FORM 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 PHARMACEUTICAL COMPOSITIONS OF QUETIAPINE OR SALTS THEREOF


2. Applicants)
(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.


EXTENDED RELEASE PHARMACEUTICAL COMPOSITIONS OF
OUETIAPINE OR SALTS THEREOF
FIELD OF THE INVENTION
The present invention relates to an extended release pharmaceutical composition comprising quetiapine or pharmaceutically acceptable salts thereof and to process of preparing extended release compositions. The extended release pharmaceutical compositions are useful in providing therapeutically effective levels of quetiapine or pharmaceutically acceptable salts thereof for extended periods of time.
BACKGROUND OF THE INVENTION
The compound, ll-[4-[2-(2-hydroxyethoxy) ethyl]-l-piperazinyl]-dibenzo [b, f] [1, 4] thiazepine (Quetiapine) [I]

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 (Seroquel® XR marketed by AstraZeneca).
The preparation and physical properties of ll-[4-[2-(2-hydroxyethoxy)ethyl]-l-piperazinyl] dibenzo[b,f][l,4]-thiazepine, and its pharmaceutically acceptable salts are described in published European Patents EP 240,228 and 282,236 as well as in U.S. Pat. No. 4,879,288.
7 JUL 2009

Drug levels can be maintained above the lower level of the therapeutic plasma concentration for longer periods of time by administering larger doses of conventionally formulated dosage forms, but this approach might produce toxic effects due to high plasma concentration of the drug. Alternatively, another approach is to administer a drug at certain intervals of time, resulting in oscillating drug levels, the so-called peak and valley effect. This approach is generally associated with several potential problems, such as a large peak (toxic effect) and valley (non-active drug level) effect, and a lack of patient compliance leading to drug therapy inefficiency or failure. To overcome such issues, extended release pharmaceutical compositions can be formulated with the objective of releasing the drug in a sustained or controlled manner for an extended period of time.
It is desirable in the treatment of a number of diseases, both therapeutically and prophylactically, to provide the active pharmaceutical ingredient in an extended release form. Desirably the extended release provides a generally uniform and constant rate of release over an extended period of time which achieves a stable and desired blood (plasma) level of the active ingredient without the need for frequent administration of the medicament.
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 dependent rate controlling polymer and 2) release rate modifying system.
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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.
WO2008/060228 discloses an extended release formulation of quetiapine together with hydroxy propyl methyl cellulose of different viscosities.
WO 20070110878 discloses sustained release composition of poorly soluble active agent with solubilizer and combination of acid soluble and pH dependent polymer.
US 20090099151 disclose modified release compositions of active agent with at least two swellable pH independent polymers.
Though several attempts have been made for the development of extended release formulations of quetiapine, the problems associated with the said dosage forms like dose dumping, initial burst release, undesired release profile and more over physical instability still remain unsolved. However, there still exists a need to develop an extended release formulation of quetiapine which provides better control over release profile and is bioequivalent to marketed formulation Seroquel XR along with reduced side effects, easier to manufacture, and involves a low formulation cost.
SUMMARY OF THE INVENTION
The present invention relates to an extended release pharmaceutical composition comprising quetiapine or a pharmaceutically acceptable salt thereof along with one or more pharmaceutically acceptable rate controlling polymers.
The invention also relates to process of preparing extended release pharmaceutical composition comprising quetiapine or a pharmaceutically acceptable salt thereof along with one or more pharmaceutically acceptable rate controlling polymers.
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In one aspect, the invention relates to an extended release pharmaceutical composition comprising a) a core of quetiapine or pharmaceutically acceptable salts thereof along with one or more pharmaceutically acceptable rate-controlling polymers; b) a functional coating around said core optionally with pharmaceutically acceptable excipients.
In another aspect, the invention relates to an extended release pharmaceutical composition comprising a) a core of quetiapine or pharmaceutically acceptable salts thereof along with one or more pharmaceutically acceptable rate-controlling polymers; b) a functional coating of one or more pharmaceutically acceptable rate-controlling polymers around said core optionally with pharmaceutically acceptable excipients.
In another aspect, the invention relates to an extended release pharmaceutical composition comprising a) a core of quetiapine or pharmaceutically acceptable salts thereof along with one or more pharmaceutically acceptable rate-controlling polymers; b) a functional coating of one or more pharmaceutically acceptable rate-controlling polymers around said core optionally with pharmaceutically acceptable excipients, wherein said pharmaceutically acceptable rate-controlling polymers comprises one or more hydrocolloid polymers.
In another aspect, the invention relates to an extended release pharmaceutical composition comprising a) a core of quetiapine or pharmaceutically acceptable salts thereof along with combination of three pharmaceutically acceptable rate-controlling polymers which are xanthan gum, alginic acid or alginate or salts and optionally polymer or copolymer of acrylic acid; b) a functional coating of one or more pharmaceutically acceptable rate-controlling polymers around said core optionally with pharmaceutically acceptable excipients, wherein said pharmaceutically acceptable rate-controlling polymer in functional coating comprises of alginic acid or alginate or salts.
In another aspect of the invention, there is provided a process of preparation of extended release pharmaceutical composition of quetiapine or pharmaceutically acceptable salts thereof, which process comprises of; i) mixing quetiapine or pharmaceutically acceptable
- 7 JUL 2009

salts thereof with one or more pharmaceutically acceptable rate-controlling polymers optionally with other pharmaceutically acceptable excipients; ii) formulating the mixture of step (i) into suitable dosage form; iii) coating the dosage form of step (ii) with one or more pharmaceutically acceptable rate-controlling polymers.
In another aspect of the invention, there is provided a process of preparation of extended release pharmaceutical composition of quetiapine or pharmaceutically acceptable salts thereof, which process comprises of: i) mixing quetiapine or pharmaceutically acceptable salts thereof with xanthan gum, alginic acid or alginate or salts and optionally polymer or copolymer of acrylic acid optionally with other pharmaceutically acceptable excipients; ii) formulating the mixture of step (i) into tablet dosage form; iii) coating the tablet dosage form of step (ii) with alginic acid or alginate or salts optionally with other pharmaceutically acceptable excipients.
In another aspect, there is provided an extended release pharmaceutical composition comprising a) a core of quetiapine or a pharmaceutically acceptable salt thereof along with one or more pharmaceutically acceptable rate-controlling polymers; b) a functional coating around said core optionally with pharmaceutically acceptable excipients, wherein said composition exhibits dissolution profile such that i) at least 10% of quetiapine or pharmaceutically acceptable salts thereof is released within 4hrs, ii) at least 30% of quetiapine or pharmaceutically acceptable salts thereof is released within 8 hrs, iii) at least 50% of quetiapine or pharmaceutically acceptable salts thereof is released within 12 hrs, iv) at least 70% of quetiapine or pharmaceutically acceptable salts thereof is released within 20hrs, as measured in USP Type I apparatus at lOOrpm in 1000ml of pH 6.8 phosphate buffer or pH 4.5 acetate buffer.
In another aspect, there is provided an extended release pharmaceutical composition comprising a) a core of quetiapine or a pharmaceutically acceptable salt thereof along with one or more pharmaceutically acceptable rate-controlling polymers; b) a functional coating around said core optionally with pharmaceutically acceptable excipients, wherein
- 7 JUL 2009

said composition exhibits Cmax from about 150 to 240 ng/ml and AUC« from about 2400 ng.hr/ml to about 3800ng.hr/ml
DETAILED DESCRIPTION OF THE INVENTION
The present invention relates to an extended release pharmaceutical composition comprising a) a core of quetiapine or pharmaceutically acceptable salts thereof along with one or more pharmaceutically acceptable rate-controlling polymers; b) a functional coating with pharmaceutical^ acceptable rate-controlling polymers around said core optionally with pharmaceutically acceptable excipients, which provides therapeutic concentrations of quetiapine or pharmaceutically acceptable salts thereof for extended periods of time.
The term "extended release" for the purposes of this invention refers to release of quetiapine over a prolonged period of time. The term 'extended release' as herein used includes sustained release, modified release, delayed release and controlled release.
The term "pharmaceutically acceptable salts" includes but is not limited to salts such as chloride, maleate, fumarate, citrate, phosphate, methane sulphonate, sulphate and the like.
The pharmaceutically acceptable "rate controlling polymers" may comprise hydrocolloid polymers. The term "hydrocolloid polymers" may comprises of hydrophilic polymers of natural origin may be vegetable, animal or microbial. They include but are not limited to gums such as xanthan gum, veegum, agar, guar gum, locust bean gum, gum arabic, okra gum; bentonite; arabinoglactin; pectin; tragacanth; scleroglucan; dextran; amylase; amylopectin; dextrin; alginic acid or other alginates such as alginic acid derivatives e.g. alginic acid or alginate or salts, propylene glycol alginate and the like or mixtures thereof. Hydrocolloid polymers iurther include natural/synthetic polymers and copolymers of acrylic acid such as polymer or copolymer of acrylic acid and the like.
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The polymer system along with functional coat used in the present system is unique and act to produce the better control over the release profile. The combination of xanthan gum, alginic acid or alginate or salts and optionally polymer or copolymer of acrylic acid results in synergistic action, wherein one polymer potentiates the activity of the other when incorporated together. Such a system controls the initial burst release of quetiapine and prevents dose dumping. Additionally, it facilitates the both diffusion controlled and erosion controlled release of quetiapine resulting in better control over initial drug release. Further, functional coat with alginate provides integrity to dosage form and better control over release profile over the entire period, till complete release occurs. This leads to a product which is bioequivalent to Seroquel XR®. The major advantage of such polymer system with functional coat is that problems of initial burst release, dose dumping, lesser controlled release profile are circumvented by using single set of hydrocolloid polymers. On the other hand, numerous attempts have been made in the art to solve the same set of problems using combination of different categories of polymers viz pH dependent, pH independent, gellable and swellable etc but the attempts were not successful.
"Bioequivalency" is established by a 90% Confidence Interval (CI) of between 0.80 and 1.25 for both Cmax and AUC under USFDA regulatory guidelines, or a 90% CI for AUC of between 0.80 to 1.25 and a 90% CI for Cmax of between 0.70 to 1.43 under the European regulatory guidelines (EMEA).
The term "confidence interval" as used herein refers to the plain meaning known to ordinary skill in the art. The confidence interval refers to a statistical range with a specified probability that a given parameter lies within the range.
Xanthan gum comprises several different grades of gum that have varying particle sizes, viscosities and molecular weights. Xanthan gum is a polysaccharide gum which contains D-glucose and D-mannose as the dominant hexose units, along with D-glucuronic acid, and can be prepared as sodium, potassium or calcium salt. Viscosity of 1% aqueous solution of xanthan gum at 25°C may range from 1200cps to 1600cps.
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Alginic acid or alginate or salts comprises different grades, which have different solution viscosities. It consists chiefly of the sodium salt of alginic acid, which is a mixture of polyuronic acids composed of residues of D-mannuronic acid and L-glucuronic acid. Viscosity of l%w/v aqueous solution, at 20°C may range from 20-400cps and viscosity may vary depending on concentration, pH, temperature or the presence of metal ions.
Polymer or copolymer of acrylic acids comprise high molecular weight polymers of acrylic acid that are crosslinked with either allyl sucrose or allyl ethers of pentaerythritol containing between 56%-68% of carboxylic acid groups. It includes different grades that vary in molecular weight, degree of cross-linking, viscosities and residual components. Viscosity of 0.5%w/v aqueous solution at 25°C may range from 300-1, 15,000cps.
In one of the embodiment, the present invention comprises 10-60%w/w of quetiapine or pharmaceutically acceptable salts thereof. The present invention preferably comprises 10-50% w/w of quetiapine with respect to composition weight.
In another embodiment, the present invention comprises l-70%w/w of one or more pharmaceutically acceptable rate-controlling polymers. The present invention preferably comprises 5 to 60% w/w of pharmaceutically rate-controlling polymers with respect to composition weight.
In one embodiment, quetiapine used in the present invention may have a D90 particle size of about 200microns, preferably of about 100 microns.
The dosage form of the invention comprises one or more of tablet, capsule, tablet in tablet, tablet in capsule, pellets, granules, powder, pellets in capsule, granules in capsule, spheroids, beads or other dosage form suitable for administration.
The dosage form of the invention further contains pharmaceutically acceptable excipients such as diluents, lubricants, binders, disintegrants and the like.
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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, microcrystalline 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
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.
The above listed excipients should be taken as merely exemplary and not limiting of the types of excipients that can be included in the formulations of the present invention. Also it has to be appreciated that there is considerable overlap between the above listed excipients in common usage since a given excipient is commonly used for any of several apparent functions. The amount of each excipient employed may vary within the ranges well known to those skilled in the art.
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The composition of the present invention may be prepared by conventional technique well known to those skilled in the art such as wet granulation, direct compression, dry compaction (slugging) and the like. Quetiapine or pharmaceutically acceptable salts thereof may be mixed with one or more rate controlling polymers, optionally with other pharmaceutically acceptable excipients. The mixed components may be wet granulated, the granules may be dried and milled, the mixture may be blended with one or more rate controlling polymers, lubricants and the blended mixture may be compressed to form tablets or filled into capsules. The tablets may be coated with a functional coat using one or more pharmaceutically acceptable rate-controlling polymers optionally followed by a non-functional coat.
The functional coat comprises of one or more pharmaceutically acceptable rate controlling polymers. The rate controlling polymer in the functional coat may be present in an amount of 1-20% by weight of the composition. The rate controlling polymer is preferably present in the range of 1 to 15% by weight of the composition.
The bioequivalence studies between Seroquel XR (200mg, Reference) and tablets of the present invention (200mg, Test) are mentioned in Table 4. The study was monitored in terms of Cmax, AUC, achieved with the test products and reference product (Seroquel XR®).The tablets of the invention are found to be bioequivalent with Seroquel XR®. Figure 1 shows mean plasma concentration time curve of test product of the invention and the reference product, Seroquel XR®.
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.
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Example: Example-1
Table-1

Ingredients Range (w/w %) Range (w/w %)
Example-1 Example-2
Quetiapine fumarate 10-50% 15-45%
Alginic acid or alginate or salts 1-15% 3-13%
Xanthan gum 5-30% 8-25%
Microcrystalline Cellulose 15-60% 20-55%
Purified water q.s. q.s.
Polymer or copolymer of acrylic acid 1-15% ~
Magnesium stearate 0.5-5% 1.5-4.5%
Functional Coating
Alginic acid or alginate or salts 1-10% 2-8%
Triethyl citrate 0.7% 0.7%
Non-functional coating
Opadry 1-5% 1.5-4.5%
Procedure: Quetiapine fumarate, microcrystalline cellulose, alginic acid or alginate or salts and xanthan gum are mixed and granulated with water. Granules are dried and mixed with polymer or copolymer of acrylic acid and magnesium stearate to form final blend. The resultant blend is compressed to form tablets and tablets are coated with alginic acid or alginate or salts functional coat and finally with aqueous dispersion of opadry.
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Dissolution studies data:
Apparatus: USP Type I - Basket, 100 rpm, pH 4.5 acetate buffer, 1000ml. Following is
the dissolution data obtained for example 1 in pH 4.5 acetate buffer.
Table-2

Time Points
(Hrs) Seroquel XR® Example 1
2 15 7
4 31 19
8 63 44
12 87 59
20 103 77
Apparatus: USP Type I - Basket, 100 rpm, pH 6.8 phosphate buffer, 1000ml. Following
is the dissolution data obtained for example 1 in pH 6.8 acetate buffer.
Table-3

Time Points (Hrs) Seroquel XR® Example 1
2 9 12
4 21 30
8 47 55
12 74 80
20 102 96
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TabIe-4 (Bioequivalence summary table)

Parameter Test Ref Ratiof%Refl
Ln(AUGc) (hr* ng/ml) 3107.73 3353.45 92.67
Ln (AUClast) (hr*ng/ml) 3026.31 3273.78 92.44
Ln (Cmax) (ng/ml) 199.47 200.07 99.70
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We claim;
1) An extended release pharmaceutical composition comprising a) a core of quetiapine or pharmaceutically acceptable salts thereof along with one or more pharmaceutically acceptable rate-controlling polymers; b) a functional coating of one or more pharmaceutically acceptable rate-controlling polymers around said core optionally with pharmaceutically acceptable excipients.
2) The composition of claim 1, wherein said pharmaceutically acceptable rate-controlling polymers comprises one or more hydrocolloid polymers.
3) The composition of claim 2, wherein said hydrocolloid polymers comprises of xanthan gum, veegum, agar, guar gum, locust bean gum, gum arabic, okra gum; bentonite, arabinoglactin, pectin, tragacanth, scleroglucan, dextran, amylase, amylopectin, dextrin, alginic acid or alginates, polymer or copolymers of acrylic acid or mixtures thereof.
4) An extended release pharmaceutical composition comprising a) a core of quetiapine or pharmaceutically acceptable salts thereof along with combination of three pharmaceutically acceptable rate-controlling polymers which are xanthan gum, alginic acid or alginates or salts thereof and optionally polymer or copolymers of acrylic acid; b) a functional coating of pharmaceutically acceptable rate-controlling polymer which comprises of alginic acid or alginate or salts around said core optionally with pharmaceutically acceptable excipients.
5) A process of preparation of extended release pharmaceutical composition of quetiapine or pharmaceutically acceptable salts thereof, which process comprises of: i) mixing quetiapine or pharmaceutically acceptable salts thereof with one or more pharmaceutically acceptable rate-controlling polymers optionally with other pharmaceutically acceptable excipients; ii) formulating the mixture of step (i) into
-7 JUL 2009

suitable dosage form; iii) coating the dosage form of step (ii) with one or more pharmaceutically acceptable rate-controlling polymers.
6) A process of preparation of extended release pharmaceutical composition of quetiapine or pharmaceutically acceptable salts thereof, which process comprises of: i) mixing quetiapine or pharmaceutically acceptable salts thereof with xanthan gum, alginic acid or alginates or salts thereof and optionally polymer or copolymers of acrylic acid optionally with other pharmaceutically acceptable excipients; ii) formulating the mixture of step (i) into tablet dosage form; iii) coating the tablet dosage form of step (ii) with alginic acid or alginates or salts thereof optionally with other pharmaceutically acceptable excipients.
7) An extended release pharmaceutical composition comprising a) a core of quetiapine or a pharmaceutically acceptable salt thereof along with one or more pharmaceutically acceptable rate-controlling polymers; b) a functional coating around said core optionally with pharmaceutically acceptable excipients, wherein said composition exhibits dissolution profile such that i) at least 10% of quetiapine is released within 4hrs, ii) at least 30% of quetiapine is released within 8 hrs, iii) at least 50% of quetiapine is released within 12 hrs, iv) at least 70% of quetiapine is released within 20hrs, as measured in USP Type I apparatus at l00rpm in 1000ml of pH 6.8 phosphate buffer or pH 4.5 acetate buffer.
8) An extended release pharmaceutical composition comprising a) a core of quetiapine or a pharmaceutically acceptable salt thereof along with one or more pharmaceutically acceptable rate-controlling polymers; b) a functional coating around said core optionally with pharmaceutically acceptable excipients, wherein said composition exhibits Cmax from about 150 to 240 ng/ml and AUCoo from about 2400 ng.hr/ml to about 38O0ng.hr/ml.
9) The composition of claim 1 or 4, wherein the composition comprises 10-60% w/w of quetiapine or pharmaceutically acceptable salts thereof.

10) The composition of claim 1 or 4, wherein the composition comprises 1-70% w/w of pharmaceutically acceptable rate controlling polymers.