Field of the Invention
The present invention relates to a novel modified release pharmaceutical composition
comprising a selective serotonin reuptake inhibitor or a pharmaceutically acceptable salt
thereof and a process of preparing the same.
Background of the Invention
Paroxetine, disclosed in U.S. Pat. No. 4,007,196 is a selective serotonin reuptake
inhibitor (SSRI) and is currently marketed worldwide for the treatment and/or
prophylaxis of depression. Paroxetine is used in the form of the crystalline hemihydrate
as disclosed in U.S. Pat. No. 4,721,723.
U.S. Pat. No. 4,839,177 relates to a system for the controlled release of active substances,
consisting of: (a) a deposit core comprising effective amount of the active substances and
having defined geometric form, (b) a support-platform applied to said deposit core
wherein the said deposit core contains, mixed with the active substance, at least one
member selected from the group consisting of (a) 5-80% by weight of the total weight of
the deposit core of a polymeric material having a high degree of swelling on contact with
water or aqueous liquids and 90-10% by weight of the total weight of the deposit core of
a gellable polymeric material, and (b) a single polymeric material having both swelling
and gelling properties and other adjuvants able to provide the mixture with suitable
characteristics for compression and for intake of water, and wherein said support
platform consists of polymeric material insoluble in aqueous liquids and partially coating
said deposit core.
U.S. Pat. No. 5,422,123 discloses a system for controlled release comprising of a deposit-
core comprising an effective amount of the active substance and having defined
geometric form, and a support-platform applied to said deposit-core, wherein said
deposit-core contains at least the active substance, and at least one member selected from
the group consisting of (1) a polymeric material which swells on contact with water or
2

aqueous liquids and a gellable polymeric material wherein the ratio of the said swellable
polymeric material to said gellable polymeric material is in the range 1:9 to 9:1, and (2) a
single polymeric material having both swelling and gelling properties, and wherein the
support-platform is an elastic support, applied to said deposit-core so that it partially
covers the surface of the deposit-core and follows changes due to hydration of the
deposit-core and is slowly soluble and/or slowly gellable in aqueous fluids. The support-
platform may comprise polymers such as hydroxypropylmethylcellulose, plasticizers
such as a glyceride, binders such as polyvinylpyrrolidone, hydrophilic agents such as
lactose and silica, and/or hydrophobic agents such as magnesium stearate and glycerides.
The polymer(s) typically make up 30 to 90% by weight of the support-platform, for
example about 35 to 40%. Plasticizer may make up at least 2% by weight of the support-
platform, for example about 15 to 20%. Binder(s), hydrophilic agent(s) and hydrophobic
agent(s) typically total up to about 50% by weight of the support-platform, for example
about 40 to 50%.
U.S. Pat. No. 6,482,440 relates to pharmaceutically active materials comprising specific
antidepressant compounds contained in microparticles formulated so as to release the
antidepressant compounds over an extended period of time.
PCT Appl. No. WO 2005/034954 relates to stable pharmaceutical compositions of
paroxetine comprising the drug, microcrystalline cellulose, at least one modified release
polymer and one or more additional pharmaceutical inert excipients, wherein the
composition is prepared by wet granulation. Compressed tablets are further coated with
enteric polymers and further with nonfunctional film coating polymers.
U.S. Pat. Appl. No. 2002/0090394 discloses a controlled and delayed release formulation
containing a selective serotonin reuptake inhibitor such as paroxetine. Release of the drug
is delayed by pH sensitive coat using hydroxypropylmethylcellulose phthalate, cellulose
acetate phthalate, and Eudragit etc. followed by controlled release. This results in
reducing the incidence of nausea and vomiting associated with the administration of
paroxetine by releasing the drug predominantly in the small intestine.
3

The present invention provides a novel modified release formulation of a selective
serotonin reuptake inhibitor or a pharmaceutically acceptable salt thereof.
Object of the Invention
The object of the present invention is to provide a novel modified release composition
comprising a SSRI or a pharmaceutically acceptable salt thereof and a process of
preparing the same.
Another object of the invention is to provide the use for treating and/or preventing the
disorders by administering an effective and/or a prophylactic amount of novel modified
release composition comprising SSRI or a pharmaceutically acceptable salt thereof, to an
individual in need thereof.
Summary of the Invention
The present invention describes novel modified release compositions of SSRI or a
pharmaceutically acceptable salts thereof comprising:
a) a controlled release core comprising one or more selective serotonin reuptake
inhibitor or pharmaceutically acceptable salts thereof, one or more controlled
release agent(s) and pharmaceutically acceptable excipient(s), and
b) one or more coatings comprising an enteric coat over the core and
c) an outer immediate release drug containing coat comprising at least 10% of the
active agent,
wherein the dosage form releases at least 10 % of the active pharmaceutical
ingredient within 2 hours.
Further, the present invention discloses the use of novel modified release composition
comprising SSRI or a pharmaceutically acceptable salt thereof for treating and/or
preventing the disorders.
4

Detailed Description of Invention
The present invention provides a novel modified release composition of SSRI or a
pharmaceutically acceptable salts thereof.
Selective serotonin reuptake inhibitors (SSRI) include but are not limited to sertraline,
fluoxetine, fluvoxamine, citalopram, escitalopram and paroxetine.
SSRI used in the present invention is suitably in the form of the free base or a
pharmaceutically acceptable salt thereof. Paroxetine is used preferably in the form of the
hydrochloride hemihydrate.
SSRI in the form of a modified release composition can be used to treat and prevent the
following disorders: Alcoholism, Anxiety, Depression, Obsessive Compulsive Disorder,
Panic Disorder, Chronic Pain, Obesity, Senile Dementia, Migraine, Bulimia, Anorexia,
Social Phobia, Pre-Menstrual Syndrome (PMS), Adolescent Depression,
Trichotillomania, Dysthymia, Substance Abuse.
These disorders are herein after referred to as "the disorders".
The term "modified release" as used herein means release, which is not immediate release
and is taken to encompass controlled release, sustained release, prolonged release, timed
release, retarded release, extended release and delayed release. The term "modified
release dosage form" as used herein can be described as dosage forms whose drug-release
characteristics of time course and/or location are chosen to accomplish therapeutic or
convenience objectives not offered by conventional dosage forms such as a solution or an
immediate release dosage form. Modified release solid oral dosage forms include both
delayed and extended release drug products (as per US FDA guideline for 'SUPAC-MR:
Modified Release Solid Oral Dosage Forms').
The modified release preparation comprises:
5

a) a controlled release core comprising one or more selective serotonin reuptake
inhibitor or pharmaceutically acceptable salts thereof, one or more controlled
release agent(s) and pharmaceutically acceptable excipient(s), and
b) one or more coatings comprising an enteric coat over the core and,
c) an outer immediate release drug containing coat comprising at least 10% of the
active agent,
wherein the dosage form releases at least 10 % of the active pharmaceutical
ingredient within 2 hours.
The modified release pharmaceutical composition of the present invention initially
releases more than 10% of the active ingredient immediately as a loading dose followed
by a lag period till about 2-4 hours, preferably about 3 hours, followed by controlled
release of the active from the core tablet for over a period of about 12 hours. About 10-25
% of active ingredient, more preferably about 15 % is present in the outer drug coat and
about 75-90% of the active, more preferably about 85% of the active is present in the
controlled release core.
Controlled release polymers used in the core of this composition include but are not
limited to one or more of cellulose derivatives, alginic acids derivatives,
polymethacrylates, polysaccharides, alkylene oxides, hydrogenated vegetable oil and the
like. Specific examples of cellulose derivatives include hydroxypropyl cellulose (HPC),
hydroxypropyl methylcellulose (HPMC), methylcellulose, carboxy methylcellulose, ethyl
cellulose and hydroxy ethyl cellulose. Alginic acid derivatives as used herein include
alginic acid and its physiologically acceptable salts such as those of sodium, potassium,
calcium, and the like. Examples of polysaccharides include chitosan, gellan, xanthan gum
and the like. Examples of alkylene oxide include polyethylene oxide. Controlled release
polymers used in the core may range from about 1-50% w/w, most preferably in the
range of 10-40 % w/w.
HPMC is cellulose ether, and is widely used as controlled release polymer. It is
commercially available as Methocel® in various grades. Examples of HPMC of low
6

viscosity grades include Methocel E-5 LV, Methocel E-15 LV, Methocel E-50 LV,
Methocel K-100 LV CR Premium and Methocel F-50 LV. Examples of HPMC of
medium viscosity grade include Methocel E4M, Methocel K4MCR, Methocel K15M
Premium, Methocel K100 M Premium and Methocel F4M.
Enteric polymers used in the enteric coat include but not limited to polymethacrylates,
various types of methacrylic acid derivatives and copolymers thereof such as various
grades available under the trade name of Eudragit®.
Pharmaceutically acceptable excipients comprise diluents, disintegrants, binders and
lubricants.
Diluents referred to in the present invention include but are not limited to one or more
selected from mannitol, dextrose, xylitol, sorbitol, sucrose, microcrystalline cellulose,
calcium carbonate, calcium phosphate dibasic, calcium phosphate tribasic, calcium
sulfate, lactose, starches, vinyl polymers and the like known to a person skilled in the art.
Binders referred to in the present invention include but are not limited to one or more
selected from those well known in the art to a person skilled in the art, as exemplified can
be celluloses such as hydroxypropyl cellulose, hydroxy ethyl cellulose, ethyl cellulose,
hydroxypropyl methyl cellulose, methyl cellulose or mixtures thereof, acrylates,
methacrylates, povidone and other materials known to have cohesive and desirable
binding properties.
Lubricants referred to in the present invention include but are not limited to one or more
selected from those well known in the art, as exemplified can be stearates, hydrogenated
vegetable oil, sodium stearyl fumarate, talc, colloidal silicon dioxide, palmitic acid,
carnauba wax, glyceryl monostearate, microcrystalline wax, polyoxyethylene
monostearates, fats and stearic acid or mixtures thereof.
7

These novel modified release pharmaceutical compositions may be prepared by various
methods known to the persons skilled in the art. The present invention preferably uses
wet granulation method to prepare modified release formulations. The selective serotonin
reuptake inhibitor is mixed with one or more controlled release polymer(s) and
pharmaceutically acceptable excipients and granulate with solvent. Dry the granules and
mix with lubricants and compress into core tablets. These core tablets are coated with one
or more coatings comprising an enteric coat over the core and an outer immediate release
drug containing coat comprising at least 10% of the active agent so that more than 10 %
of the active ingredient is released within 2 hours.
Coating(s) may further comprise film coating composition(s) and other coating aids like
plasticizers and film formers.
Examples of plasticizers include one or more of polyethylene glycol, triethyl citrate,
triacetin, diethyl phthalate, dibutyl stearate, dibutyl sebacate, oleic acid, alcohol, mineral
oil, castor oil, lanolin, petrolatum, propylene glycol, glycerol and the like.
Examples of film forming polymers include one or more of ethyl cellulose, HPMC, HPC,
methylcellulose, hydroxyethyl cellulose; waxes such as polyethylene glycol. The coating
may be performed by conventional means using commercially available, ready-to-coat
preparations, sold under various brand names such as various grades of Opadry®,
Surelease® Dispersions or mixtures thereof and the like.
The following examples are illustrative of the present invention, and the example should
not be considered as limiting the scope of this invention in any way, as these examples
and other equivalents thereof will become apparent to those versed in the art, in the light
of the present disclosure, and the accompanying claims.
Various types of novel modified release pharmaceutical composition of SSRI such as
paroxetine are described in the following examples:
8

Examples:

Formula: - Core Tablet
Sr.No. Ingredients % w/w
1 Paroxetine Hydrochloride 15.5
Hemihydrate (85%)
2 Hydroxypropylmethyl cellulose 15-30
3 Lactose monohydrate 25-45
4 Microcrystalline Cellulose 5-25
5 Hydrogenated Vegetable oil 5-15
6 Lubricant 0.5-2
7 Solvent Q.S.

Enteric Coal
S.No. Composition % w/w
1 Methacrylic acid polymers 4-8
2 Plasticizer Q.S.
3 Glidant Q.S.
4 Solvent Q.S.
Drug Coat
S.No. Composition % w/w
Paroxetine HCL Hemihydrate
1 (15%) 2.5
2 Film Coating Q.S.
3 Solvent Q.S.
Manufacturing Procedure:
Mix Paroxetine HC1 hemihydrate, a portion of lactose, and hydroxypropylmethyl
cellulose and granulated with a suitable solvent. Granules are dried and sifted to a
suitable size and mixed with remaining portion of lactose, microcrystalline cellulose and
hydrogenated vegetable oil. The final blend is lubricated and then compressed to tablets.
9

Enteric coating composition is prepared using enteric polymers as described in the
example and coated over the compressed core tablet using conventional coating
techniques.
Drug coating composition is prepared containing 15 % of active ingredient along with the
film forming polymers as described in the example and coated over the enteric coat using
conventional coating techniques.
Dissolution Study:
Dissolution profile of these novel modified release compositions of Paroxetine is
conducted using Type II USP dissolution apparatus and the results are as follows:
Medium: - 0.1N HCL followed by pH 6.8 phosphate buffer
RPM: - 50
Time (Hrs.) Cumulative % Drug Release
0 0
2 10-30
4 15-40
8 40-75
12 More than 80%
Volume:- 1000 ml.
Dissolution study is also performed in other media and the results are as follows:
Media: 0.1 N HC1 for 2 hours; pH 6.5 phosphate buffer till 3 hours; and pH 7 phosphate
buffer

Time (Hrs.) Cumulative % Drug Release
0 0
2 10-25
4 15-35
8 35-70
12 More than 80
10

We Claim:
1. A modified release pharmaceutical composition comprising
a) a controlled release core comprising one or more selective serotonin reuptake
inhibitor or pharmaceutically acceptable salts thereof, one or more controlled
release agent(s) and pharmaceutically acceptable excipient(s), and
b) one or more coatings comprising an enteric coat over the core and,
c) an outer immediate release drug coating comprising at least 10% of the active
agent,
wherein the dosage form releases more than 10 % of the active pharmaceutical
ingredient within 2 hours.
2. The modified release solid dosage form of claim 1, wherein about 10 to about 25 %
of the drug is present in the outer most coating and about 75 to about 90 % of the
drug is present in the controlled release core.
3. The modified release solid dosage form of claim 1, wherein the selective serotonin
reuptake inhibitor is paroxetine, citalopram, escitalopram, paroxetine, sertraline,
fluoxetine or their pharmaceutically acceptable salts.
4. The modified release solid dosage form of claim 1, wherein the controlled release
agents in the core are selected from the group comprising hydrophilic polymer or
hydrophobic release-controlling agent or combinations thereof.
5. A modified release pharmaceutical composition according to claim 4, wherein, the
hydrophilic controlled release agent(s) is selected from the group comprising
cellulose derivatives, alginic acid derivatives, polysaccharides, alkylene oxides or
mixtures thereof.
6. A modified release pharmaceutical composition according to claim 4, wherein,
the hydrophobic controlled release agent(s) is selected from the group comprising
hydrogenated vegetable oils, polymethacrylates, ethyl cellulose or mixtures
thereof.
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7. The modified release solid dosage form of claim 1, wherein pharmaceutically
acceptable excipients are selected from the group comprising diluents, binders,
lubricants, glidants, and plasticizers.
8. The modified release solid dosage form of claim 7, wherein the diluents are selected
from the group comprising mannitol, dextrose, xylitol, sorbitol, sucrose,
microcrystalline cellulose, calcium carbonate, calcium phosphate dibasic, calcium
phosphate tribasic, calcium sulfate, lactose, starches, vinyl polymers, or mixtures
thereof.
9. The modified release solid dosage form of claim 7, wherein the binders are selected
from the group comprising hydroxypropyl cellulose, hydroxy ethyl cellulose, ethyl
cellulose, hydroxypropyl methyl cellulose, methyl cellulose, starch, acrylates,
methacrylates, povidone or mixtures thereof.
10. Te modified release solid dosage form of claim 7, wherein the lubricants are selected
from the group comprising stearates, aerosil, hydrogenated vegetable oil, sodium
stearyl fumarate, talc, colloidal silicon dioxide, palmitic acid, carnauba wax, glyceryl
monostearate, microcrystalline wax, polyoxyethylene monostearates, fats and stearic
acidor mixtures thereof.
11. A modified release pharmaceutical composition according to claim 7, wherein, the
plasticizers are selected from the group comprising polyethylene glycol, triethyl
citrate, triacetin, diethyl phthalate, dibutyl stearate, dibutyl sebacate, oleic acid,
alcohol, mineral oil, castor oil, lanolin, petrolatum, propylene glycol, glycerol or
mixtures thereof.
12. The modified release dosage form of claim 1, wherein the enteric coat comprises
enteric polymers selected from the group comprising polymethacrylates or
methacrylic acid polymers or copolymers or combinations thereof.
13. The process for preparing a modified release pharmaceutical composition of selective
serotonin reuptake inhibitor comprising:
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a) mixing the active ingredient with one ore more controlled release polymer(s)
and one or more pharmaceutically acceptable excipients;
b) granulating the mixture with solvent,
c) drying the granules; mixing with lubricants and compressing into controlled
release core tablets and,
d) coating the compressed tablets with one or more coating(s) comprising an
enteric coat over the core and,
e) an outer immediate release drug containing coat.
14. A modified release pharmaceutical composition comprising
a) a controlled release core comprising paroxetine or pharmaceutically acceptable
salts thereof, one or more controlled release agent(s) and pharmaceutically
acceptable excipient(s), wherein, about 85 % of the active is present in the core
and,
b) one or more coatings comprising an enteric coat over the core providing a lag
time for about 1 -4 hours and,
c) an outer immediate release drug containing coat comprising at least 10% of the
active agent,
wherein the dosage form releases at least 10 % of the active pharmaceutical
ingredient within 2 hours.
13
15. A modified release pharmaceutical composition which release at least 10% of the
active within 2 hours followed by a lag phase till about 3 hours, then controlled
release of active, releasing more than about 80% of the active for over about 12
hours.

A modified release pharmaceutical composition comprises a controlled release core
comprising one or more selective serotonin reuptake inhibitor or pharmaceutically
acceptable salts thereof, one or more controlled release agent(s) and pharmaceutically
acceptable excipient(s), and one or more coatings comprising an enteric coat over the
core and, an outer immediate release drug coating comprising at least 10% of the active
agent, wherein the dosage form releases more than 10 % of the active pharmaceutical
ingredient within 2 hours. The process for preparing the modified release pharmaceutical
composition of selective serotonin reuptake inhibitor comprises mixing the active
ingredient with one ore more controlled release polymer(s) and one or more
pharmaceutically acceptable excipients; granulating the mixture with solvent, drying the
granules; mixing with lubricants and compressing into controlled release core tablets and,
coating the compressed tablets with one or more coating(s) comprising an enteric coat
over the core and, an outer immediate release drug containing