Field of The Invention
The present invention relates to a sustained release dosage form comprising Quetiapine or
a pharmaceutically acceptable salt(s), polymorphs, solvates, hydrates thereof and process
for its preparation.
Background of The Invention
Quetiapine and its salts, particularly Quetiapine hemifumarate, have been employed as
pharmaceutically active agents in the treatment of schizophrenia and bipolar mania.
Quetiapine fumarate is a psychotropic agent belonging to a chemical class of
dibenzothiazepine derivatives. The chemical designation is 2-[2-(4-dibenzo
[b,f][l,4]thiazepin - 11-y1-1-piperazinyl)ethoxy]-ethanol fumarate (2:1) (salt). It is present
in tablets as the fumarate salt.
US 4,879,288 disclose the product Quetiapine and its pharmaceutically acceptable salt(s)
along with preparation process.
Dosing regimens for antipsychotics is generally two or three tablets per day. These
dosing regimens have proved disadvantageous because of lack of convenience, and more
importantly, lack of compliance. Control of Quetiapine plasma levels is useful during
treatment. For example, when a patient presents with acute psychosis, it may be desirable
to introduce an immediate large dosage of Quetiapine, followed by the maintenance of
sustained plasma level of Quetiapine. Single dosage forms that provide particular plasma
profiles of Quetiapine are thus desirable. Many techniques have been used to provide
sustained release pharmaceutical dosage forms in order to maintain therapeutic serum
levels of medicaments and to minimize the effects of missed doses of drugs caused due to
lack of patient compliance.
It is typically the goal of all sustained-release preparations to provide a longer period of
pharmacological response after the administration of the dosage form than that which is
ordinarily experienced after the administration of the immediate release dosage forms.
Desirably the sustained 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.
However, it is often not possible to readily predict whether a particular sustained release
formulation will provide the desired sustained release of a relatively sparingly soluble to
insoluble drug, and it has generally been found that it is necessary to carry out
considerable experimentation to obtain sustained release formulations of such drugs
having the desired bioavailability when ingested.
US 5,948,437 disclose sustained release formulation of Quetiapine and its salt using
gelling agents.
US 2005158383 is related to a dual retard solid dosage formulation comprising a matrix
comprising a therapeutically effective amount of Quetiapine or a pharmaceutically
acceptable salt thereof; and a wax material.
WO 2007/133583 A2 is related to a zero order modified release dosage form having a
matrix core comprising hydrophobic agent, which acts as a release retardant and a
modified release coating.
The recommended initial dose is 300 mg/day. Patients should be titrated within a dose
range of 400 - 800 mg/day depending on the response and tolerance of the individual
patient. Dose increases can be made at intervals as short as 1 day and increments of up to
300 mg/day.
For some patients, the Quetiapine dosage required for therapeutic effect is quite high,
especially if a sustained release dosage form is administered. For example, the largest
current dosage form is a 300 mg tablet, administered two or three times daily. Thus an
equivalent once a day dosage form would contain high amount of Quetiapine.
When a high dosage of Quetiapine is combined with excipients, the resulting dosage form
(e.g., tablets, capsules, etc.) may be considerably larger than is desirable. Also, the
dosage form can be undesirably large when Quetiapine is combined with other active
agents, especially other high dose active agents. The large size of these dosage forms can
be difficult for patients, especially elderly patients, to swallow. Further, large dosage

form size may increase the risk of choking upon oral administration and may reduce
patient compliance.
Thus there exists a need for a dosage form comprising a high dose amount of Quetiapine
that has a smaller size than the conventional dosage forms containing substantially the
same dose amount of Quetiapine.
The present invention addresses these and other needs for improved Quetiapine dosage
forms, particularly controlled release and/or sustained release dosage forms.
The present invention relates to a pharmaceutical composition and more particularly to a
sustained release pharmaceutical composition comprising Quetiapine or a
pharmaceutically acceptable salt thereof.
Objects of The Invention
It is an object of the present invention to provide a sustained release dosage form
comprising matrix 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 excipient(s) thereof.
Another object of the present invention to provide a sustained release dosage form
comprising: a first granulation comprising Quetiapine or its pharmaceutically acceptable
salts, polymorphs, solvates, hydrates thereof and one or more release controlling material;
and a second granulation comprising one or more release controlling material which is
the same or different than the one or more release controlling material of the first
granulation and optionally quetiapine or its pharmaceutically acceptable salts,
polymorphs, solvates, hydrates thereof.
Another object of the present invention to provide a method of preparing a sustained
release dosage form comprising: first granulation comprising Quetiapine or its
pharmaceutically acceptable salts, polymorphs, solvates, hydrates thereof and one or
more release controlling material followed by milling; and second granulation using
milled granules of first granulation and one or more release controlling material which is
the same or different than the one or more release controlling material of the first

granulation followed by milling; blending the said milled granules after second
granulation with lubricant followed by compression to form a sustained release dosage
form.
Another object of the present invention to provide a sustained release dosage form
comprising: immediate release matrix comprising Quetiapine or a pharmaceutically
acceptable salt, polymorphs, solvates, hydrates thereof and one or more pharmaceutically
acceptable excipients; and sustained release coating comprising one or more release
controlling material.
Another object of the present invention to provide a sustained release dosage form
comprising an active agent Quetiapine or a pharmaceutically acceptable salt, polymorphs,
solvates, hydrates thereof; wherein the active agent is present in an amount of more than
40% by weight of the total weight of the core.
Yet another object of the present invention to provide a sustained release dosage form
comprising a. first granulation comprising Quetiapine or its pharmaceutically acceptable
salts, polymorphs, solvates, hydrates thereof and one or more release controlling material;
and a second granulation comprising one or more release controlling material which is
the same or different than the one or more release controlling material of the first
granulation; wherein Quetiapine is present in an amount of more than 40% by weight of
the total weight of the core.
Detailed Description of The Invention
In accordance with the above-mentioned objects and others, the present invention in
certain embodiments is directed to a sustained release Quetiapine dosage form comprises
a matrix, wherein the matrix comprises a pharmaceutically effective amount of
Quetiapine and a non-gellable release controlling polymer.
The non-gellable release controlling polymer is selected from, but not limited to,
cellulose acetate, acrylic polymer such as Poly (ethyl acrylate, methyl methacrylate)
polymer e.g. Eudragit NE 30D®,, ammonioalkyl methacrylate copolymers e.g Eudragit
RL/RS® etc.

In another aspect, the present invention is directed to a sustained release solid oral dosage
form comprising a multi-granular formulation, preferably a bigranular formulation with
Quetiapine or a pharmaceutically acceptable salt, polymorphs, solvates, hydrates
(hereinafter referred as Quetiapine) thereof in the granulation.
Preferably, the dosage form comprises a first granulation comprising one or more release
controlling material and Quetiapine and a second granulation comprising one or more
controlling material, which is the same, or different than the one or more release
controlling material of said first granulation and optionally quetiapine or its
pharmaceutically acceptable salts, polymorphs, solvates, hydrates thereof.
The release rate of the drug from the dosage form can be sustained by adjusting the ratio
of the two granulations.
In certain embodiments the present invention is directed to a sustained release dosage
form comprising: a normal release matrix comprising Quetiapine and one or more
pharmaceutically acceptable excipient(s); and a sustained release coating comprising one
or more release controlling material.
In yet another embodiment the present invention is directed to a sustained release dosage
form comprising an active agent Quetiapine, and one or more release controlling
material, wherein the active agent is present in an amount of more than 40% by weight of
the total weight of the core.
In another embodiment the present invention is directed to sustained release dosage form
wherein the dosage form can be bilayered compositions having drug i.e. quetiapine
fumarate in one or both layers. Both layers may have sustained release or one layer has
immediate release and the other sustained.
Further the dosage form can have drug comprising beads or pellets having similar or
different release profiles.
The term "active agent" "drug" "active" can be interchangeably used.
The term "sustained release" refers to any composition or dosage form, which is other
than immediate release such as extended release", "sustained release", "controlled

release", "pulsatile release" "timed release" "programmed release" "delayed release"
and/or "rate controlled" compositions or dosage forms.
The term "core" encompasses the drug Quetiapine as defined, one or more
pharmaceutically acceptable excipients optionally one or more release controlling
material.
The dosage forms of the present invention may further comprise pharmaceutically
acceptable excipients known in the art. These include but are not limited to binders,
lubricants, glidants, fillers, diluents and the like.
The amounts of additive employed will depend upon how much active agent is to be
used. One excipient can perform more than one function.
Binders include, but are not limited to, microcrystalline cellulose such as products known
under the registered trade marks Avicel, Filtrak, Heweten or Pharmacel.
Lubricants may be selected from, but are not limited to, those conventionally known in
the art such as Magnesium, Aluminium or Calcium or Zinc stearate, polyethylene glycol,
glyceryl behenate, mineral oil, sodium stearyl fumarate, stearic acid, hydrogenated
vegetable oil and talc.
Glidants include, but are not limited to, silicon dioxide; magnesium trisilicate, powdered
cellulose, starch, talc and tribasic calcium phosphate.
Fillers or diluents, which include, but are not limited to confectioner's sugar,
compressible sugar, dextrates, dextrin, dextrose, fructose, lactitol, mannitol, sucrose,
starch, lactose, xylitol, sorbitol, talc, microcrystalline cellulose, calcium carbonate,
calcium phosphate dibasic or tribasic, calcium sulphate, and the like can be used.
One or more of these additives can be selected and used by the skilled artisan having
regard to the particular desired properties of the solid oral dosage form. The amount of
each type of additive employed, e.g. glidant, binder, disintegrant, filler or diluent and
lubricant may vary within ranges conventional in the art.
The sustained release dosage form of the invention, wherein the core can be formed by
various methods known in the art.

In certain embodiments, the present invention is further directed to a method of preparing
a sustained release dosage form as described herein.
a) first granulation comprising Quetiapine and one or more release controlling
material
b) followed by milling
c) second granulation using milled granules of first granulation and one or more
release controlling material
d) followed by milling;
e) blending the said milled granules after second granulation with lubricant
f) followed by compression to form a sustained release dosage form.
Alternatively, the blend of step e is filled into capsules.
The tablets were further coated by using any of the conventional coating techniques, such
as pan or perforated pan, well known to the persons skilled in the art.
These coating layers comprise of one or more excipients selected from the group
comprising coating agents, opacifiers, taste-masking agents, colouring agents, antitacking
agents and the like.
Coating agents which are useful in the coating process, include, but are not limited to,
polymers based on methacrylic acid such as Poly(butyl methacrylate, (2-
dimethylaminoethyl) methacrylate, methyl methacrylate) copolymer for e.g. those
marketed under the brand name of Eudragit. These may be applied from aqueous or non-
aqueous systems or combinations of aqueous and non-aqueous systems as appropriate.
Additives can be included along with the film formers to obtain satisfactory films. These
additives can include plasticizers such as dibutyl phthalate, triethyl citrate, polyethylene
glycol and the like, antitacking agents such as talc, stearic acid, magnesium stearate and
colloidal silicon dioxide and the like, surfactants such as polysorbates and sodium lauryl
sulphate and opacifying agents such as titanium dioxide and the like. All these excipients
can be used at levels well known to the persons skilled in the art.
The following are non-limiting examples, which serve to illustrate the invention.
Examples:
Example 1:


Quetiapine Fumarate, sodium citrate and lactose were sifted and uniformly mixed. The
blend was granulated with Ammonio methacrylate copolymer dispersion. The granules so
formed were dried, milled and sifted through #40 mesh. The above granulate was further
granulated with cellulose acetate solution. The granules so formed were dried, milled and
sifted through #20 mesh. These granules were uniformly mixed with remaining amount
of lactose, talc and magnesium stearate. The blend was compressed into tablets using
suitable punch. The tablets were then further film coated.
Example 2:

Examples 2 and 3 were prepared as given in example 1.
Example 4:


Quetiapine Fumarate, trisodium citrate dihydrate, sodium chloride, dicalcium phosphate
dihydrate and lactose were sifted and uniformly mixed. The above blend was wet
granulated and the granules were dried, milled and sifted. The granules were lubricated
with talc and magnesium stearate and core tablets are compressed using suitable punch.
The core tablets were coated with a solution of cellulose acetate.
Example 5:

Quetiapine Fumarate, trisodium citrate dihydrate, dicalcium phosphate dihydrate and
lactose were sifted and uniformly mixed. The above blend was wet granulated and the
granules were dried, milled and sifted. The granules were lubricated with talc and
magnesium stearate and core tablets were compressed using suitable punch. The core
tablets were coated with a dispersion of Methacrylate copolymer, mixed with talc.
The preparations being now on the market have several drawbacks. Due to the large
amount of the excipients the tablet size is relatively large, and large tablets are difficult to
swallow, especially for aged patients and uncooperative pateints. Besides, due to the high
excipient content the costs of materials of the manufacturing procedure are relatively
high. The tablets according to the invention are of considerably smaller weight than the

known tablets. Thus an improved therapeutical applicability has been achieved. Besides,
the production of such tablets is more economical.
Table 1: Comparative Weight of Tablets Comprising Quetiapine Fumarate

Dissolution
The in vitro specifications for generic products are established based on a dissolution
profile. In the case of a generic drug product, the dissolution specifications are generally
the same as the reference listed drug.
Dissolution was carried out for the first 5 hours in pH 4.8 buffer, followed by pH 6.6
phosphate buffer. The following compositions were tested: sustained release tablets
comprising of 200mg of Quetiapine fumarate, prepared according to example 1 as test
and Seroquel XR® having quetaipine Fumarate 200mg by Astrazeneca as reference.
The results obtained are summarized below in table 2.
Table 2: Dissolution profile of Quetiapine Fumarate 200mg Sustained Release
Tablets (Example 1)


We claim:
1. 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
excipient(s).
2. A sustained release dosage form as in claim 1 wherein the dosage form comprises the
drug in the matrix.
3. A sustained release dosage form as in claim 1 wherein the dosage form includes
tablets, capsules, pellets, granules.
4. A sustained release dosage form as in claim 1 wherein the non-gellable release
controlling polymer is selected from the group comprising cellulose acetate, acrylic
polymer such as Poly (ethyl acrylate, methyl methacrylate) polymer, ammonio
methacrylate copolymers.
5. A sustained release dosage form as in claim 1 is further coated.
6. A sustained release dosage form comprising:

a) first granulation comprising Quetiapine or its pharmaceutically acceptable salts,
polymorphs, solvates, hydrates thereof and one or more release controlling
material; and
b) second granulation comprising one or more release controlling material which is
the same or different than the one or more release controlling material of the first
granulation and optionally quetiapine or its pharmaceutically acceptable salts,
polymorphs, solvates, hydrates thereof.
7. A sustained release dosage form as in claim 6, wherein the release controlling
material is selected from hydrophobic material such as glycerides, hydrogenated
castor oil, hydrogenated vegetable oil, oils, waxes or wax-like substances, fats, fatty
acids, lipids, sustained starches, fatty alcohols, proteins, shellac, or polymers selected

from the group comprising water insoluble cellulose, non-gellable polymers such as
cellulose acetate, acrylic polymers such as Poly (ethyl acrylate, methyl methacrylate)
polymer.
8. A sustained release dosage form as in claim 6 has in vitro release profile such that not
less than 50% of drug is released in about 8 hours.
9. A sustained release dosage form as in claim 6 has in vitro release profile such that not
less than 70% of drug is released in about 12hrs.
10. A sustained release dosage form as in claim 6 has in vitro release profile such that not
less than 80% of drug is released in about 20hrs.
11. A method of preparing a sustained release dosage form comprising: first granulation
comprising Quetiapine or its pharmaceutically acceptable salts, polymorphs, solvates,
hydrates thereof and one or more release controlling material followed by milling of
granules; and second granulation using milled granules of first granulation and one or
more release controlling material which is the same or different than the one or more
release controlling material of the first granulation followed by milling; blending the
said milled granules after second granulation with lubricant followed by compression
to form a sustained release dosage form.
12. A sustained release dosage form comprising:

a) immediate release core comprising Quetiapine or a pharmaceutically acceptable
salt, polymorphs, solvates, hydrates thereof and one or more pharmaceutically
acceptable excipients; and
b) sustained release coating comprising one or more non-gellable release controlling
material.
13. A sustained release dosage form comprising an active agent Quetiapine or a
pharmaceutically acceptable salt, polymorphs, solvates, hydrates thereof; wherein the
active agent is present in an amount of more than 40% by weight of the total weight
of the core.

14. A sustained release dosage form as in claim 13, wherein the release controlling
material is selected from hydrophobic material or hydrophilic material.
15. A sustained release dosage form as in claim 13 is small in size.
16. A sustained release dosage form comprising:

a) first granulation comprising Quetiapine or its pharmaceutically acceptable salts,
polymorphs, solvates, hydrates thereof and one or more release controlling
material; and
b) second granulation comprising one or more release controlling material which is
the same or different than the one or more release controlling material of the first
granulation.;
wherein Quetiapine is present in an amount of more than 40% by weight of the total
weight of the core.

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
excipient(s). A sustained release dosage form comprising first granulation comprising
Quetiapine or its pharmaceutically acceptable salts, polymorphs, solvates, hydrates
thereof and one or more release controlling material; and second granulation
comprising one or more release controlling material which is the same or different
than the one or more release controlling material of the first granulation and
optionally quetiapine or its pharmaceutically acceptable salts, polymorphs, solvates,
hydrates thereof. A method of preparing the sustained release dosage form by first
and second granulation followed by milling; blending the said milled granules after
second granulation with lubricant followed by compression to form a sustained
release dosage form. A sustained release dosage form comprising immediate release
core comprising Quetiapine or a pharmaceutically acceptable salt, polymorphs,
solvates, hydrates thereof and one or more pharmaceutically acceptable excipients;
and sustained release coating comprising one or more non-gellable release controlling
material.