FORM 2
THE PATENTS ACT 1970
(39 of 1970)
AND
The Patents Rules, 2003
COMPLETE SPECIFICATION
(See section 10 and rule 13)
1. TITLE OF THE INVENTION:
"SUSTAINED RELEASE DOSAGE FORM OF QUETIAPEVE"
2. APPLICANTS:
(a) NAME: INDOCO REMEDIES LIMITED
(b) NATIONALITY: Indian Company incorporated under the
Indian Companies ACT, 1956
(c) ADDRESS: Indoco House, 166 CSX Road, Santacruz (East),
Mumbai - 400 098, Maharashtra, 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 a novel sustained release oral dosage form of quetiapine
or its pharmaceutically acceptable salts and processes for their preparation thereof.
BACKGROUND OF THE INVENTION
Quetiapine is a psychotropic agent belonging to a class, the dibenzothiazepine derivatives. It is represented by formula (I) and is covered under US 4,879,288 in USA and EP Patent Nos. 0240228 Bl and 282,236 Bl in Europe.

Although, the exact mechanism of action is not entirely known, but it is thought that the primary mechanism which is responsible for its antipsychotic effect is its antagonist activity at dopamine, norepinephrine, alpha-adrenergic receptors, histamine and serotonin receptors and more specifically the D1 and D2 dopamine receptor, the alpha-1 and alpha-2 adrenergic receptor, and 5-HT1A and 5-HT2 serotonin receptor subtypes.
Quetiapine was first approved as quetiapine fumarate in conventional oral tablet dosage form. Later it was also marketed as sustained release tablets for the treatment of schizophrenia, depressive episodes associated with bipolar disorder, acute manic episodes associated with bipolar I disorder (as either monotherapy or adjunct therapy to lithium or valproate), and maintenance treatment of bipolar 1 disorder (as adjunct therapy to lithium or divalproex).
Since, in most cases the drug, quetiapine is to be taken for years or throughout the life span of the patient; the sustained release dosage forms are preferred as they are commonly taken only once, compared with counterpart conventional forms that may have to be taken twice or thrice daily to achieve the same therapeutic effect. Typically, these provide an immediate release of drug that promptly produces the desired therapeutic effect, followed by gradual release of additional amounts of drug to maintain this effect over a predetermined period. Further, the sustained plasma drug levels provided by the

drug often eliminate the need for night dosing, which benefits the patients. Thus, even though, till date, quetiapine fumarate is available both as conventional as well as sustained release tablets, however, sustained release preparation, marketed as Seroquel XR® tablets are more preferred.
While quetiapine fumarate has been in clinical practice since 2007 in USA and since 2008 in Europe as sustained preparations, however, it's highly hydrophilic nature makes it amenable to dose dumping i.e. a phenomenon which can cause exaggerated release of a drug. This can greatly increase the concentration of a drug in the body and thereby produce adverse effects or even drug-induced toxicity. Further, because of its very low density, it is very prone for segregation within tabletting processes, making direct tabletting very difficult. Many studies and attempts have been made to address these issues, of which noteworthy disclosures are: Parikh et al in US Pat. No. 5.948,437 discloses a sustained release formulation comprising quetiapine fumarate and a gelling agent. The gelling agent that has been claimed in the patent is hydroxypropyl methylcellulose (HPMC) having a viscosity of about 3,500 to 5,600 cps and 40 to 60 cps. Daniel Brown et ai in US Publication No. 20080287418 claims a formulation comprising quetiapine or a pharmaceutically acceptable salt thereof wherein the quetiapine content is about 9.6% to about 10.4% by weight and the formulation comprises about 30% HPMC by weight and about 7.2% sodium citrate dihydrate by weight. HPMC used in the above mentioned formulations forms gel in contact with water whereas sodium citrate used acts as a pH modifier which regulates the pH and helps to get the suitable dissolution profile, and hence avoid dose dumping.
Further, US Patent Publication No. 20080221079 by Jansen claims the formulation comprising quetiapine or its salts like quetiapine fumarate, intimate mixture of polyvinylactate and polyvinylpyrrolidone and optionally an acid like fumaric acid. WO Publication No. WO 0121179 by Daniel Brown discloses the granule formulation comprising quetiapine or its pharmaceutical ly acceptable salt and a freely or very water-soluble binder selected from maltodextrin, mannitol, xylitol, pre-gelatinised starch, sucrose or poly [I- (2-oxo-l-pyrrolidinyl) ethylene],
Still further, US Patent Publication No. 20080193527 by Amenos et al claims a granule formulation for the preparation of pharmaceutical compositions having a core comprising quetiapine. or a pharmaceutical ly acceptable salt thereof as an active ingredient, and a binder agent, a diluent agent and/or a disintegrant agent; and a coating layer comprising a

lubricant agent which is selected from glyceryl behenate, glyceryl palmitoestearate and macrogol.
Similarly, Boehm et al in US Patent Publication No. 20050158383 claims solid dosage formulation comprising a matrix wherein the matrix comprises a therapeutically effective amount of quetiapine or a pharmaceutically acceptable salt thereof; and a wax material like carnauba wax, glyceryl behenate, castor wax, or any combination thereof and controlled release dosage form does not contain a gelling agent.
Also, WO Publication No. WO 2007000778 by Jain et al claims a sustained release formulation comprising at least one active agent and at least two swellable pH independent polymers wherein at least one is hydrophilic.
Yet another disclosure has been made in US Patent Publication No. 20090317473 by Naringrekar et al wherein the controlled release composition having a matrix wherein matrix comprises an active agent and a non-gelling polymer selected from cellulose acetate phthalate, cellulose acetate succinate, hypromellose phthalate, hypromellose acetate succinate, a methacrylic acid-methyl methacrylate co-polymer, PVA phthalate, HEC phthalate. etc.
Also, US Patent Publication No. 20090264408 by Gulati et al claims an extended release dosage form comprising quetiapine and a rate-controlling polymer selected from polyethylene oxide, sodium alginate and natural gum and combinations thereof.
US Patent Publication No. 20100178333 by Mandal et al claims a once a day sustained release dosage form comprising a phenothiazine derivative or its pharmaceutically acceptable salt, a channelizer for facilitaing release of the phenothiazine derivative or its pharmaceutically acceptable salt from the dosage form through the pores that are formed by the channelizer, a release controlling agent and suitable pharmaceutical excipients.
Also, WO Patent Publication No. 2010082220 by Vaya et al relates to sustained release pharmaceutical composition of quetiapine comprising non gelling agents such as carrageenan and pharmaceutically acceptable excipients.
WO Patent Publication No. WO2010001413 by Velhal et al claims a sustained release dosage form comprising Quetiapine or a pharmaceutically acceptable salt, polymorphs, solvates, hydrates thereof and one or more non-gellable release controlling polymer and one or more pharmaceutically acceptable excipients

European Patent Publication No. EP2153834 claims an extended release multiparticulate system comprising quetiapine or a pharmaceutical acceptable salt, pharmaceutical acceptable excipients and atleast one hydrophobic release controlling agent
it would be abundantly evident that although the above mentioned disclosures overcome the disadvantages like dose dumping and poor tabletting properties of quetiapine fumarate; however, most of these fail to provide any disclosure and data about in vitro and in vivo profiles; which substantiates their claim.
Therefore, although various sustained release preparations with quetiapine fumarate are suggested in the art, there still exists a need to develop modified release composition which can provide sustained delivery of active agent, which are easier and economical to manufacture.
OBJECTS OF THE INVENTION
Accordingly, it is an object of the present invention to provide a sustained release pharmaceutical composition for oral administration of quetiapine which is capable of slowly releasing the quetiapine at a predetermined rate for a longtime.
Another object of the present invention is to provide a process for the preparation of sustained release pharmaceutical composition by a simple process which is convenient to manufacture on a commercial scale,
Yet another object of the present invention is to provide a sustained-release, pharmaceutical composition of quetiapine that resists dose dumping.
BRIEF DESCRIPTION OF FIGURES
The above and other objects and features of the present invention will become apparent from the following description of the invention, when taken in conjunction with the accompanying drawing which respectively shows:
FIG. 1 shows a comparative drug release profile of tablets obtained using Formula 1 A, 1B, and 1C (of example 1) in 0.1 N HCl for initial two hours, followed by 6.8 phosphate buffer for remaining 14 hours using Apparatus 1 (Basket) at 100 rpm in at 37° C; showing the effect of various concentrations of polyethylene glycol.

FIG. 2 shows a comparative drug release profile of tablets obtained using Formula 2A,2B (of example 2) in 0.1 N HCI for initial two hours, followed by 6.8 phosphate buffer for remaining 14 hours using Apparatus 1 (Basket) at 100 rpm in at 37° C; showing the effect of Calcium carbonate.
Detailed Description of the invention:
The invention will now be described in details in connection with certain preferred and
optional embodiments so that various aspects thereof may be more fully understood and
appreciated.
The present invention provides a sustained release oral dosage form which has a suitable
in-vitro release profile and improved stability. Specifically, the invention provides a
sustained release oral dosage form comprising
a) quetiapine or its pharmaceutically acceptable salts;
b) combination of hydrophilic polymer and hydrophobic polymer(s);
c) solubiliser and
d) alkalizing agent
alongwith one or more pharmaceutically acceptable excipient(s),
The invention provides a sustained release oral dosage form in a matrix tablet wherein the release of active ingredients in digestive fluids occurs when the matrix erodes or drug diffuses from matrix on swelling.
As used herein, the term "quetiapine" can be understood to include quetiapine or its pharmaceutically acceptable salts, preferably quetiapine fumarate, also known as quetiapine hemifumarate. Quetiapine may be used in the crystalline or amorphous form, either as a free compound or as a solvate.
"Hydrophilic polymer", which can be utilized in the formulation of the present invention, is Hydroxypropylcellulose (HPC). Hydroxypropylcellulose has a typical attribute i.e. the viscosity of the polymer is dependent on its molecular weight. Molecular weight of the polymer influences the drug release from Hydroxypropylcellulose matrix system. Low molecular weight Hydroxypropylcellulose (80 kDa) releases drug mainly by erosion. Drug release from high molecular weight Hydroxypropylcellulose is predominantly by simultaneous diffusion and erosion.
On the other hand, even if hydroxylpropylmethylcellulose is more hydrophilic than hydroxypropyl cellulose, it cannot be neatly categorized in this fashion as the

hydrophobic association between methoxy substituents results in increased erosion resistance. As a result, molecular weight variation over the range of 300 to 1000 KDa has little effect on HPMC release profiles, thus providing no flexibility to modulate release. Molecular weight variation is a more effective tool in modulating release rates for hydroxypropylcellulose and hydroxyethylcellulose based systems.
High molecular weight hydroxypropyl cellulose is preferred in the present invention which has a viscosity between 1500-3000 cps (1%) and molecular weight between 370 KDa to 1150 KDa whereas low molecular weight hydroxypropyl cellulose has viscosity between 300-600 cps (10%) and molecular weight around 80 KDa. It is also found that hydroxypropyl cellulose works better when it is used in combination. However, increase in combination of a high molecular weight hydroxypropyl cellulose alone above results in 40 % disintegration of the tablet, and shows adverse effect on the release profile of the drug. Whereas the corresponding increase in the concentration of high molecular weight Hydroxypropyl methylcellulose results in swelling of the matrix and retardation of drug release profile. Preferably, the ratio of low and high molecular weight hydroxypropyl cellulose is used in the present invention is 5:3 or more preferably 2:1 in order to achieve desirable drug release profile.
In the present invention, mechanism of drug release is predominantly by erosion due to higher proportion of low molecular weight Hydroxypropyl cellulose. To counteract this mechanism and to retard the drug release, it is preferable to use hydroxypropyl cellulose in combination with water insoluble, hydrophobic polymer such as cellulose acetate phthalate, cellulose acetate succinate, hypromellose phthalate, hydroxypropyl cellulose phthalate, hypromellose acetate succinate, polyvinylacetate phthalate, hydroxyethyl cellulose phthalate. cellulose acetate, cellulose triacetate, cellulose acetate maleate, cellulose acetate trimellitate, cellulose acetate butyrate, cellulose acetate propionate. polyethylene, polyvinyl chloride, polyethylene vinyl acetate, polydimethyl siloxane, polyether urethane, stearyl alcohol, polymethacrylates such as methacrylic acid-methyl methacrylate co-polymers, methacrylic acid-ethylacrylate co-polymers, methacrylic acid-methyl acrylate-methyl methacrylate co-polymers.
Preferably, the hydrophobic release modifying polymer includes but not limited to, various pharmaceutically acceptable methacrylates sold under the brand name EUDRAGIT ®.

Eudragit NE is a non-ionic copolymer consisting of polymethacrylic acid esters, insoluble over the entire pH range of the digestive tract.
Preferably, the combination of high molecular weight and low molecular weight hydroxypropyl cellulose can be used in the range of 15 to 40 % w/w along with Eudragit NE in the range of 0.5- 25%w/w to achieve the desired drug release.
Quetiapine fumarate has a moderate solubility in water; however this solubility is pH
dependent i.e. it is soluble in acidic pH but decreases with increase in pH which results in
reduced and variable bioavailability.
One of the most important features of this invention is the use of combination of
solubiliser and alkaiizer in the range of 1 to 20 % w/w and 1 to 15 % w/w respectively
provides suitable in-vitro dissolution profile.
Preferably the solubiliser agent used in the present invention is polyethylene glycol,
Poloxomer and surface active agents known in the art.
In the present invention, Polyethylene Glycol (PEG) acts as a solubility modifier which
controls the drug release in various pH range. High molecular weight PEGs like PEG
1000, 2000, 4000. 6000 or even 8000 are more preferred in the present formulation.
Further, the addition of an alkalizing agent in the said formulation creates a favorable local alkaline microenvironment within and in an immediate vicinity of the tablet and controls the drug release, and provides better stability to the composition under normal and stressed condition. Suitable alkalizing agents are pharmaceutically acceptable compound such as but not limited to, alkaline earth metal carbonate, alkali metal carbonates, alkali earth metal bicarbonates, alkali metal hydroxide, alkali earth metal hydroxide, alkali metal oxide and alkali earth metal oxide, which includes, but not limited to, magnesium oxide, calcium carbonate, sodium carbonate, potassium carbonate, sodium bicarbonates, potassium bicarbonates, ammonia solution, diethanolamine, monoethanolamine, potassium citrate, sodium borate, sodium citrate dehydrate, triethanolamine, sodium hydroxide and potassium hydroxides or mixtures thereof. Preferably, the alkalizing agent is Calcium carbonate.
However, as mentioned hereinbefore, the combination of polyethylene glycol and calcium carbonate in the suitable range is very critical to achieve suitable in-vitro dissolution profile. The combination of PEG: Calcium carbonate used is 3:1 and preferably 2:1 and more preferably 1:1.

In preferred embodiment, the present invention provides a sustained release tablet comprising Quetiapine or its pharmaceutical acceptable salts along with release retardant polymer(s). polyethylene glycol (PEG), calcium carbonate and one or more pharmaceutically acceptable excipients.
Other pharmaceuticaliy acceptable excipients which can be used in the preparation of the sustained release formulation are selected from binders, fillers, glidants, disintegrants, and lubricants.
Binder such as starch, pregelatinized starch, povidone, low viscosity HPMC and others can be used in small amount in a range 0.5 to 10% of the formulation. Also, 0.5 % to 10% of polymers like Eudragit NE-30D, Eudragit L 30 D, Eudragit-S-100, polyvinyl alcohol, carbomer, copovidone etc. can be used as granulating agent.
Bulking agent or filler that is used in the present invention is microcrystalline cellulose, however, other bulking agent or fillers may also be used.
The lubricant and glidant include one or more of talc, colloidal silicon dioxide, magnesium stearate, sodium stearyl fumarate and mixtures thereof.
The particle size of the pharmaceutically active ingredient may be between 1 μm to 250 urn, preferably lμm to 100 μm.
The tablets can be coated further with a hydrophobic release-modifying polymer or film forming polymer to achieve the desired drug release profile.
The coating solution comprises of shellac, zein, hydroxypropyl cellulose, hydroxypropyl methylcellulose, ethyl cellulose, polymethacrylates, polyvinyl acetate phthalate, cellulose acetate phthalate, triacetin, dibutylsebacate, a mixture of polyethylene glycol, titanium dioxide and hydroxypropyl methyl cellulose and the likes.
The formulation can be prepared by a wet granulation method, dry granulation, or a direct compression method.
The sustained release formulation for oral administration of quetiapine slowly releases the drug into blood at a uniform rate and maintains its constant level and can be effectively used for the treatment of schizophrenia, depressive episodes associated with bipolar

disorder, acute manic episodes associated with bipolar I disorder, and maintenance treatment of bipolar l disorder.
Thus, in a typical embodiment, the process for the preparation of sustained release dosage form of quetiapine comprises the steps of:
1. Mixing quetiapine and excipients in a rapid mix granulator;
2. wet granulating the mixed blend;
3. drying and milling the mixture;
4. blending the mixture with lubricant and finally compressing the blended mixture to form tablets;
5. Coating the tablets.
In a preferred embodiment, sustained release dosage form of quetiapine is prepared by
1. Mixing Quetiapine , release retardant polymers, Polyethylene glycol, Calcium carbonate and other pharmaceutically acceptable excipients in a rapid mix granulator;
2. wet granulating the mixed blend with water;
3. drying and milling the mixture;
4. blending the mixture with magnesium stearate and finally compressing the blended mixture to form tablets.
5. Coating the tablets
Following examples illustrating the embodiments of the present invention are provided.
However, it is exemplary only and should not be regarded as limitations of the present
invention.
Example 1: To study the effect of different concentrations of Polyethylene glycol
4000

Sr.
No Ingredients Formula 1A
Quantity (ms/tablet) Formula IB
Quantity (mg/tablet) Formula 1C
Quantity (mg/tablet)
1
2 Quetiapine Fumarate
eg. to Quetiapine
Polyethylene glycol (PEG 4000) 230
(200)
20 230 (200) 230 (200)

50 80 48
Lactose Monohydrate 78 62.8

4 Microcrystalline Cellulose (Avicel PH 101) 77.8 63 47.8
5 Calcium Carbonate 30 30 30
6 Hydroxy propyl 81.6 81.6 81.6

cellulose (High viscosity)
7 Hydroxy propyl cellulose (Low viscosity) 122.4 122.4 122.4
8 Magnesium Stearate 10.2 10.2 10.2
9. Colloidal silicon dioxide (Aerosil) 10 10 10
Total 660 660 660
Procedure: Ingredients Quetiapine Fumarate, Hydroxypropyl cellulose, PEG 4000, Calcium carbonate, microcrystalline cellulose and lactose were sieved and mixed in rapid mixer granulator for 10-15 minutes. The mass was wetted with water. The wet mass was dried to achieve suitable granules. The dried granules were blended with Colloidal silicon dioxide and Magnesium stearate. The lubricated mass was compressed into tablets.
Dissolution characteristics of Tablet formulation
Tablel : Dissolution profile of Formula 1A, 1 B, 1C (of Example 1) in 0.1 N HCI for initial two hours, followed by 6.8 phosphate buffer for remaining 14 hours using Apparatus ! (Basket) at 100 rpm in at 37° C.

Time
(in
hours) % Drug release

Formula 1A Formula 1B Formula 1C
I 18.0 22.0 21.0
2 34.7 35.1 39.0
4 38.0 39.9 48.8
6 40.0 47.9 73.2
8 46.8 65.6 94.0
10 60.8 90.2 98.3
12 84.1 94.2 103.3
16 87.4 98.9 106.0
Tablets of the quetiapine and other pharmaceutically acceptable excipients according to the composition described in Formula 1A, 1B or 1C were prepared and the effect of different concentrations of polyethylene glycol was studied. As can be seen through the data, the increase in the quantity of PEG 4000 increases the dissolution. Thus, the selection of suitable quantity of PEG is important to achieve suitable in-vitro dissolution profile. This is also illustrated in Figure I. Example 2: To study the effect of Calcium carbonate

Sr. No Ingredients Formula 2A Quantity (mg/tablet) Formula 2B Quantity (mg/tablet)
1 Quetiapine Fumarate eq. to Quetiapine 230 (200) 230 1 (200)

2 Polyethylene glycol (PEG 4000) 50 50
3 Calcium Carbonate — 15
4 Microcrystalline cellulose (Avicel PH 101) 78 70.5
5 Lactose monohydrate 78 70.5
6 Hydroxy propyl cellulose (High viscosity) 123 123
7 Hydroxy propyl cellulose (Low viscosity) 81 81
8 Magnesium Stearate 15 15
9. Colloidal silicon dioxide (Aerosil) 10 10
Tablet weight 665 665
Procedure: Ingredients Quetiapine Fumarate, Hydroxypropyl cellulose, PEG 4000, Calcium carbonate, microcrystalline cellulose and lactose were sieved and mixed in rapid mixer granulator for 10-15 minutes. The mass was wetted with water. The wet mass was dried to achieve suitable granules. The dried granules were blended with Colloidal silicon dioxide and Magnesium stearate. The lubricated mass was compressed into tablets.
Dissolution characteristics of Tablet formulation
Table 2- Dissolution profile of Formula 2A, 2B (of Example 2) in 0.1 N HCl for initial two hours, followed by 6.8 phosphate buffer for remaining 14 hours using Apparatus 1 (Basket) at 100 rpm in at 37° C.

Time
(in
hours) % Drug release

Formula 2A Formula 2B
1 25.6 22.6
2 37.2 34.2
4 50.3 38.2
6 59.6 46.5
8 68.5 53.4
10 79.20 65.4
12 87.40 76.2
16 96,10 82.0
Tablets of the Quetiapine and other pharmaceutically acceptable excipients according to the composition described in Formula 2A, 2B were prepared and the effect of calcium carbonate was studied. Increase in the quantity of calcium carbonate in the formulation retards the dissolution of the drug. This is illustrated in figure 2
Example 3 - Quetiapine Fumarate Extended Release Tablet 200mg using water in granulation


Sr.
No Ingredients Example 3
Quantity
mg/tablet
1 Quetiapine Fumarate eq. to Quetiapine 230 (200)
2 Polyethylene glycol (PEG 4000) 50
3 Calcium Carbonate 15
4. Microcrystalline Cellulose 40
5 6 Lactose Monohydrate
Hydroxypropylcellulose (Klucel HXF) 41 94
7 Hydroxypropylcellulose (Klucel EXF) 141
8 Magnesium Stearate 15
9 Colloidal silicon dioxide (Aerosil) 9
Tablet weight 635
Procedure: Ingredients Quetiapine Fumarate, Hydroxypropyl Cellulose, PEG 4000,
Calcium carbonate , Microcrystalline cellulose and Lactose monohydrate were sieved,
and mixed in rapid mixer granulator for 10-15 minutes. The mass was wetted with water.
The wet mass was dried to achieve suitable granules. The dried granules were blended
with Colloidal silicon dioxide and magnesium stearate. The lubricated mass was
compressed into tablets.
Dissolution characteristics of Tablet formulation
Table 3: Dissolution profile of Example 3 in 0.1 N HC1 for initial two hours, followed by
6.8 phosphate buffer for remaining 14 hours using Apparatus 1 (Basket) at 100 rpm in at
37° C.

Time in hours % drug release Example 3
1 13.3
2 20.4
4 31.5
6 44.9
8 51.6
10 12 63.40

78.70
16 89.60
Example 4 and 5: Quetiapine Fumarate Extended Release Tablets 200mg using Eudragit NE 40D and Eudragit L 30D

Sr. No Ingredient Example 4 Example 5

Quantity (me/tab) % age Quantity (me/tab) % age
35.11
1. Quetiapine Fumarate eq. to Quetiapine 230 200 35.38 230 200

2. Polyethylene glycol (PEG 4000) 50 7.69 50 7.63
3. Calcium carbonate 30 4.62 30 4.58

4. Microcrystalline cellulose (AvicelPH 101) 16 2.46 23 3.51
5. Lactose monohydrate
(Pharmatose 200 M) 15 2.31 23 3.51
6. Hydroxy propyl cellulose (Low viscosity) 157 24.15 157 24.00
7. Hydroxy propyl cellulose (High viscosity) 78 12.00 78 11.91
8. Eudragit NE 40D 125 (50) 7.69
9. Eudragit L 30 D 133 20.31
10. Magnesium Stearate 15 2.31 15 2.29
11. Colloidal silicon dioxide (Aerosil) 9 1.38 9 1.37
Tablet weight 650 655
Procedure:
Ingredients Quetiapine Fumarate, HPC, PEG 4000, Calcium carbonate, Microcrystalline cellulose, and Lactose were sieved and mixed in rapid mixer granulator for 10-15 minutes. The mass was wetted with Eudragit NE 30D or Eudragit L 30D. The wet mass was dried to achieve suitable granules. The dried granules were blended with magnesium stearate and aerosil. The lubricated mass was compressed into tablets. Dissolution characteristics of Tablet formulation
Table 4: The dissolution was performed in 0.1 N HCl for initial two hours, followed by 6.$ phosphate buffer for remaining 14 hours using Apparatus 1 (Basket) at 100 rpm in at 37° C.

Time in hours % Drug release example 4 % Drug release example 5
1 21.7 11.S
2 31.1 22.5
4 38.1 36.4
6 46.0 48.3
8 57.1 50.6
10 67.6 58.9
12 80.0 68.7
16 90.9 76.4
Example 6 - Quetiapine Fumarate Extended Release Tablets 200mg, 300mg using Eudragit NE 40D in granulation

Sr.no.
Ingredients Formula 6A
Quantity
(mg/tablet) Formula 6B Quantity
(mg/tablet)
1 Quetiapine Fumarate eq. to Quetiapine 230 (200) 345 (300)
2. Polyethylene glycol (PEG 4000) 50 75
Calcium Carbonate 30 45
4. Microcrystalline cellulose (Avicel PH 101) 14 21
5. Lactose monohydrate (Pharmatose 200M) 14 21
6. Hydroxypropyl cellulose (Klucel EXF) 150 225
7. Hvdroxypropylcellulose (Klucel HXF) 75 112.5
8. Eudragit NE 40D 100 150
9. Magnesium Stearate 12 18
10. Colloidal silicon dioxide (Aerosil) 5 7.5
Tab. Wt 620 930
Procedure: Ingredients Quetiapine Fumarate, Hydroxypropyl cellulose, PEG 4000, Calcium carbonate , microcrystalline cellulose and lactose were sieved and mixed in rapid mixer granulator for 10-15 minutes. The mass was wetted with Eudragit NE 40D . The wet mass was dried to achieve suitable granules. The dried granules were blended with Colloidal silicon dioxide and Magnesium stearate . The lubricated mass was compressed into tablets.
Dissolution characteristics of Tablet formulation
Table 5: Dissolution profile of Formula 6A, 6B (of example 6) in 0.1 N HCl for initial two hours, followed by 6.8 phosphate buffer for remaining 14 hours using Apparatus 1 (Basket) at 100 rpm in at 37° C.

Time (hrs) % Drug release

Formula 6 A Formula 6 B
1 16.31 12.7
2 37.37 21.6
4 33.52 25.8
6 53.6 34.5
8 81.02 48.1
10 88.78 68.1
12 93.35 81.9
16 93.61 90.1

Example 7 - Quetiapine Fumarate Extended Release Tablets 400mg using Eudragit NE 40D in granulation

Sr.no
Ingredients Example 7
Quantity
(mg/tablet)
] Quetiapine Fumarate eq. to Quetiapine 460 (400)
2. Polyethylene glycol (PEG 4000) 75
J. Calcium Carbonate 45
4. Microcrystalline cellulose (Avicel PH 101) 42
6.
7. Hydroxypropyl cellulose (Klucel EXF) 225

Hydroxypropyl cellulose (Klucel HXF) 112.5
8. 9. Eudragit NE40D 150 (60)

Magnesium Stearate 18
10. Colloidal silicon dioxide (Aerosil) 7.5
Tablet weight 1045
Procedure: Ingredients Quetiapine Fumarate, Hydroxypropyl cellulose, PEG 4000, Calcium carbonate, microcrystalline cellulose and lactose were sieved and mixed in rapid mixer granulator for 10-15 minutes. The mass was wetted with Eudragit NE 40D. The wet mass was dried to achieve suitable granules. The dried granules were blended with Colloidal silicon dioxide and Magnesium stearate. The lubricated mass was compressed into tablets.
Table 6: Dissolution profile of example 7 in 0.1 N HC1 for initial two hours, followed by 6.8 phosphate buffer for remaining 14 hours using Apparatus 1 (Basket) at 100 rpm in at 37° C.

Time (hrs) % Drug release

Example 7
1 16.31
2 37.37
4
6 33.52 ,
53.6
8 81.02
10 88.78
12 93.35 93.61
16


Example 8 - Quetiapine Fumarate Extended Release Tablets 200mg using Eudragit NE 30D in granulation

Sr.no.
Ingredients Example S Quantity
(mg/tablet)
1 Quetiapine Fumarate eq. to Quetiapine 230 (200)
2.
3. Polyethylene glycol (PEG 4000)
Calcium Carbonate 50 30
4 Lactose monohydrate (Pharmatose 200 M) 23
5. Microcrystalline cellulose (Avice-IPH 101) 23
6. Hydroxypropyl cellulose (Klucel EXF) 157
7. Hydroxypropycellulose (Klucel HXF) 78
8. Eudragit NE 30D 133 (40)
9. Magnesium Stearate 15
10. Colloidal silicon dioxide (Aerosil) 9
Tablet Weight 655
Procedure: Ingredients Quetiapine Fumarate, Hydroxypropyl cellulose, PEG 4000, Calcium carbonate, microcrystalline cellulose and lactose were sieved and mixed in rapid mixer granulator for 10-15 minutes. The mass was wetted with Eudragit NE 30D. The wet mass was dried to achieve suitable granules. The dried granules were blended with Colloidal silicon dioxide and Magnesium stearate. The lubricated mass was compressed into tablets.
Table 7; Dissolution profile of example 8 in 0.1 N HC1 for initial two hours, followed by 6.8 phosphate buffer for remaining 14 hours using Apparatus 1 (Basket) at 100 rpm in at 37° C.

Time (hrs) % Drug release
Example 8

16.31
2 37.37
4 33.52
6 53.6
8 81.02 88.78
10

12 93.35
16 93.61
The release profile of the above mentioned examples are equivalent to the marketed product Seroquel XR®.

We Claim,
1. A pharmaceutical composition in a solid oral dosage form comprising
a) quetiapine or its pharmaceutically acceptable salts;
b) combination of hydrophilic and hydrophobic release retardant polymer(s);
c) a solubiliser;
d) an alkalizer and
optionally with one or more pharmaceutically acceptable excipient(s) wherein the said dosage form is provided in sustained release.
2. The pharmaceutical composition according to claim 1, wherein quetiapine salt is quetiapine fumarate.
3. The pharmaceutical composition according to claim 1, wherein quetiapine is used in the range of 15 to 50 % w/w.
4. The pharmaceutical composition according to claim 1, wherein release retardant polymers are selected from cellulose polymer and polymethacrylate based polymer.
5. The pharmaceutical composition according to claims I and 5, wherein the cellulose polymer is hydroxypropyl cellulose used in the range of 10 to 40 % w/w.
6. The pharmaceutical composition according to claims 1, 5 and 6, wherein hydroxypropyl cellulose used is the combination of high molecular weight and low molecular weight hydroxy propyl cellulose.
7. The pharmaceutical composition according to claims 1 and 5, wherein the polymethacrylate based polymer is Eudragit NE used in the range of 0.5 to 30 % w/w
8. The pharmaceutical composition according to claim 1, wherein solubiliser is polyethylene glycol used in the range of 0.2 to 20 % w/w.
9. A pharmaceutical composition of claim 1 and 9. wherein the molecular weight of polyethylene glycol is preferably in the range of 1000-8000, most preferably 4000,
10. The pharmaceutical composition according to claim 1, wherein alkalizer is calcium carbonate used in the range of 0.2 to 30 %.
11. The pharmaceutical composition according to claim 1, wherein pharmaceutically acceptable excipients comprises of binders, fillers, glidants, disintegrants, and lubricants,

12. The pharmaceutical composition according to claim 1, wherein the composition is tablet.
13. The pharmaceutical composition according to claim 1 and 12, wherein the process used for manufacturing the said composition is wet granulation, dry granulation or direct compression.
14. A pharmaceutical composition of claim 1 and 12. wherein the tablet is coated.