FIELD OF INVENTION
The present invention relates to novel pharmaceutical composition, comprising a
combination of desvenlafaxine or its pharmaceutically acceptable form and one or more
second active drug, where the second active drug causes direct or indirect monoamine
receptor agonism, increases synthesis of monoamines /or triggers the release of
monoamines, inhibits monoamine transport or its reuptake for the treatment of CNS
disorders. The present invention also relates to a pharmaceutical kit comprising a
combination of desvenlafaxine or its pharmaceutically acceptable form and a second
active drug.
BACKGROUND OF INVENTION
The nontricyclic compound venlafaxine, chemically named (±)-1-[2-(dimethylamino)-1-
(4-methoxyphenyl)ethyl]-cyclohexanol, is an antidepressant which has been studied
extensively and which is described in, for example, U.S. Pat. No. 4.761,501 and Pento, J.
T. Drugs of the Future 13(9): 839-840 (1988). Its hydrochloride salt is currently
commercially available in the United States under the trade name Effexor®. Effexor®,
which is a racemic mixture of the (+) and (-) enantiomers of venlafaxine, is indicated for
the treatment of depression. The mechanism of action of venlafaxine is by inhibition of
the uptake of the monoamine neurotransmitters i.e. serotonin and norepinephrine and to a
lesser degree, venlafaxine also inhibits dopamine reuptake, but it has no inhibitory
activity on monoamine oxidase.
Venlafaxine has adverse effects including, but not limited to, sustained hypertension,
headache, asthenia, sweating, nausea, constipation, somnolence, dry mouth, dizziness,
insomnia, nervousness, anxiety, blurred or blurry vision, and abnormal
ejaculation/orgasm or impotence in males. Physicians' Desk Reference pp. 3293-3302
(53rd ed., 1999); see also Sinclair, J. et al. Rev. Contemp. Pharmacother. 9:333-344
(1998). These adverse effects can significantly limit the dose level, frequency, and
duration of drug therapy.
2

Bertilsson L. et.al.. British Journal of Clinical Pharmacology, Volume 53, Issue 2, 111-
122.Venlafaxine undergoes Cytochrome P450 CYP2D6 dependent metabolism to the
active major metabolite O-desmethylvenlafaxine. while its N-desmethylation is catalyzed
by CYP3A4, and possibly by CYP2C19 and CYP2C9. Cytochrome P450 CYP2D6 is the
most extensively characterized polymorphic drug-metabolizing enzyme. Poor
metabolizers of CYP2D6 had a more than 4-fold lower oral clearance of venlafaxine
compared to Extensive metabolizers, mainly due to a decreased capacity to form the O-
desmethylated metabolites. A relationship between the Poor metabolizer phenotype and
cardiovascular toxicity of venlafaxine has been suggested, based on four patients with
Poor metabolizer phenotype which was either genetically determined or due to inhibition
of CYP2D6 activity by concomitant drugs. The side effects reported included
palpitations, shortness of breath and proarrhythmias due to the heterogeneity in cardiac
repolarization.
Klamerus, K. J. et al. J. Clin. Pharmacol. 32:716-724 (1992). In vitro studies suggest that
O-desmethylvenlafaxine is a more potent inhibitor of norepinephrine and dopamine
uptake than the parent compound venlafaxine. Muth, E. A. et al. Drug Develop. Res.
23:191-199 (1991). O-desmethylvenlafaxine has also been reported to have a half-life
(t1/2) of about 10 hours, which is approximately 2.5 times as long as that of venlafaxine.
Klamerus, K. J. et al. J. Clin. Pharmacol. 32:716-724 (1992). Studies directed at
understanding the activity of O-desmethylvenlafaxine as compared to its parent have
been hampered, however, by the metabolic difference between laboratory animals and
man in their exposure to venlafaxine. Howell. S. R. et al. Xenobiotica 24(4): 315-327
(1994).
US 6,673,838 discloses an oral dosage form comprising a therapeutically effective
amount of O-desmethylvenlafaxine succinate and a rate controlling polymer material like
hydroxyalkyl celluloses, poly (ethylene) oxides, alkyl celluloses, carboxymethyl
celluloses, hydrophilic cellulose derivatives, and polyethylene glycol. However, the
effects of the hydrogel formulation have been observed to be variable when the ODV
hydrogel tablet is given with food.
3

US 7,001,920 discloses oral dosage form comprising O-desmethylvenlafaxine formate
and rate controlling polymers like hydroxy alkyl cellulose, hydroxypropyl alkylcellulose,
poly (ethylene) oxide, alkyl cellulose, carboxymethyl cellulose; hydrophilic cellulose
derivatives, or polyethylene glycol.
Lincoln.J et.al. Current psychiatry. Vol.7. No.6, 89-96.Unlike Venlafaxine,
desvenlafaxine does not depend on cytochrome P450 (CYP) 2D6 for biotransformation.
As a result plasma concentrations vary less among individual patients, which should
result in more predictable efficacy and tolerability.
Bupropion, chemically named, (+-)-1- (3-chlorophenyl)-2-[(l,l-dimethylethyl)amino]-l-
propanone hydrochloride and by its generic name amfebutamone is an antidepressant
chemically unrelated to tricyclics, tetracyclics. selective serotonin re-uptake inhibitors
(SSRIs), or other known antidepressant agents.
It is believed that bupropion works by inhibiting the reuptake of the monoamines
dopamine, serotonin, and norepinephrine. an action, which results in more dopamine,
serotonin, and norepinephrine made available to transmit messages to other nerves.
Accordingly, bupropion is unique in that its major effect is on dopamine, an effect that is
not shared by the SSRIs (e.g. paroxetine, fluoxetine, sertraline or the tricyclic
antidepressants or TCAs (e.g. amitriptyline, imipramine. and desipramine).
U.S. 5,358,970 discloses a formulation of bupropion hydrochloride which is stabilized
with a stabilizer which has specific acid properties under particular test conditions.
RE 33,994 is limited to a bupropion
hydrochloride controlled release formulation which releases 10-45% of
bupropion hydrochloride within two hours: 25-70% bupropion hydrochloride
within 4 hours and 40-90% of bupropion hydrochloride within six hours.
Wellbutrin SR is a commercially available twice a day dosage form of
bupropion hydrochloride which contains carnauba wax, cysteine
******************4

hydrochloride, hydroxypropyl methylcellulose. magnesium stearate.
microcrystalline cellulose, polyethylene glycol and titanium dioxide.
WO2007002597 discloses pharmaceutical compositions, formulations and medicaments
comprising a bupropion salt, in particular, modified-release tablets comprising an
effective amount of bupropion hydrobromide, and the use of the bupropion salt to prepare
a medicament which may optionally contain venlafaxine to treat a condition selected
from the group consisting of depression, addiction disorder, smoking cessation, obesity,
and seasonal effective disorder.
US2006058293 discloses compositions for affecting weight loss comprising bupropion
and a second compound, where the second compound causes increased agonism of a
melanocortin 3 receptor (MC3-R) or a melanocortin 4 receptor (MC4-R) compared to
normal physiological conditions, antagonizes cannabinoid receptor activity, or is useful in
the treatment of bipolar disorders. Use of venlafaxine as the second compound is
disclosed.
US2002161016 discloses a method for treating premature ejaculation, by administration
of a therapeutically effective amount of an antidepressant drug Bupropion optionally in
combination with venlafaxine.
Seritan.L.A. Current psychiatry, Vol.7, No.2, 57-69.Bupropion is a potent inhibitor of
CYP2D6, of which venlafaxine is a substrate. This pharmacokinetic interaction will lead
to increased levels of venlafaxine concentration in blood potentiating the incidence of
adverse effects associated with venlafaxine leading to poor tolerability and unpredictable
efficacy and pharmacokinetics in patients.
There is still a need for medicaments that are even more efficient for treating patients
suffering from CNS disorders having lowered risk of drug-drug interactions and more
predictable efficacy, tolerability and pharmacokinetics in patients. The present invention
overcomes the limitations of the prior art, by replacing venlafaxine with desvenlafaxine.
5

The present invention is not limited to the combination of desvenlafaxine and bupropion
alone, however, covers the combination of desvenlafaxine or its pharmaceutically
acceptable form with one or more second active compounds selected from the group
comprising of a compound that increases synthesis/ or release of monoamines, direct/
indirect monoamine receptor agonist, monoamine transport inhibitors and monoamine
reuptake inhibitors. This combination/composition shows additive/synergistic effect as
compared to when taken alone.
To the best of applicants' knowledge, the present therapeutic combination for the
treatment of CNS disorders is novel and completely unsuggested by the prior art.
OBJECTIVE OF THE INVENTION
The primary object of the invention is to address the need in the prior art by providing a
pharmaceutical composition containing desvenlafaxine or its pharmaceutically acceptable
form and one or more second active drug, wherein the said second active drug is selected
from the group comprising of a compound that increases synthesis/ or release of
monoamines, direct/ indirect monoamine receptor agonist, monoamine transport
inhibitors and monoamine reuptake inhibitors for the treatment of CNS disorders.
Another object of the present invention is to provide a novel therapeutic combination
containing desvenlafaxine or its pharmaceutically acceptable form and atleast one
monoamine reuptake inhibitor for the treatment of CNS disorders.
Yet another object of the present invention is to provide novel therapeutic composition
containing desvenlafaxine or its pharmaceutically acceptable form and atleast one
monoamine reuptake inhibitor with pharmaceutically acceptable carriers for the treatment
of CNS disorders.
Yet another object of the present invention is to provide a therapeutic combination with
reduced incidence of adverse effects.
6

Yet another object of the invention is to provide a pharmaceutical composition containing
desvenlafaxine or its pharmaceutically acceptable form and one or more second active
drug, wherein the said second active drug is selected from the group comprising of a
compound that increases synthesis/ or release of monoamines, direct/ indirect monoamine
receptor agonist, monoamine transport inhibitors and monoamine reuptake inhibitors
optionally with additional active agents for the treatment of CNS disorders.
Another object of the present invention is to develop a kit for a patient to use in the
treatment of CNS disorders. The kit includes a container housing the pharmaceutical
composition containing desvenlafaxine or its pharmaceutically acceptable form and
second active drug, wherein the said second active drug is selected from the group
comprising of a compound that increases synthesis/ or release of monoamines, direct/
indirect monoamine receptor agonist, monoamine transport inhibitors and monoamine
reuptake inhibitors, during storage and prior to administration; wherein the kit shows
reduced incidence of adverse effects.
SUMMARY OF THE INVENTION
The present invention provides a pharmaceutical composition/combination containing
desvenlafaxine or its pharmaceutically acceptable form and one or more second active
drug, wherein the said second active drug is selected from the group comprising of a
compound that increases synthesis/ or release of monoamines, direct/ indirect monoamine
receptor agonist, monoamine transport inhibitors and monoamine reuptake inhibitors for
the treatment of CNS disorders.
The present invention provides novel therapeutic composition containing desvenlafaxine
or its pharmaceutically acceptable form and atleast one monoamine reuptake inhibitor for
the treatment of CNS disorders.
The present invention, more particularly, provides novel therapeutic composition
containing desvenlafaxine or its pharmaceutically acceptable form and atleast one
monoamine reuptake inhibitor, preferably bupropion, for the treatment of CNS disorders.
7

The present invention relates to provide such pharmaceutical compositions having better
tolerability, predictable efficacy, reduced drug interaction, reduced inter-individual
variability associated with genetic polymorphism leading to predictable
pharmacokinetics, along with reduced incidence of adverse effects in patients.
The present invention also relates to provide a pharmaceutical composition containing
desvenlafaxine or its pharmaceutically acceptable form and one or more second active
drug, wherein the said second active drug is selected from the group comprising of a
compound that increases synthesis/ or release of monoamines, direct/ indirect monoamine
receptor agonist, monoamine transport inhibitors and monoamine reuptake inhibitors
optionally with additional active agents for the treatment of CNS disorders.
The present invention relates to formulation of said pharmaceutical composition in a
modified release, immediate release composition or the combination thereof.
The present invention relates to providing a kit for a patient to use in the treatment of
CNS disorders. The kit includes a pharmaceutical composition as provided herein, a
container housing the pharmaceutical composition during storage and prior to
administration; and instructions, e.g., written instructions on a package insert or label, for
carrying out drug administration in a manner effective to treat CNS disorders; wherein
the kit shows reduced incidence of adverse effects.
DETAILED DESCRIPTION OF THE INVENTION
Before describing the present invention in detail, it is to be understood that this invention
is not limited to specific dosage forms, carriers, or the like, as such may vary. It is also to
be understood that the terminology used herein is for the purpose of describing particular
embodiments only, and is not intended to be limiting.
It must be noted that as used in this specification and the appended claims, the singular
forms "a," "an", and "the" include plural referents unless the context clearly dictates
otherwise. Thus, for example, reference to "an active agent" or "a pharmacologically
8

active agent" includes a single active agent as well as two or more different active agents
in combination, reference to "a carrier" includes mixtures of two or more carriers as well
as a single carrier, and the like.
In describing and claiming the present invention, the following terminology will be used
in accordance with the definitions set out below.
The terms "active agent," "pharmacologically active agent" and "drug" are used
interchangeably herein to refer to a chemical compound that induces a desired
pharmacological, physiological effect.
The term "pharmaceutically acceptable form" includes, but not limited to,
pharmaceutically acceptable salts, prodrugs, racemic mixtures, solvate, hydrate,
anhydrate, clathrate, derivatives, conformational and/or optical isomers, crystalline
polymorphs, isotopic variants or active metabolites.
The "pharmaceutically acceptable salts" are the salts prepared from pharmaceutically
acceptable non-toxic acids, including inorganic acids and organic acids. The compounds
of the present invention, which are basic in nature, are capable of forming a wide variety
of salts with various inorganic and organic acids. Acids that can be used to prepare
pharmaceutically acceptable acid addition salts of such basic compounds of the invention
are those that form non-toxic acid addition salts, i.e., salts containing pharmacologically
acceptable anions, such as, but not limited to, hydrochloride, hydrobromide, hydroiodide,
nitrate, sulfate, bisulfate, phosphate, acid phosphate, formate, acetate, propionate,
succinate, camphorsulfonate, citrate, acid citrate, fumarate, gluconate, isothionate, lactate,
malate, mucate, gentisate, isonicotinate, saccharate, tartrate, bitartrate, para-
toluenesulfonate, glycolate, glucuronate, maleate, furoate, glutamate, ascorbate, benzoate,
anthranilate, salicylate, phentylacetate, mandelate, embonate (pamoate),
methanesulfonate, ethanesulfonate, pantothenate, benzenesulfonate, stearate, sulfanilate,
alginate, p-toluenesulfonate, and galacturonate. Particularly preferred anions are
9

hydrobromide, hydrochloride, phosphate, acid phosphate, maleate, sulfate, and acid
phosphate. Most preferred anions are hydrochloride and maleate.
"Optional" or "optionally" means that the subsequently described circumstance may or
may not occur, so that the description includes instances where the circumstance occurs
and instances where it does not.
The term" Therapeutic Combination " or "combination" in the sense of the present
invention is to be understood as meaning that the individual
components (i.e. desvenlafaxine or its pharmaceutically acceptable form on one hand and
one or more second active drug on the other hand) can be administered in a manner
which is known and customary per se simultaneously (in the form of a combination
medicament), more or less at the same time (from separate pack units) or successively
(directly one after the other or else with a relatively large time interval).
The term "CNS disorder" means disorders associated with central nervous system which
include, but not limited to, depression, generalized anxiety disorder, social anxiety
disorder, panic disorder, bipolar disorder, apathy, schizophrenia, obsessive compulsive
disorder, mania, disruptive behaviour disorder (attention deficit disorder/ attention
deficit/ hyperactivity disorder), smoking cessation, eating disorder, insomnia, fatigue,
psychomotor retardation, suicidal tendencies, substance abuse disorder, sexual
dysfunction, premenstrual syndrome disorder, post-traumatic stress disorder, and
seasonal effective disorder, speech disorders, senile dementia, Alzheimer's type dementia,
memory loss, amnesia/amnestic syndrome, disturbances of consciousness, coma,
Parkinson's disease, Lennox syndrome, autism, hyperkinetic syndrome, disorders
ameliorated by inhibition of neuronal monoamine reuptake; and pain, particularly chronic
pain and the like. Also within the meaning of central nervous system disorders are
disorders caused by cerebrovascular diseases including, but not limited to, cerebral
infarction, cerebral bleeding, cerebral arteriosclerosis, cerebral venous thrombosis, head
injuries, migraine, treatment or prevention of incontinence in humans and the like.
10

The tern "sexual dysfunction" encompasses sexual dysfunction in men and women
caused by psychological and/or physiological factors. Examples of sexual dysfunction
include, but are not limited to, erectile dysfunction, premature ejaculation, vaginal
dryness, vaginismus, decreased libido, lack of sexual excitement, anorgasmia, or inability
to obtain orgasm. The term "sexual dysfunction" further encompasses psychosexual
dysfunction. Examples of psychosexual dysfunction include, but are not limited to,
inhibited sexual desire, inhibited sexual excitement, inhibited female orgasm, inhibited
male orgasm, premature ejaculation, functional dyspareunia, functional vaginismus, and
atypical psychosexual dysfunction.
The terms " reduced incidence of adverse effects " means eliminating or reducing at least
one adverse effect associated with the administration of a particular compound or mixture
of compounds or reducing the intensity and/ or frequency of adverse effect/effects.
The term "modified release", includes, but not limited to, controlled release, sustained
release, delayed release, extended release, timed release, pulsed release and instant
release.
The term "controlled release," "sustained release," "extended release," and "timed
release" are intended to refer interchangeably to any drug-containing formulation in
which release of the drug is not immediate, i.e., with a "controlled release" formulation,
oral administration does not result in immediate release of the drug into an absorption
pool. The terms are used interchangeably with "nonimmediate release" as defined in
Remington: The Science and Practice of Pharmacy, 21st Ed., Lippencott Williams &
Wilkins (2006). The terms "sustained release" and "extended release" are used in their
conventional sense to refer to a drug formulation that provides for gradual release of a
drug over an extended period of time.
The term "delayed release" is used in its conventional sense to refer to a drug formulation
in which there is a time delay provided between oral administration of a drug dosage
form and the release of the drug therefrom. "Delayed release" may or may not involve
11

gradual release of drug over an extended period of time, and thus may or may not be
"sustained release."
"Enteric coating" or "enterically coated" as used herein relates to the presence of
polymeric materials in a drug formulation that result in an increase in the drug's
resistance to disintegration in the stomach. Typically, the polymeric material is present as
a coating surrounding a drug-containing core, but the polymeric material may also be
present in admixture with the drug itself within a coated formulation.
The term "synergy" or "synergistic" interchangeably refer to the combined effects of two
active agents that are greater than their additive effects. Synergy can also be achieved by
producing an efficacious effect with combined inefficacious doses of two active agents.
The measure of synergy is independent of statistical significance.
The term "additive effect" refers to the combined effects of two active agents that are
equal to the sum of the effect of each drug alone.
The term "second active drug" refers to a drug selected from the group comprising of a
compound that increases synthesis/ or release of monoamines, direct/ indirect monoamine
receptor agonist, monoamine transport inhibitors, monoamine reuptake inhibitors.
The term "adverse effects" refers to adverse effects associated with venlafaxine and
includes, but not limited to, sustained hypertension, headache, asthenia, sweating, nausea,
constipation, somnolence, dry mouth, dizziness, insomnia, nervousness, anxiety, blurred
or blurry vision, and abnormal ejaculation/orgasm or impotence in males.
The present invention provides a therapeutic combination containing desvenlafaxine or a
pharmaceutically acceptable form thereof and one or more second active drug, wherein
the second active drug is selected from the group comprising of comprising of a
compound that causes direct or indirect monoamine receptor agonism, increases synthesis
of monoamines /or triggers the release of monoamines, inhibits monoamine transport or
12

its reuptake, optionally with additional active agents, for the treatment of CNS disorders,
wherein the therapeutic combination shows additive or synergistic effects.
The second active drug is selected from the group comprising of, but not limited to,
levodopa, deprenyl, bupropion, carbidopa, pergolide, ropinirole, pramipexole, selegiline,
entacapone, tolcapone, fencamfamine, amfenolic acid, quinpirole, troparil, vanoxerine,
aminepptine, citalopram, escitalopram, fluoxetine, fluvoxamine, paroxetine and
sertraline, milnacipran, mirtazapine, duloxetine, (-) 1-(1-dimethylaminomethyl-5-
methoxybenzo-cyclobutan-1-yl) cyclohexanol (S33005), sibutramine, amineptine,
GW353162 ,SEP-225289, DOV 216,303 and (+)-1-(3,4-dichlorophenyl)-3-azabicyclo-
[3.1.0]hexane hydrochloride (DOV 21,947), and the like or a pharmaceutically acceptable
form thereof.
The additional active agents are selected from the class of, but not limited to, vasoactive
agents. Exemplary vasoactive agents include, but not limited to, nitroglycerin, isosorbide
dinitrate, erythrityl tetranitrate, amyl nitrate, sodium nitroprusside, molsidomine,
linsidomine chlorhydrate, S-nitroso-N-acetyl-d, 1-penicillamine, S-nitroso-N-cysteine and
S-nitroso-N-glutathione, diazenium diolates ("NONOates"), phenoxybenzamine,
dibenamine, doxazosin, terazosin, phentolamine, tolazoline, prazosin, trimazosin,
alfuzosin, tamsulosin, indoramin, ergotamine, acetergamine, brazergoline, bromerguride,
cianergoline, delorgotrile, disulergine, ergonovine maleate, ergotamine tartrate,
etisulergine, lergotrile, lysergide, mesulergine, metergoline, metergotamine, nicergoline,
pergolide, propisergide, proterguride, diazoxide, hydralazine, minoxidil nimodepine,
pinacidil, cyclandelate, dipyridamole, isoxsuprine, chlorpromazine, haloperidol,
yohimbine, prostaglandin and its analogs, carboprost tromethamine, dinoprost
tromethamine, dinoprostone, lipoprost, gemeprost, metenoprost, sulprostone, tiaprost,
vasoactive intestinal peptide, or a pharmaceutically acceptable form thereof.
The present invention relates to provide such therapeutic combination containing
desvenlafaxine or a pharmaceutically acceptable form thereof and one or more second
active drug, optionally with additional active agents; having better tolerability,
predictable efficacy, reduced drug interaction, reduced inter-individual variability
13

associated with genetic polymorphism leading to predictable pharmacokinetics, along
with reduced incidence of adverse effects in patients.
More preferably, the present invention provides a therapeutic combination containing
desvenlafaxine or a pharmaceutically acceptable form thereof and one or more
monoamine reuptake inhibitor, or a pharmaceutically acceptable form thereof, optionally
with additional active agents, for the treatment of CNS disorders, wherein monoamine
reuptake inhibitors, are selected from the group comprising of, but not limited to,
serotonin reuptake inhibitors, norepinephrine reuptake inhibitors, dopamine reuptake
inhibitors, serotonin-norepinephrine reuptake inhibitors, norepinephrine-dopamine
reuptake inhibitors, Serotonin-norepinephrine-dopamine or "triple reuptake inhibitors".
More preferably, the present invention provides a therapeutic combination containing
desvenlafaxine or a pharmaceutically acceptable form thereof and bupropion or its
pharmaceutically acceptable form thereof, for the treatment of CNS disorders.
The present invention also relates to provide a pharmaceutical composition containing
one or more serotonin norepinephrine reuptake inhibitors and one or more second active
drug, wherein the said second active drug is selected from the group comprising of a
compound that increases synthesis/ or release of monoamines, direct/ indirect monoamine
receptor agonist, monoamine transport inhibitors, serotonin reuptake inhibitors,
norepinephrine reuptake inhibitors, dopamine reuptake inhibitors, norepinephrine-
dopamine reuptake inhibitors, Serotonin-norepinephrine-dopamine or "triple reuptake
inhibitors" optionally with additional active agents, for the treatment of CNS disorders,
wherein the said pharmaceutical composition shows additive or synergistic effects.
More preferably the present invention relates to provide a pharmaceutical composition
containing desvenlafaxine or its pharmaceutically acceptable form and one or more
second active drug, wherein the said second active drug is selected from the group
comprising of a compound that increases synthesis/ or release of monoamines, direct/
indirect monoamine receptor agonist, monoamine transport inhibitors and monoamine
14

reuptake inhibitors, optionally with additional active agents, for the treatment of CNS
disorders, wherein the said pharmaceutical composition shows additive or synergistic
effects. The pharmaceutical composition contains one or more pharmaceutically
acceptable excipients.
The said second active drug is selected from the group comprising of, but not limited to,
levodopa, deprenyl, bupropion, carbidopa, pergolide, ropinirole, pramipexole, selegiline,
entacapone, tolcapone, fencamfamine, amfenolic acid, quinpirole, troparil, vanoxerine,
aminepptine, citalopram, escitalopram, fluoxetine, fluvoxamine, paroxetine and
sertraline, milnacipran, mirtazapine, duloxetine, (-) 1-(1-dimethylaminomethyl-5-
methoxybenzo-cyclobutan-1-yl) cyclohexanol (S33005), sibutramine, amineptine,
GW353162 ,SEP-225289, DOV 216,303 and (+)-1-(3,4-dichlorophenyl)-3-azabicyclo-
[3.1.0]hexane hydrochloride (DOV 21,947), and the like or a pharmaceutically acceptable
form thereof.
The additional active agents are selected from the class of, but not limited to, vasoactive
agents. Exemplary vasoactive agents include, but not limited to, nitroglycerin, isosorbide
dinitrate, erythrityl tetranitrate, amyl nitrate, sodium nitroprusside, molsidomine,
linsidomine chlorhydrate, S-nitroso-N-acetyl-d, 1-penicillamine, S-nitroso-N-cysteine and
S-nitroso-N-glutathione, diazenium diolates ("NONOates"), phenoxybenzamine,
dibenamine, doxazosin, terazosin, phentolamine, tolazoline, prazosin, trimazosin,
alfuzosin, tamsulosin, indoramin, ergotamine, acetergamine, brazergoline, bromerguride,
cianergoline, delorgotrile, disulergine, ergonovine maleate, ergotamine tartrate,
etisulergine, lergotrile, lysergide, mesulergine, metergoline, metergotamine, nicergoline,
pergolide, propisergide, proterguride, diazoxide, hydralazine, minoxidil nimodepine,
pinacidil, cyclandelate, dipyridamole, isoxsuprine, chlorpromazine, haloperidol,
yohimbine, prostaglandin and its analogs, carboprost tromethamine, dinoprost
tromethamine, dinoprostone, lipoprost, gemeprost, metenoprost, sulprostone, tiaprost,
vasoactive intestinal peptide, or a pharmaceutically acceptable form thereof.
The present invention relates to provide such pharmaceutical composition containing
desvenlafaxine or a pharmaceutically acceptable form thereof and one or more second
active drug, optionally with additional active agents; having better tolerability,
15

predictable efficacy, reduced drug interaction, reduced inter-individual variability
associated with genetic polymorphism leading to predictable pharmacokinetics, along
with reduced incidence of adverse effects in patients.
More preferably, the present invention provides a pharmaceutical composition containing
desvenlafaxine or a pharmaceutically acceptable form thereof and one or more
monoamine reuptake inhibitor, or a pharmaceutically acceptable form thereof, optionally
with additional active agents for the treatment of CNS disorders, wherein monoamine
reuptake inhibitors, are selected from the group comprising of, but not limited to,
serotonin reuptake inhibitors, norepinephrine reuptake inhibitors, dopamine reuptake
inhibitors, serotonin-norepinephrine reuptake inhibitors, norepinephrine-dopamine
reuptake inhibitors, Serotonin-norepinephrine-dopamine or "triple reuptake inhibitors".
The pharmaceutical composition contains one or more pharmaceutically acceptable
excipients.
More preferably, the present invention provides a pharmaceutical composition containing
desvenlafaxine or a pharmaceutically acceptable form thereof and bupropion or its
pharmaceutically acceptable form thereof, for the treatment of CNS disorders, wherein
the pharmaceutical composition contains one or more pharmaceutically acceptable
excipients.
The present invention relates a pharmaceutical composition containing desvenlafaxine or
a pharmaceutically acceptable form thereof and one or more second active drug,
optionally with additional active agents, wherein low dose of individual drugs can be
used. At low doses, bupropion has more dopamine reuptake inhibiting action than
noradrenaline reuptake. Desvenlafaxine at low doses has more serotonin reuptake
inhibiting action than noradrenaline. Thus when these two drugs are combined at low
doses, the combination will have more serotonin and dopamine reuptake inhibition as
compared to noradrenaline reuptake inhibition with lower incidence of adverse effects.
16

In one of the embodiment of present invention the pharmaceutical composition of
desvenlafaxine or a pharmaceutically acceptable form thereof and bupropion or a
pharmaceutically acceptable form thereof, wherein the dose of desvenlafaxine or its
pharmaceutically acceptable form can range from 5mg to 600mg, more preferably
12.5mg to 400mg and the dose of bupropion or its pharmaceutically acceptable form can
range from 10mg to 600mg, more preferably 25mg to 450mg.
The compositions described herein can be administered orally, transmucosally,
sublingually, buccally, intranasally, transurethrally, rectally, by inhalation, transdermally,
parenterally in a variety of dosage forms including, but not limited to, aerosols, beads,
capsules, caplets, cataplasms (poultices), coated tablets, creams, dispersible granules,
dressings, dry powders, powder for reconstitition, dragees, effervescent tablets,
emulsions, eutectic mixture, films, gels, granules, gum, implants, inserts, lotions,
lozenges, lyophilized cakes and powders, liposomes, microgranules, minitablets,
minispheres, microcapsules, micropellets, modified release formulations, molded
formulations, multilayer tablet, nanoparticles,ointments, osmotic devices, pastes,
patches,pellets,pills, sachets, slurries, solutions, spheroids, stents, suspensions,
suppository, syrups, and tablets, tablet in a tablet, tablet in a capsule, troches, or The
compositions may contain one or more pharmaceutically acceptable excipients suitable
for such dosage forms. Suitable excipients include, but not limited to, antioxidants,
diluents, fillers, surfactants, polymers, hydrogels, ion-exchange resins, vehicles,
solubility enhancers, suspending agents, chelating agents, emollients, humectants,
binders, plasticizers, glidants, lubricants, pH modifying agents, pore forming agents,
emulsifiers, absorption accelerators, wetting agents, absorbents, osmotic salts,
preservatives, viscosity modifying agents, and propellants. Carriers, such as, for example,
water, glycols, oils, alcohols, flavoring agents, preservatives, coloring agents, and the like
in the case of oral liquid preparations (such as suspensions, solutions, and elixirs) or
aerosols; or carriers such as starches, sugars, micro-crystalline cellulose, diluents,
granulating agents, lubricants, binders, and disintegrating agents can be used in the case
of oral solid preparations.
17

Diluents may be included in the formulations to dissolve, disperse or otherwise
incorporate the carrier. Examples of diluents include, but are not limited to, water,
buffered aqueous solutions, organic hydrophilic diluents, such as monovalent alcohols,
and low molecular weight glycols and polyols (e.g. propylene glycol, polypropylene
glycol, glycerol, butylene glycol).
Binders suitable for use in pharmaceutical compositions and dosage forms include, but
are not limited to, corn starch, potato starch, or other starches, gelatin, natural and
synthetic gums such as acacia, sodium alginate, alginic acid, other alginates, powdered
tragacanth, guar gum, cellulose and its derivatives (e.g., ethyl cellulose, cellulose acetate,
carboxymethyl cellulose calcium, sodium carboxymethyl cellulose), polyvinyl
pyrrolidone, methyl cellulose, pre-gelatinized starch, hydroxypropyl methyl cellulose,
microcrystalline cellulose, and mixtures thereof.
Suitable forms of microcrystalline cellulose include, for example, the materials sold as
AVICEL-PH-101, AVICEL-PH-103 AVICEL RC-581, and AVICEL-PH-105. An
exemplary suitable binder is a mixture of microcrystalline cellulose and sodium
carboxymethyl cellulose sold as AVICEL RC-581. Suitable anhydrous or low moisture
excipients or additives include AVICEL-PH-103.TM. and Starch 1500 LM.
Examples of suitable fillers for use in the pharmaceutical compositions and dosage forms
disclosed herein include, but are not limited to, talc, calcium carbonate (e.g., granules or
powder), microcrystalline cellulose, powdered cellulose, dextrates, kaolin, mannitol,
silicic acid, sorbitol, starch, pre-gelatinized starch, and mixtures thereof. The binder/filler
in pharmaceutical compositions of the present invention is typically present in about 50
to about 99 weight percent of the pharmaceutical composition.
Disintegrants are used in the compositions of the invention to provide tablets that
disintegrate when exposed to an aqueous environment. Too much of a disintegrant will
produce tablets which may disintegrate in the bottle. Too little may be insufficient for
disintegration to occur and may thus alter the rate and extent of release of the active
ingredient(s) from the dosage form. Thus, a sufficient amount of disintegrant that is
18

neither too little nor too much to detrimentally alter the release of the active ingredient(s)
should be used to form the dosage forms of the compounds disclosed herein.
Disintegrants that can be used to form pharmaceutical compositions and dosage forms of
the invention include, but are not limited to, agar-agar, alginic acid, calcium carbonate,
microcrystalline cellulose, croscarmellose sodium, crospovidone, polacrilin potassium,
sodium starch glycolate, potato or tapioca starch, other starches, pre-gelatinized starch,
other starches, clays, other algins, other celluloses, gums or mixtures thereof.
Lubricants which can be used to form pharmaceutical compositions and dosage forms of
the invention include, but are not limited to, calcium stearate, magnesium stearate,
mineral oil, light mineral oil, glycerin, sorbitol, mannitol, polyethylene glycol, other
glycols, stearic acid, sodium lauryl sulfate, talc, hydrogenated vegetable oil (e.g., peanut
oil, cottonseed oil, sunflower oil, sesame oil, olive oil, corn oil, and soybean oil), zinc
stearate, ethyl oleate, ethyl laureate, agar, or mixtures thereof. Additional lubricants
include, for example, a syloid silica gel (AEROSIL 200, manufactured by W.R. Grace
Co. of Baltimore, Md.), a coagulated aerosol of synthetic silica (marketed by Degussa
Co. of Piano, Tex.), CAB-O-SIL (a pyrogenic silicon dioxide product sold by Cabot Co.
of Boston, Mass.), or mixtures thereof.
Rate controlling polymers are optionally used along with other adjuvants to formulate
modified release composition. Rate controlling polymers may be further classified into
water-soluble polymers and water insoluble polymers. Examples of rate controlling
polymers include, but are not limited to hydroxy alkyl cellulose, hydroxypropyl alkyl
cellulose where alkyl is 1 to 7 carbons selected from methyl, ethyl, isopropyl, butyl,
pentyl, and hexyl and wherein the cellulose component is from 9,000 to 1,250,000
molecular weight, such as hydroxypropyl methyl cellulose, hydroxy propylethyl
cellulose, hydroxypropyl isopropyl cellulose, hydroxy propyl butyl cellulose and
hydroxypropylhexylcellulose; poly (ethylene) oxide, alkyl cellulose, such as ethyl
cellulose and methyl cellulose; carboxymethyl cellulose; hydrophilic cellulose
derivatives, and polyethylene glycol.
19

Examples of hydrophilic polymers may include but not limited to hydroxypropyl
methylcellulose, hydroxypropyl cellulose, methyl cellulose, vinyl acetate copolymers,
polysaccharides as alginates, xanthan gum, Chitosan, carrageenan, dextran, and the like,
polyalkylene oxides as polyethylene oxide and the like.
Examples of hydrophobic polymers may include but not limited to acrylates, cellulose
derivatives as ethyl cellulose, cellulose acetate and the likes, methacrylates, high
molecular weight polyvinyl alcohols, hydrogenated vegetable oil, waxes and the like. The
polymers used can also be eroding or non-eroding or combination of both.
Polymers for effecting delayed release include, but are not limited to, cellulosic polymers
such as cellulose acetate, cellulose acetate phthalate, cellulose acetate trimellitate,
hydroxypropylmethyl cellulose phthalate, cellulose ester-ether phthalate,
hydroxypropylcellulose phthalate, alkali salts of cellulose acetate phthalate, alkaline earth
salts of cellulose acetate phthalate, hydroxypropylmethyl cellulose hexahydrophthalate,
cellulose acetate hexahydrophthalate, and carboxymethylcellulose sodium; acrylic acid
polymers and copolymers preferably formed from acrylic acid,. methacrylic acid, acrylic
acid alkyl esters, methacrylic acid alkyl esters, and the like, e.g. copolymers of acrylic
acid, methacrylic acid, methyl acrylate, ethyl acrylate, methyl methacrylate and/or ethyl
methacrylate (such as a terpolymer of ethyl acrylate, methyl methacrylate and
trimethylammonioethyl methacrylate chloride (available as Eudragit® RS from Rohm
America L.L.C., of Piscataway, N.J.)); vinyl polymers and copolymers such as polyvinyl
pyrrolidone, polyvinyl acetate, polyvinylacetate phthalate, vinylacetate crotonic acid
copolymer, and ethylene-vinyl acetate copolymers; and shellac, ammoniated shellac,
shellac-acetyl alcohol, and shellac n-butyl stearate.
Auxiliary coating aids such as plasticizer include, but not limited to, acetyltributyl citrate,
triacetin, acetylated monoglyceride, oils, acetyltriethylcitrate,glycerin, sorbitol,
diethyloxalate, diethylmalate, diethylfumarate,dibutylsuccinate, diethylmalonate,
dioctylphthalate, dibutylsebacate,triethylcitrate, tributylcitrate, glyceroltributyrate,
20

glyceryl triacetate, polyethylene glycol (molecular weight of from 380 to 420), propylene
glycol.
Suitable stabilising agents may be used in the formulations of the invention, to reduce the
degradation of bupropion hydrochloride on storage, include, but are not limited to,
shellac, any of its constituent aliphatic polyhydroxy acids presented as lactones, lactides
and inter-esters, saturated polyglycolised glycerides containing C 8 to C 18 saturated
fatty acids such as gelucire, ascorbic acid, benzoic acid, L-cysteine hydrochloride,
glycine hydrochloride, malic acid, sodium metasulfite, citric acid, tartaric acid, and L-
cystine dihydrochloride and fumaric acid.
Suitable emulsifiers include, but are not limited to, straight chain or branched fatty acids,
polyoxyethylene sorbitan fatty acid esters, sorbitan fatty acid esters, propylene glycol
stearate, glyceryl stearate, polyethylene glycol, fatty alcohols, polymeric ethylene oxide-
propylene oxide block copolymers, and combinations thereof.
Suitable surfactants include, but are not limited to, anionic surfactants, non-ionic
surfactants, cationic surfactants, and amphoteric surfactants. Examples of anionic
surfactants include, but are not limited to, ammonium lauryl sulfate, sodium lauryl
sulfate, ammonium laureth sulfate, sodium laureth sulfate, alkyl glyceryl ether sulfonate,
triethylamine lauryl sulfate, triethylamine laureth sulfate, triethanolamine lauryl sulfate,
triethanolamine laureth sulfate, monoethanolamine lauryl sulfate, monoethanolamine
laureth sulfate, diethanolamine lauryl sulfate, diethanolamine laureth sulfate, lauric
monoglyceride sodium sulfate, potassium lauryl sulfate, potassium laureth sulfate,
sodium lauryl sarcosinate, sodium lauryl sarcosinate, lauryl sarcosine, cocoyl sarcosine,
ammonium cocoyl sulfate, ammonium lauroyl sulfate, sodium cocoyl sulfate, sodium
lauroyl sulfate, potassium cocoyl sulfate, potassium lauryl sulfate, triethanolamine lauryl
sulfate, triethanolamine lauryl sulfate, monoethanolamine cocoyl sulfate,
monoethanolamine lauryl sulfate, sodium tridecyl benzene sulfonate, sodium dodecyl
benzene sulfonate, sodium and ammonium salts of coconut alkyl Methylene glycol ether
sulfate; tallow alkyl triethylene glycol ether sulfate, tallow alkyl hexaoxyethylene sulfate,
21

disodium N-octadecylsuIfosuccinnate, disodium lauryl sulfosuccinate, diammonium
lauryl sulfosuccinate, tetrasodium N-(1 ,2-dicarboxyethyl)-N- octadecylsulf- osuccinnate,
diamyl ester of sodium sulfosuccinic acid, dihexyl ester of sodium sulfosuccinic acid,
dioctyl esters of sodium sulfosuccinic acid, docusate sodium, and combinations thereof.
Ion-exchange resins are generally used to prepare complexes with active ingredient
and/or excipients. Ion-exchange resins are water-insoluble, cross-linked polymers
containing covalently bound salt forming groups in repeating positions on the polymer
chain. The ion-exchange resins suitable for use consist of a pharmacologically inert
organic or inorganic matrix and contain cationic groups. The organic matrix may be
synthetic (e.g., polymers or copolymers of acrylic acid, methacrylic acid, sulfonated
styrene, sulfonated divinylbenzene), or partially synthetic (e.g., modified cellulose and
dextrans). The inorganic matrix can also be, e.g., silica gel modified by the addition of
ionic groups. The covalently bound salt forming groups may be strongly acidic (e.g.,
sulfonic acid or sulfuric acid) or weakly acidic (e.g., carboxylic acid). Such ion-
exchangers are described by H. F. Walton in "Principles of Ion Exchange" (pp. 312-343).
Suitable resins include, but are not limited to, those resins available under the trademark
DOWEX(R).
Absorption accelerators include, but are not limited to, quaternary ammonium
compounds.
Wetting agents, include, but are not limited to, cetyl alcohol and glycerol monostearate,
fatty acid esters of sorbitan, poloxamers, and polyethylene glycols.Absorbents include,
but are not limited to, kaolin and bentonite clay.
Lipophilic solvents or vehicles include, but not limited to, fatty oils such as sesame oil, or
synthetic fatty acid esters, such as ethyl oleate or triglycerides, or liposomes.
Viscosity enhancing agents include, but not limited to, sodium carboxymethyl cellulose,
sorbitol, or dextran.
22

Suitable solubility enhancing agents include solvents such as water; diols, such as
propylene glycol and glycerol; mono-alcohols, such as ethanol, propanol, and higher
alcohols; DMSO; dimethylformamide; N3N- dimethylacetamide; 2-pyrrolidone; N- (2-
hydroxyethyl) pyrrolidone, N- methylpyrrolidone, 1-dodecylazacycloheptan-2-one and
other n-substituted- alkyl-azacycloalkyl-2-ones and other n-substituted-alkyl-
azacycloalkyl-2- ones (azones).
Suitable suspending agents include, but are not limited to, alginic acid, bentonite,
carbomer, carboxymethylcellulose and salts thereof, hydroxyethylcellulose,
hydroxypropylcellulose, microcrystalline cellulose, colloidal silicon dioxide, dextrin,
gelatin, guar gum, xanthan gum, kaolin, magnesium aluminum silicate, maltitol,
triglycerides, methylcellulose, polyoxyethylene fatty acid esters, polyvinylpyrrolidone,
propylene glycol alginate, sodium alginate, sorbitan fatty acid esters, tragacanth, and
combinations thereof.
The present invention relates to provide a pharmaceutical composition containing
desvenlafaxine or its pharmaceutically acceptable form and one or more second active
drug, wherein the said second active drug is selected from the group comprising of a
compound that increases synthesis/ or release of monoamines, direct/ indirect monoamine
receptor agonist, monoamine transport inhibitors and monoamine reuptake inhibitors,
optionally with additional active agents, for the treatment of CNS disorders.
More preferably, the present invention provides a pharmaceutical composition containing
desvenlafaxine or a pharmaceutically acceptable form thereof and one or more
monoamine reuptake inhibitor, or a pharmaceutically acceptable form thereof, optionally
with additional active agents for the treatment of CNS disorders, wherein monoamine
reuptake inhibitors, are selected from the group comprising of, but not limited to,
serotonin reuptake inhibitors, norepinephrine reuptake inhibitors, dopamine reuptake
inhibitors, serotonin-norepinephrine reuptake inhibitors, norepinephrine-dopamine
reuptake inhibitors, Serotonin-norepinephrine-dopamine or "triple reuptake inhibitors".
23

The pharmaceutical composition contains one or more pharmaceutically acceptable
excipients.
The pharmaceutical compositions described herein, can be administered in a variety of
dosage forms including, but not limited to, aerosols, beads, bioadhesive tablets, capsules,
caplets, cataplasms (poultices), coated tablets, creams, dispersible granules, dispersible
tablet, dressings, dry powders, powder for reconstitition, dragees, effervescent tablets,
emulsions, eutectic mixture, films, gels, granules, gum, implants, inserts, lotions,
lozenges, lyophilized cakes and powders, liposomes, microgranules, minitablets,
minispheres, microcapsules, micropellets, modified release formulations, molded
formulations, multilayer tablet, nanoparticles, ointments, osmotic devices, pastes,
patches, pellets, pills, rapidly diintegrating/dissolving tablet, sachets, slurries, solutions,
spheroids, stents, suspensions, suppository, syrups, and tablets, tablet in a tablet, tablet in
a capsule, troches.
The formulations of the present invention can exist as multi-unit or single-unit
formulations. The term "multi-unit" as used herein means a plurality of discrete or
aggregated particles, beads, pellets, granules, tablets, or mixtures thereof, for example,
without regard to their size, shape, or morphology. Single-unit formulations include, for
example, tablets, caplets, and pills.
The pharmaceutical dosage forms according to the present invention can be prepared by
any of the methods known to those skilled in the art at the time of the invention.
For example tablets can be prepared by compressing a drug-containing blend, e.g., blend
of granules, prepared using a direct blend, wet-granulation, co-granulation process or dry-
granulation process. Tablets may also be molded rather than compressed, starting with a
moist material containing a suitable water-soluble lubricant. However, preferred tablets
herein are manufactured using compression rather than molding.
24

The dosage forms may also include immediate release and/or formulations adapted for
modified release. The modified release composition may be osmotic controlled system,
diffusion controlled drug delivery system comprising of reservoir-based system and/or
matrix based system and combinations thereof.
Reservoir based system may comprise of atleast one functional coating and /or non-
functional coating. The coatings include moisture barriers, control-release coats, enteric
coats, coatings that affect physical stability and/or coatings that affect the appearance of
the composition.
The pharmaceutical formulations according to the invention can be coated by standard
aqueous and nonaqueous techniques using hydrophilic and/or hydrophobic polymers.
A non-limiting list of suitable modified release materials for use in the coating
composition or matrix based formulation of the present invention includes hydrophilic
and/or hydrophobic materials, such as sustained release polymer gums, acrylic resins,
waxes, and oils such as hydrogenated castor oil, and hydrogenated vegetable oil. Suitable
sustained-release polymers include alkylcelluloses such as ethylcellulose, acrylic and
methacrylic acid polymers and copolymers (such as Eudragit®); and cellulose ethers,
such as hydroxyalkylcelluloses (e.g., hydroxypropylmethylcellulose) and
carboxyalkylcelluloses, polyvinylpyrrolidone, carbomers, vinyl acetate copolymers,
polysaccharides as alginates, xanthan gum, Chitosan, carrageenan, dextran, and the like,
polyalkylene oxides as polyethylene oxide and the like. Examples of acrylic and
methacrylic acid polymers and copolymers include methyl methacrylate, methyl
methacrylate copolymers, ethoxyethyl methacrylates, ethyl acrylate, trimethyl
ammonioethyl methacrylate, cyanoethyl methacrylate, aminoalkyl methacrylate
copolymer, poly(acrylic acid), poly(methacrylic acid), methacrylic acid alkylamine
copolymer, poly(methyl methacrylate), poly(methacrylic acid)(anhydride),
polymethacrylate, polyacrylamide, poly(methacrylic acid anhydride), and glycidyl
methacrylate copolymers. Waxes include for example natural and synthetic waxes, fatty
acids, fatty alcohols, and mixtures of the same (e.g., beeswax, carnauba wax, stearic acid
25

and stearyl alcohol). Cellulosic polymers for use in the core of the present invention
include hydroxyethyl cellulose hydroxypropylmethyl cellulose, hydroxypropylcellulose,
methyl cellulose, sodium carboxy methyl cellulose, and mixtures thereof.
In certain embodiments, the polymer is present in an amount from about 5% to about
90% by weight of the functional coating content of modified release composition.
When two or more active agents are combined in a single pharmaceutical dosage form,
possible interactions among the active agents, and among the active agents and the
excipients, must be considered. Such consideration is well within the purview of those
skilled in the art of pharmaceutical formulation. The present composition thus
encompasses pharmaceutical compositions wherein two or more of the active agents are
separated from each other within the pharmaceutical dosage form, by, for example,
separating potentially interacting compounds from each other within the pharmaceutical
dosage form, as in separate flat layers of a tablet (e.g., a bilayer or trilayer tablet),
concentric layers, coated beads or granules (which may be incorporated into a
compressed tablet or into a capsule), and/or by using buffers . It will also be appreciated
by those in the art that such dosage forms, wherein two or more active agents are
physically separated from the other active agents, can be manufactured so that different
active agents will have different release profiles, e.g., if one active agent is formulated
with an enteric coating, another active agent is formulated in a sustained release matrix,
and the like. Alternatively, non-reactive pharmaceutically active derivatives of one or
more of the potentially interacting compounds may be used.
Preferably, the oral dosage forms containing desvenlafaxine and second active agent may
be formulated to provide immediate and/or modified release of desvenlafaxine and
immediate and/or modified release of the second active agent optionally with immediate
and/or modified release of additional active agent. The modified release profiles for
desvenlafaxine and second active agent, or both can be achieved by sustained, including
delayed and extended release, and pulsatile formulations.
26

The pharmaceutical composition according to the invention can be delayed release
formulation of desvenlafaxine and second active agent optionally with pore forming
agents and or water-soluble polymers.
Polymers for effecting delayed release include, but are not limited to, cellulosic polymers
such as cellulose acetate, cellulose acetate phthalate, cellulose acetate trimellitate,
hydroxypropylmethyl cellulose phthalate, cellulose ester-ether phthalate,
hydroxypropylcellulose phthalate, alkali salts of cellulose acetate phthalate, alkaline earth
salts of cellulose acetate phthalate, hydroxypropylmethyl cellulose hexahydrophthalate,
cellulose acetate hexahydrophthalate, and carboxymethylcellulose sodium; acrylic acid
polymers and copolymers preferably formed from acrylic acid,. methacrylic acid, acrylic
acid alkyl esters, methacrylic acid alkyl esters, and the like, e.g. copolymers of acrylic
acid, methacrylic acid, methyl acrylate, ethyl acrylate, methyl methacrylate and/or ethyl
methacrylate (such as a terpolymer of ethyl acrylate, methyl methacrylate and
trimethylammonioethyl methacrylate chloride (available as Eudragit® RS); vinyl
polymers and copolymers such as polyvinyl pyrrolidone, polyvinyl acetate,
polyvinylacetate phthalate, vinylacetate crotonic acid copolymer, and ethylene-vinyl
acetate copolymers; and shellac, ammoniated shellac, shellac-acetyl alcohol, and shellac
n-butyl stearate.
In addition to the common dosage forms set out above, active ingredients can also be
administered by controlled release means or delivery devices that are well known to those
of ordinary skill in the art. The invention thus encompasses single unit dosage forms
suitable for oral administration such as, but not limited to, tablets, capsules, gelcaps, and
caplets that are adapted for controlled-release.
The sustained or extended release or extended-release formulations can also be prepared
using natural ingredients, such as minerals, including titanium dioxide, silicon dioxide,
zinc oxide, and clay. Suitable controlled-release formulations known to those of ordinary
skill in the art, including those described herein can be readily selected for use with the
pharmaceutical compositions of the invention.
27

All controlled-release pharmaceutical products have a common goal of improving drug
therapy over that achieved by their non-controlled counterparts. Ideally, the use of an
optimally designed controlled-release preparation in medical treatment is characterized
by a minimum of drug substance being employed to cure or control the condition in a
minimum amount of time. Advantages of controlled-release formulations include: 1)
extended activity of the drug; 2) reduced dosage frequency; and 3) increased patient
compliance. In addition, controlled-release formulations can be used to affect the time of
onset of action or other characteristics, such as blood levels of the drug, and thus can
affect the occurrence of side effects.
Most controlled-release formulations are designed to initially release an amount of drug
that promptly produces the desired therapeutic effect, and gradually and continually
release of other amounts of drug to maintain this level of therapeutic effect over an
extended period of time. In order to maintain this constant level of drug in the body, the
drug must be released from the dosage form at a rate that will replace the amount of drug
being metabolized and excreted from the body. Various inducers, including, but riot
limited to, pH, temperature, enzymes, water, or other physiological conditions or
compounds, can stimulate controlled-release of an active ingredient.
The dosage form of the present invention may be administered once a day, twice a day,
once weekly, twice weekly, once a month, and twice a month, wherein the dose of
desvenlafaxine or its pharmaceutically acceptable form can range from 25mg to 500mg.
The method of preparation of the present invention involves preparation of granules of
individual drugs which are filled in the form of granules or powder or compressed into
minitablets or pellets, beads which are in turn filled into capsules or compressed into
tablets.
A modified release formulation comprising a pharmaceutically acceptable tablet
comprising of desvenlafaxine/second active drug core, optionally coated with release
28

modifying polymers or release retarding polymers or non-functional coating, second
active drug/desvenlafaxine loading over the core, optionally over coating loaded core
with functional or non-functional coating.
Capsules are also preferred dosage forms, in which case the active agent containing
composition can be encapsulated in the form of a liquid or solid (including, but not
limited to, particulates such as beads, granules, minitablets, microcapsules, minispheres
powders, pellets, spheroids). Furthermore, the capsule may comprise of, but not limited
to, immediate release and/or modified release beads, granules, minitablets,
microcapsules, minispheres, nanoparticles, powders, pellets, pills, spheroids or
combinations thereof.
Capsules include push-fit capsules made of gelatin, as well as soft, sealed capsules made
of gelatin and a plasticizer, such as glycerol or sorbitol. The push-fit capsules can contain
the active ingredients in admixture with fillers, binders, lubricants and, optionally,
stabilizers. In soft capsules, the active compounds can be dissolved or suspended in
suitable liquids, such as fatty oils, liquid paraffin, or liquid polyethylene glycols. In
addition, stabilizers can be added. All formulations for oral administration should be in
dosages suitable for such administration.
In certain embodiments, the capsule contains active ingredients in admixture with
suitable excipients in a suitable dosage form and optionally the capsule may be coated
with hydrophilic and/or hydrophobic polymer.
In an embodiment of the present invention, the hard gelatin capsule comprises of
granules. These granules comprised of a core and an optional outer coating, the core of
said minitablets comprising desvenlafaxine or its pharmaceutically acceptable form
thereof and second active drug/drugs optionally with conventional excipients and the said
coating comprising a hydrophobic polymer and / or a hydrophilic polymer. Optionally the
granules can be compressed into tablets.
29

In an embodiment of the present invention, the hard gelatin capsule comprises of
granules. These granules comprised of core comprising desvenlafaxine/atleast one second
active drug/drugs, optionally coated with modifying polymers or release retarding
polymers, second active drug/ desvenlafaxine loading over the core, optionally over
coating loaded core. Optionally the granules can be compressed into tablets.
Preferably pellets can be prepared by the conventional methods, optionally coated and
then compressed in to tablets or filled in to capsules, which can be optionally coated.
In an embodiment of the present invention, the hard gelatin capsule comprises of pellets.
These pellets comprised of desvenlafaxine / atleast one second active drug loaded core
comprising inert material, optionally coated with modifying polymers or release retarding
polymers, atleast one second active drug/ desvenlafaxine drug loading over the drug
loaded core, optionally over coating loaded core. Optionally the pellets can be
compressed into tablets.
In an embodiment of the present invention, the hard gelatin capsule comprises of pellets.
These pellets comprised of a core and an outer coating, the core of said pellets
comprising desvenlafaxine or its pharmaceutically acceptable form thereof and second
active drug/drugs optionally with conventional excipients and the said coating comprising
a hydrophobic polymer and / or a hydrophilic polymer. Optionally the granules can be
compressed into tablets.
In an embodiment of the present invention, the hard gelatin capsule comprises of mini-
tablets. These mini-tablets comprised of a core and an outer coating, the core of said
minitablets comprising desvenlafaxine or its pharmaceutically acceptable form thereof
and atleast one second active drug optionally with conventional excipients and the said
coating comprising a hydrophobic polymer and / or a hydrophilic polymer. Optionally the
minitablets can be compressed into tablets.
30

In an embodiment of the present invention, the hard gelatin capsule comprises of mini-
tablets. These mini-tablets comprised of core comprising desvenlafaxine/ atleast one-
second active drug, optionally coated with modifying polymers or release retarding
polymers, atleast one second active drug/desvenlafaxine loading over the core, optionally
over coating loaded core. Optionally the minitablets can be compressed into tablets.
In an embodiment of the present invention, the hard gelatin capsule comprises of mini-
tablets. These mini-tablets comprised of desvenlafaxine/ atleast one second active drug
loaded core comprising inert material, optionally coated with modifying polymers or
release retarding polymers, atleast one second active drug /desvenlafaxine loading over
the drug loaded core, optionally over coating loaded core. Optionally the minitablets can
be compressed into tablets.
In an embodiment of the present invention, the coating on mini-tablet comprises of water
insoluble polymer and/or water-soluble polymer. In a preferred embodiment, the water
insoluble polymer is ethyl cellulose, present in an amount from about 5% to about 90%
by weight of the functional coating content of modified release composition. Ethyl
cellulose and hydroxypropyl methylcellulose of the present invention covers all the
viscosities and the grades know in the field of the invention.
The coating polymers include all water soluble and/or soluble polymers known in the art.
The scope of the present invention is not limited to hard gelatin capsules. The scope of
the invention includes cellulose capsules or any capsule known to the person skilled in
the art.
In another embodiment, the individual dosage units are compacted in a single tablet, and
may represent integral but discrete segments thereof (e.g., layers) or be present in an
admixture. Layered tablets, with each layer containing a different active agent and/or
providing a different release profile, provide several manufacturing advantages. Such
tablets may be made in single step compression, thereby eliminating the operations of
methods necessary for preparing coated core dosage forms. Layered tablets additionally
31

eliminate the concomitant steps of in process and quality controls for manufacturing two
or more different tablets. Further, layers containing only excipients can be interspersed
between layers that contain active agents, to prevent possible interactions between or
among the active agents. With tablets containing different dosage units in admixture,
drug-containing beads, granules or particles with different drug release profiles (e.g.,
immediate and delayed release profiles), and/or drug-containing beads, granules or
particles containing different active agents, can be compressed together into a single
tablet using conventional tableting means. In the admixture, there is a random possibility
of the different active agents coming into contact with each other. However, protective
and/or delayed release coatings provided on the granules or other dosage units provide a
physical barrier, thereby minimizing direct physical contact between the active agents.
In an embodiment of the present invention, a modified/immediate release formulation
comprises a pharmaceutical bilayer tablet comprising a first layer comprising
desvenlafaxine or its pharmaceutically acceptable form and a second layer comprising of
atleast one second active drug optionally separated with a separating layer.
In one embodiment, desvenlafaxine or its pharmaceutically acceptable form, atleast one
second active agent, and vasoactive agent are each individually contained within separate
layers of a multilayered tablet.
In another embodiment, wherein the dosage form of the invention comprises a tablet
containing active agent beads in a blended matrix, wherein at least one of the active
agents is formulated into beads and at least one of the other active agents is formulated
into the matrix of the tablet that surrounds the beads. The beads may be uncoated, be
coated with a protective layer, be enterically coated, be coated or otherwise formulated
for sustained released, or be coated or otherwise formulated for delayed release. The
matrix may be formulated for immediate release, delayed release, or sustained release. In
a preferred embodiment, desvenlafaxine or its pharmaceutically acceptable form is
individually formulated into a plurality of beads, said beads being formulated for
sustained release, while atleast one second active agent is comprised within the matrix,
32

said matrix being formulated for immediate release. In a particularly preferred
embodiment, tablet further comprises vasoactive agent blended together with the second
active agent in the matrix.
This invention further encompasses anhydrous pharmaceutical compositions and dosage
forms which comprises the active ingredients, since water can facilitate the degradation
of some compounds. For example, the addition of water (e.g., 5%) is widely accepted in
the pharmaceutical arts as a means of simulating long-term storage in order to determine
characteristics such as shelf life or the stability of formulations over time. In effect, water
and heat accelerate decomposition. Thus the effect of water on a formulation can be of
great significance since moisture and/or humidity are commonly encountered during
manufacture, handling, packaging, storage, shipment, and use of formulations.
Anhydrous pharmaceutical compositions and dosage forms of the invention can be
prepared using anhydrous or low moisture containing ingredients and low moisture or
low humidity conditions.
An anhydrous pharmaceutical composition should be prepared and stored such that its
anhydrous nature is maintained. Accordingly, anhydrous compositions are preferably
packaged using materials known to prevent exposure to water such that they can be
included in suitable formulary kits. Examples of suitable packaging include, but are not
limited to, hermetically sealed foils, plastic or the like, unit dose containers, blister packs,
and strip packs.
The present invention also relates to a pharmaceutical composition consisting of a
hydrogel matrix.
The preferred embodiment of the present invention also relates to multiparticulate
formulation of desvenlafaxine that contains a multiparticulate form of desvenlafaxine and
one or more second active drug, which allows convenient dosing to patients.
33

The use of a multiparticulate formulation facilitates dosing to pediatric patients, geriatric
patients. The smaller size of the multiparticulates, in a capsule or pouch or any other
container, also allows dosing through nasogastric or gastrostomy tube. Suitably, the
multiparticulate desvenlafaxine and/ one or more second active drug is present in
spheroid, bead, minitablets or pellet.
The multiparticulate composition of the invention are composed, at a minimum, of a core
composed of desvenlafaxine, one or more second active drug and one or more diluents,
binders, fillers, glidants, anti-adherents, a pH adjuster and/or an adjuvant.
In another embodiment, the present invention relates to the use of multiparticulate
formulations of the invention in the preparation of medicaments for delivery to a
pediatric or geriatric patient.
In one embodiment, the multiparticulate desvenlafaxine/ second active drug containing
core is optionally coated, which is optionally coated with polymer, further loaded with
second active drug/ desvenlafaxine optionally coated with polymer. The multiparticulates
can be placed into a suitable capsule shell or compressed into tablets, using techniques
know to those of skill in the art.
This invention further encompasses rapidly disintegrating tablets. Preferred rapidly
disintegrating tablet includes effervescent tablets. Generally, effervescent tablets contain
the active agents in combination with additives such as sodium bicarbonate and an
organic acid, e.g., tartaric acid or citric acid. In the presence of water, these additives
react to liberate carbon dioxide thereby facilitating the disintegration of the tablet. Once
the tablet is substantially disintegrated, an individual swallows the resultant solution
thereby providing systemic adsorption of the active agent.
Another version of a rapidly disintegrating tablet includes "open matrix network" tablets.
In addition, the pharmaceutical composition comprising the therapeutic combination may
be administered via a chewing gum formulation. Gum formulations containing
34

pharmacologically active agents and techniques for preparing such formulations are well
known in the art.
This invention further encompasses parenteral administration of the pharmaceutical
composition. For injection, the active ingredients can be formulated into preparations by
dissolving, suspending or emulsifying them in an aqueous or nonaqueous solvent, such as
vegetable or other similar oils, synthetic aliphatic acid glycerides, esters of higher
aliphatic acids or propylene glycol; and if desired, with conventional additives such as
solubilizers, isotonic agents, suspending agents, emulsifying agents, stabilizers and
preservatives. Preferably, a combination of the invention can be formulated in aqueous
solutions, preferably in physiologically compatible buffers such as Hanks's solution,
Ringer's solution, or physiological saline buffer. Pharmaceutical formulations for
parenteral administration include aqueous solutions of the active compounds in water-
soluble form. Additionally, suspensions of the active compounds can be prepared as
appropriate oily injectable suspensions. Alternatively, the active ingredient can be in
powder form for constitution with a suitable vehicle, e.g., sterile pyrogen-free water,
before use.
This invention further encompasses transmucosal or transdermal drug delivery. For
transmucosal or transdermal administration, penetrants appropriate to the barrier to be
permeated are used in the formulation. Transdermal delivery systems can include, e.g.,
patches. For transmucosal administration, penetrants appropriate to the barrier to be
permeated are used in the formulation. Such penetrants are generally known in the art.
This invention further encompasses administration of the pharmaceutical composition
intranasally or by inhalation. Compositions for nasal administration are generally liquid
formulations for administration as a spray or in the form of drops, although powder
formulations for intranasal administration, e.g., insufflations, are also known.
Formulations for inhalation may be prepared as an aerosol, either a solution aerosol in
which the active agents are solubilized in a carrier (e.g., propellant) or a dispersion
35

aerosol in which the active agents are suspended or dispersed throughout a carrier and an
optional solvent. Non-aerosol formulations for inhalation may take the form of a liquid,
typically an aqueous suspension, although aqueous solutions may be used as well.
Pharmaceutical compositions suitable for use in the present invention include
compositions wherein the active ingredients are contained in a therapeutically effective
amount. The amount of composition administered will, of course, be dependent on the
subject being treated, on the subject's weight, the severity of the disorder, the manner of
administration and the judgment of the prescribing physician. Determination of an
effective amount is well within the capability of those skilled in the art, especially in light
of the detailed disclosure provided herein. Generally, an efficacious or effective amount
of a combination of desvenlafaxine or its pharmaceutically acceptable form and one or
more second active drug is determined by first administering a low dose or small amount
of desvenlafaxine alone, the second active drug alone or a combination of desvenlafaxine
and second active drug, and then incrementally increasing the administered dose or
dosages, adding the second medication as needed, until a desired effect is observed in the
treated subject, with minimal or no toxic side effects. Applicable methods for
determining an appropriate dose and dosing schedule for administration of a combination
of the present invention are described, for example, in Goodman and Gilman's The
Pharmacological Basis of Therapeutics, 10.sup.th Ed., Hardman, Limbird and Goodman-
Gilman, Eds. McGraw-Hill.
Dosage amount and interval can be adjusted individually to provide plasma levels of the
active compounds, which are sufficient to maintain therapeutic effect. Preferably,
therapeutically effective serum levels will be achieved by administering single daily
doses, but efficacious multiple daily dose schedules are included in the invention. In
cases of local administration or selective uptake, the effective local concentration of the
drug may not be related to plasma concentration. One having skill in the art will be able
to optimize therapeutically effective local dosages without undue experimentation.
36

The present invention relates to a kit for conveniently and effectively carrying out the
methods in accordance with the present invention. Such kits are especially suited for, but
not limited to, the delivery of solid oral forms such as tablets, capsules, caplets. Such a kit
preferably includes a number of unit dosages.
The kit comprises of a pharmaceutical composition containing one or more serotonin
norepinephrine reuptake inhibitors and one or more second active drug, wherein the said
second active drug is selected from the group comprising of a compound that increases
synthesis/ or release of monoamines, direct/ indirect monoamine receptor agonist,
monoamine transport inhibitors, serotonin reuptake inhibitors, norepinephrine reuptake
inhibitors, dopamine reuptake inhibitors, norepinephrine-dopamine reuptake inhibitors,
Serotonin-norepinephrine-dopamine or "triple reuptake inhibitors" optionally with
additional active agents, having better tolerability, predictable efficacy, reduced drug
interaction, reduced inter-individual variability associated with genetic polymorphism
leading to predictable pharmacokinetics, along with reduced incidence of adverse effects
in patients.
More preferably the kit comprises of a pharmaceutical composition containing
desvenlafaxine or its pharmaceutically acceptable form thereof and one or more second
active drug, wherein the said second active drug is selected from the group comprising of
a compound that causes direct or indirect monoamine receptor agonism, increases
synthesis of monoamines /or triggers the release of monoamines, inhibits monoamine
transport or its reuptake, optionally with additional active agent; a container housing the
pharmaceutical composition during storage and prior to administration; and instructions
for carrying out drug administration in a manner effective to treat CNS disorders.
The said second active drug is selected from the group comprising of, but not limited to,
levodopa, deprenyl, bupropion, carbidopa, pergolide, ropinirole, pramipexole, selegiline,
entacapone, tolcapone, fencamfamine, amfenolic acid, quinpirole, troparil, vanoxerine,
aminepptine, citalopram, escitalopram, fluoxetine, fluvoxamine, paroxetine and
37

sertraline, milnacipran, mirtazapine, duloxetine and the like or a pharmaceutically
acceptable form thereof.
The kit may contain additional active agents. The additional active agents are selected
from the class of, but not limited to, vasoactive agents. Exemplary vasoactive agents
include, but not limited to, nitroglycerin, isosorbide dinitrate, erythrityl tetranitrate, amyl
nitrate, sodium nitroprusside, molsidomine, linsidomine chlorhydrate, S-nitroso-N-acetyl-
d, 1-penicillamine, S-nitroso-N-cysteine and S-nitroso-N-glutathione, diazenium diolates
("NONOates"), phenoxybenzamine, dibenamine, doxazosin, terazosin, phentolamine,
tolazoline, prazosin, trimazosin, alfuzosin, tamsulosin, indoramin, ergotamine,
acetergamine, brazergoline, bromerguride, cianergoline, delorgotrile, disulergine,
ergonovine maleate, ergotamine tartrate, etisulergine, lergotrile, lysergide, mesulergine,
metergoline, metergotamine, nicergoline, pergolide, propisergide, proterguride,
diazoxide, hydralazine, minoxidil nimodepine, pinacidil, cyclandelate, dipyridamole,
isoxsuprine, chlorpromazine, haloperidol, yohimbine, prostaglandin dinoprost
tromethamine, dinoprostone, lipoprost, gemeprost, metenoprost, sulprostone, tiaprost,
vasoactive intestinal peptide, or a pharmaceutical ly acceptable form thereof.
The present invention relates to provide kit containing desvenlafaxine or a
pharmaceutically acceptable form thereof and one or more second active drug, optionally
with additional active agents; having better tolerability, predictable efficacy, reduced
drug interaction, reduced inter-individual variability associated with genetic
polymorphism leading to predictable pharmacokinetics, along with reduced incidence of
adverse effects in patients.
When the compositions are to be delivered with periodic discontinuation, a package or kit
can include placebos on those days when the composition is not delivered. Alternatively,
dietary supplements, can be included to provide a kit in which a dosage is taken once a
day or twice a day or once weekly or twice weekly or once a month, or twice a month.
38

A number of packages or kits are known in the art for the use in dispensing
pharmaceutical agents for oral use. Desirably, the package is a labeled blister package,
dial dispenser package, or divided bottle or a divided foil packet.
An example of such a kit is a so-called blister pack. Blister packs are well known in the
packaging industry and are being widely used for the packaging of pharmaceutical unit
dosage forms (tablets, capsules, and the like). Blister packs generally consist of a sheet of
relatively stiff material covered with a foil of a preferably transparent plastic material.
During the packaging process, recesses are formed in the plastic foil. The recesses have
the size and shape of individual tablets or capsules to be packed or may have the size and
shape to accommodate multiple tablets and/or capsules to be packed. Next, the tablets or
capsules are placed in the recesses accordingly and the sheet of relatively stiff material is
sealed against the plastic foil at the face of the foil which is opposite from the direction in
which the recesses were formed.
As a result, the tablets or capsules are individually sealed or collectively sealed, as
desired, in the recesses between the plastic foil and the sheet. Preferably the strength of
the sheet is such that the tablets or capsules can be removed from the blister pack by
manually applying pressure on the recesses whereby an opening is formed in the sheet at
the place of the recess. The tablet or capsule can then be removed via said opening.lt
maybe desirable to provide a written memory aid, where the written memory aid is of the
type containing information and/or instructions for the physician, pharmacist or subject,
e.g., in the form of numbers next to the tablets or capsules whereby the numbers
correspond with the days of the regimen which the tablets or capsules so specified should
be ingested or a card which contains the same type of information. Another example of
such a memory aid is a calendar printed on the card e.g., as follows "First Week,
Monday, Tuesday,"... etc.... "Second Week, Monday, Tuesday,..." etc. Other variations of
memory aids will be readily apparent. A "daily dose" can be a single tablet or capsule or
several tablets or capsules to be taken on a given day.
The container can be in any conventional shape or form as known in the art which is
made of a pharmaceutically acceptable material, for example a paper or cardboard box, a
39

glass or plastic bottle or jar, a re-sealable bag (for example, to hold a "refill" of tablets for
placement into a different container), or a blister pack with individual doses for pressing
out of the pack according to a therapeutic schedule. The container employed can depend
on the exact dosage form involved, for example a conventional cardboard box would not
generally be used to hold a liquid suspension. It is feasible that more than one container
can be used together in a single package to market a single dosage form.
Another specific embodiment of a kit is a dispenser designed to dispense the daily doses
one at a time in the order of their intended use. Preferably, the dispenser is equipped with
a memory-aid, so as to further facilitate compliance with the regimen. An example of
such a memory-aid is a mechanical counter which indicates the number of daily doses
that has been dispensed.
In certain embodiments, a kit comprises the dispenser which permit the strength of the
individual doses of desvenlafaxine or its pharmaceutically acceptable form and one or
more second active drug, wherein the said second active drug is selected from the group
comprising of a compound that causes direct or indirect monoamine receptor agonism,
increases synthesis of monoamines /or triggers the release of monoamines, inhibits
monoamine transport or its reuptake; or of both to be altered as frequently as which the
attending physician deems desirable. The kit comprisind the dispenser may further
contain additional active agents. The dispensers of this invention meet these needs by
dispensing the pharmaceutical compositions in metered or measured doses.
In certain embodiments, a kit for delivering the pharmaceutical composition through an
inhalation route to a mammal is provided which comprises a device that forms an aerosol
from the composition, for inhalation by the mammal. The kit includes an aerosol
packaging assembly having a container accommodating a pressurized product and an
outlet capable of releasing the pressurized product.
In certain embodiments, a kit of the present invention comprises desvenlafaxine or its
pharmaceutically acceptable form thereof and one or more second active drug selected
from the group comprising of a compound that causes direct or indirect monoamine
receptor agonism, increases synthesis of monoamines /or triggers the release of
40

monoamines, inhibits monoamine transport or its reuptake, optionally with additional
active agent; in the same/ different formulations.
In certain embodiments of the present invention the kit may also provide actives in
uniform formulation.
In certain embodiments, the kits provide / contain desvenlafaxine or its pharmaceutically
acceptable form thereof and one or more second active drug, wherein the second active
drug is selected from the group comprising of comprising of a compound that causes
direct or indirect monoamine receptor agonism, increases synthesis of monoamines /or
triggers the release of monoamines, inhibits monoamine transport or its reuptake,
optionally with additional active agent; in graduated dosages over the course of
treatment, either increasing or decreasing, but usually increasing to an efficacious dosage
level.
In certain embodiments, the kit comprise of pharmaceutical composition containing
combination of desvenlafaxine or a pharmaceutically acceptable form thereof and one or
more monoamine reuptake inhibitors, wherein monoamine reuptake inhibitors, are
selected from the group comprising of, but not limited to, serotonin reuptake inhibitors,
norepinephrine reuptake inhibitors, dopamine reuptake inhibitors, serotonin-
norepinephrine reuptake inhibitors, norepinephrine-dopamine reuptake inhibitors,
Serotonin-norepinephrine-dopamine or "triple reuptake inhibitors" for the treatment of
CNS disorders.
In one preferred embodiment, the kit comprise of pharmaceutical composition containing
combination of desvenlafaxine or a pharmaceutically acceptable form thereof, and
bupropion or a pharmaceutically acceptable form thereof, for the treatment of CNS
disorders.
Although the foregoing invention has been described in some detail by way of illustration
and example for purposes of clarity of understanding, it will be readily apparent to those
of ordinary skill in the art in light of the teachings of this invention that certain changes
41

and modifications may be made thereto without departing from the spirit or scope of the
appended claims. The invention will be described in greater detail by way of specific
examples.
The following examples are offered for illustrative purposes, and are not intended to limit
the invention in any manner. Those of skill in the art will readily recognize a variety of
noncritical parameters, which can be changed or modified to yield essentially the same
results.

The beads/ minitablets may be prepared by mixing ingredients in a high shear granulator.
The granulated material is extruded with an extruder, and then spheronized into beads
using a spheronizer. The beads/ minitablets of step 1 and 2 are then filled into capsule or
compressed into tablets. Optionally coated .
42


43
Step 1 involves preparation of desvenlafaxine beads which are further coated in step 2.
Step 3 involves preparation of fluvoxamine granules further compressed into minitablets.
The minitablets may be optionally coated. The Desvenlafaxine beads and Fluvoxamine
minitablets aree then filled into capsules or optionally compressed into tablet.



44
Step 1 involves formulation of desvenlafaxine beads which are further coated in step 2.
Step 3 involves modified release coating of Bupropion on coated beads of step 2. The
beads are filled into capsules or optionally compressed into tablets.



Step 1 involves preparation of coated desvenlafaxine pellets. Step 2 involves preparation
of milnacipran pellets. Step 3 involves coating of milnacipran pellets. The pellets of step
1 and 3 are directly filled in to capsules.

Drug loading involves drug loading of Desmethylvenlafaxine on to sugar spheres, using
Fluidized bed coater. The resulting drug loaded spheres are then coated. The coated drug
45

loaded spheres are reloaded with bupropion HCl and later recoated using Eudragit based
coating.

The part A ingredients were granulated and blended as appropriate and well known in the
pharmaceutical industry. The subsequent granules were compressed to form the first layer
of the tablet.
46
The part B ingredients were granulated and blended as appropriate and well known in the
pharmaceutical industry. The subsequent granules were compressed over part A to form
second layer of the tablet.



The part A ingredients were granulated and blended as appropriate and well known in the
pharmaceutical industry. The subsequent granules were compressed to form the first layer
of the tablet.
The part B ingredients were granulated and blended as appropriate and well known in the
pharmaceutical industry. The subsequent granules were compressed over part A to form
second layer of the tablet.
The part C ingredients were granulated and blended as appropriate and well known in the
pharmaceutical industry. The subsequent granules were compressed over second layer to
47
form third layer of the tablet.



All the ingredients were mixed and granulated. The granules were dried. After drying
and lubrication the granules were compressed. The tablets are coated with an acetone
solution of cellulose acetate and polyethylene glycol. Then each tablet is drilled.

48
The ingredients are mixed and granulated. The granules are further compressed into
tablets.



49
The ingredients of step 1 are mixed and granulated. The granules are compressed to form
tablets. The tablets are coated in step 2. Step 3 further involves modified release coating
of bupropion. The coated tablets of step 3 are further coated with immediate release
coating of bupropion. The tablets may then be optionally coated.


The ingredients are mixed and granulated. The granules are further compressed into
tablets.

The ingredients are mixed and granulated. The granules are further compressed into
tablets. The tablets are then coated.
Claims:
1. A pharmaceutical combination containing Desvenlafaxine or its pharmaceutically
acceptable form thereof and atleast one second active drug, wherein the said
second active drug is selected from the group comprising of a compound or its
pharmaceutically acceptable forms that causes direct or indirect monoamine
receptor agonism, increases synthesis of monoamines /or triggers the release of
monoamines, inhibits monoamine transport or its reuptake for the treatment of
CNS disorders.

The present invention provides a pharmaceutical composition/combination containing
desvenlafaxine or its pharmaceutically acceptable form and one or more second active
drug, wherein the said second active drug is selected from the group comprising of a
compound that increases synthesis/ or release of monoamines, direct/ indirect monoamine
receptor agonist, monoamine transport inhibitors and monoamine reuptake inhibitors for the treatment of CNS disorders. The present invention provides novel therapeutic composition containing desvenlafaxine or its pharmaceutically acceptable form and atleast one monoamine reuptake inhibitor for the treatment of CNS disorders. The present invention, more particularly, provides novel therapeutic composition containing desvenlafaxine or its pharmaceutically acceptable form and atleast one
monoamine reuptake inhibitor, preferably bupropion, for the treatment of CNS disorders.
The present invention relates to provide such pharmaceutical compositions having better
tolerability, predictable efficacy, reduced drug interaction, reduced inter-individual variability associated with genetic polymorphism leading to predictable pharmacokinetics, along with reduced incidence of adverse effects in patients. The present invention also relates to provide a pharmaceutical composition containing
desvenlafaxine or its pharmaceutically acceptable form and one or more second active
drug, wherein the said second active drug is selected from the group comprising of a
compound that increases synthesis/ or release of monoamines, direct/ indirect monoamine
receptor agonist, monoamine transport inhibitors and monoamine reuptake inhibitors optionally with additional active agents for the treatment of CNS disorders. The present invention relates to formulation of said pharmaceutical composition in a modified release, immediate release composition or the combination thereof.
The present invention relates to providing a kit for a patient to use in the treatment of
CNS disorders. The kit includes a pharmaceutical composition as provided herein, a container housing the pharmaceutical composition during storage and prior to administration; and instructions, e.g., written instructions on a package insert or label, for carrying out drug administration in a manner effective to treat CNS disorders; wherein the kit shows reduced incidence of adverse effects.