable excipients; granulating the blend with a solution/dispersion of water-insoluble polymer; mixing the granules with a rate controlling polymer selected from polyethylene oxide, sodium alginate and natural gum and combinations thereof and one or more of other pharmaceutically acceptable excipients; and compressing the resultant blend into a tablet.
10) The extended release dosage form of quetiapine according to any of the
preceding Claims, wherein the dosage form exhibits the following in vitro
dissolution profile, when measured in a USP dissolution apparatus type I, at
10Orpm, at a temperature of 37±0.5°C in 900ml of 0.1N hydrochloric acid;
- at most about 50% of the drug is released in 2 hour;
- at most about 75% of the drug is released in 4 hours and
- at most about 99% of the drug is released in 8 hours.