Field of the invention
The present invention relates to novel controlled release pharmaceutical compositions
comprising Milnacipran or pharmaceutically acceptable salts thereof.
Background of the invention
Milnacipran (cis-2-amino methyl-N, N-diethyl-1 -phenyl cyclopropane carboxamide) is a
psychoactive drug, which is a selective norepinephrine and serotonin reuptake inhibitor.
It is used for the treatment of clinical depression and chronic pain especially
fibromyalgia.
Milnacipran was first disclosed in US Pat. No 4,478,836. Milnacipran is currently
available as Savella® immediate release tablets in USA and is used for the
management of fibromyalgia.
Milnacipran has demonstrated numerous adverse reactions in human clinical trials with
tolerability decreasing with increasing dose (Puech A. et al., 1997, Int. Clin.
Psychopharm, 12:99-108). Milnacipran may induce a locally mediated nausea via
gastric irritation and the rapid onset of nausea was observed even prior to achieving
peak plasma levels. An immediate release formulation of Milnacipran may not be
suitable for a once-daily dosing regimen for treatment of depression and other related
diseases due to Milnacipran's relatively short, half-life, which is 8 hours approximately.
Moreover, the currently available immediate release formulation of Milnacipran is not
ideal for the treatment of health conditions that require Milnacipran doses equal or
above 100 mg/day given either as once a day or twice a day due to the high incidence
of treatment-emergent side effects that lead to poor patient tolerance. Higher doses are
required in the treatment of severe depression and other associated disorders.
Milnacipran dosing regime of 100-250 mg daily was recently reported for the treatment
of fibromyalgia (U.S. Pat. No.6,602,911). It would be very difficult to reach the upper
limits of the dose range using the currently available formulation due to the dose related
treatment, emergent side effects and the need to titrate over a long period to reach the
required dose.
Various approaches have been tried to develop controlled release pharmaceutical
compositions of Milnacipran in order to lower the incidence and intensity of side effects,
especially for higher dosages, and lower or reduce the frequency of dosing.
US 6,699,506 discloses a pharmaceutical composition with prolonged release, for oral
administration of a single daily dose of 60 to 140 mg of Milnacipran, having a multi-
particulate form containing a plurality of microgranules each comprising an active
microsphere containing a saccharose and/or starch nucleus of a size between 200 and

2000 µm and containing 150 to 1000 µm of Milnacipran and a binding agent, each
microgranule being coated with a film having a base of at least one polymer insoluble in
water but permeable to physiological liquids.
WO 2006/132307 provides a stabilized Milnacipran-containing composition in which
Milnacipran or a salt thereof is allowed to exist in a porous carrier, packing a powder
containing Milnacipran or a salt thereof in an HPMC capsule, or combining an additive
which does not cause an interaction with Milnacipran with time.
WO 2006/088305 discloses a gastric-retentive controlled release mono-matrix tablet
composition, comprising: a) at least one pharmacologically active substance; b)
hydrogel-forming materials consisting of polyethylene oxide and at least one component
selected from poloxamers and colloidal silica; and c) a carbon dioxide-generating
material. The composition of the present invention floats in gastric juice and can
continuously release the active substance in the stomach at a constant rate for at least
2 hours.
US 2004/0132826 and US 2006/0024366 provide an extended release dosage unit of
Milnacipran (optionally containing the immediate release portion) coated with delayed
release coating. The Milnacipran composition, when administered orally, first passes
through the stomach releasing from zero to less than 10% of the total Milnacipran dose
and then enters the intestines where drug is released slowly over an extended period of
time.
Although above mentioned patents and patent applications provide controlled release
dosage forms, but production of dosage forms of these references is lengthy, expensive
process or requires specialized equipments or techniques.
There exists a need to develop a novel controlled release pharmaceutical composition
comprising Milnacipran or pharmaceutically acceptable salts thereof, which offers
advantages like simple manufacturing process, compact dosage form, use of
conventional manufacturing equipment, high throughput, easy scaie-up, economic, etc.
Additionally there is a need to provide a controlled release pharmaceutical composition
comprising Milnacipran or pharmaceutically acceptable salts thereof, wherein
composition provides complete dissolution between 8 to 20 hrs or the pharmaceutical
composition of the present invention can be suitably designed to provide controlled
release compositions that control release over prolonged periods of time, at least for 12
hours after oral administration.
Thus the present invention provides a novel controlled release pharmaceutical
composition comprising Milnacipran or pharmaceutically acceptable salts thereof, to
control release over prolonged periods of time.

Object of the invention:
Therefore, as a first object, the present invention provides controlled release
pharmaceutical compositions comprising Milnacipran or pharmaceutically acceptable
salts thereof and hydrophobic release controlling agent.
Yet another object of the present invention is to provide controlled release
pharmaceutical compositions comprising Milnacipran or pharmaceutically acceptable
salts' thereof and hydrophobic release-controlling agent adapted to release the active
over a predetermined time period, at least for 12-14 hours. A suitable dissolution test is
where the measurement is carried out in a type II dissolution (50 rpm) apparatus or type
I dissolution (100 rpm) apparatus according to U.S. pharmacopoeia in aqueous buffer at
37°C or variations on this as well known to one who is skilled in the art.
The present invention proposes controlled release pharmaceutical compositions of
Milnacipran or pharmaceutically acceptable salts thereof wherein the complete
dissolution time that is the time for release of 90 % of the total amount of the drug is
between 8 to 20 hours, preferably between 8 to 12 hours.
Yet another object of the invention proposes controlled release pharmaceutical
compositions of Milnacipran or pharmaceutically acceptable salts thereof wherein
pharmaceutical composition releases at least 90% of the active in 12 hrs.
Yet another object of the invention proposes controlled release pharmaceutical
compositions of Milnacipran or pharmaceutically acceptable salts thereof, which exhibits
a mean Cmax in the range from 50 ng/ml to 2000 ng/ml in fasted conditions.
Yet another object of the invention provides once daily controlled release
pharmaceutical composition comprising Milnacipran or pharmaceutically acceptable
salts thereof and hydrophobic release controlling agent for the management of
fibromyalgia.
Yet another object of the invention provides a once daily controlled-releasa
pharmaceutical composition comprising Milnacipran or pharmaceutically acceptable
salts thereof and hydrophobic release controlling agent which has substantially similar
bioavailability under fed condition to that of commercially available Milnacipran
hydrochloride (Savella®) Tablets administered twice daily.

Brief Description of the Drawings:
Fig 1 shows a release profile of controlled release dosage forms of Milnacipran HCI of
example 1, in 900 ml 0.1N HCI, USP apparatus Type I (Basket) at 100 rpm for 2 hrs
followed by 900 ml Phosphate buffer pH 6.8 USP apparatus Type I (Basket) at 100 rpm.
Fig 2 shows a release profile of controlled release dosage forms of Milnacipran HCI of
example 2, in 900 ml 0.1N HCI, USP apparatus Type I (Basket) at 100 rpm for 2 hrs
followed by 900 ml Phosphate buffer pH 6.8 USP apparatus Type I (Basket) at 100 rpm.
Fig 3 shows a release profile of controlled release dosage forms of Milnacipran HCI of
example 3, in 900 ml 0.1N HCI, USP apparatus Type I (Basket) at 100 rpm for 2 hrs
followed by 900 ml Phosphate buffer pH 6.8 USP apparatus Type I (Basket) at 100 rpm.
Fig 4 shows a release profile of controlled release dosage forms of Milnacipran HCI of
example 4, in 900 ml 0.1N HCI, USP apparatus Type I (Basket) at 100 rpm for 2 hrs
followed by 900 ml Phosphate buffer pH 6.8 USP apparatus Type I (Basket) at 100 rpm.
Fig 5 shows a release profile of controlled release dosage forms of Milnacipran HCI of
example T1, in 900 ml 0.1M HCI, USP apparatus Type I (Basket) at 100 rpm for 2 hrs
followed by 900 ml Phosphate buffer pH 6.8 USP apparatus Type I (Basket) at 100 rpm.
Fig 6 shows a release profile of controlled release dosage forms of Milnacipran HCI of
example T2 in 900 ml 0.1N HCI, USP apparatus Type I (Basket) at 100 rpm.
Fig 7: Comparative plasma concentration against time for SavellaTM (Milnacipran HCI)
Tablets 50 mg (b.i.d.) vs. once daily Milnacipran Controlled Release Tablets 100 mg
as Test Products (T1 & T2).
Detailed Description of the Invention
The present invention is directed to novel controlled release pharmaceutical
compositions comprising Milnacipran or pharmaceutically acceptable salts thereof,
which provides complete dissolution between 8 to 20 hrs or the pharmaceutical
composition of the present invention can be suitably designed to provide controlled
release compositions that control release of the active over prolonged periods of time, tX
least for, 12 hours after oral administration.
As used herein "Milnacipran" also encompasses pharmaceutically acceptable,
pharmacologically active derivatives of Milnacipran including both individual
enantiomers of Milnacipran (dextrogyral and levrogyral enantiomers) and their
pharmaceutically acceptable salts, mixtures of Milnacipran enantiomers and their
pharmaceutically acceptable salts, and active metabolites of Milnacipran and their
pharmaceutically acceptable salts, unless otherwise noted.
As used herein, "pharmaceutically acceptable salts" refer to derivatives of Milnacipran
wherein the Milnacipran is modified by making acid-addition or base-addition salts

thereof. Examples of pharmaceutically acceptable salts include, but are not limited to,
mineral or organic acid salts of basic residues such as amines; alkali or organic salts of
acidic residues such as carboxylic acids. The pharmaceutically acceptable salts include
the conventional non-toxic salts or the quaternary ammonium salts of the parent
compound formed, for example, from non-toxic inorganic or organic acids. For example,
such conventional non-toxic salts include those derived from inorganic acids such as
hydrochloric, hydrobromic, sulfuric, sulfamic, phosphoric, nitric and the like; and the
salts prepared from organic acids such as acetic, propionic, succinic, glycolic, stearic,
lactic, malic, tartaric, citric, ascorbic, pamoic, maleic, hydroxymaleic, phenylacetic,
glutamic, benzoic, salicylic, sulfanilic, 2-acetoxybenzoic, fumaric, tolunesulfonic,
methanesulfonic, ethane disulfonic, oxalic, isethionic and the like. The most preferable
salt is hydrochloric salt.
The amount of Milnacipran or pharmaceutically acceptable salts thereof to be used in
present invention ranges from about 25 to about 500 mg.
The term "controlled release compositions" herein refers to any composition or dosage
form which comprises an active drug and which is formulated to provide a ionger
duration of pharmacological response after administration of the dosage form than is
ordinarily experienced after administration of a corresponding immediate release
composition comprising the same drug in the same amount. Controlled release
compositions include, inter alia, those compositions described elsewhere as "extended
release", "sustained release", "prolonged release", "programmed release", "time
release" and/or "rate controlled" compositions or dosage forms.
The controlled release pharmaceutical compositions of the present invention are
prepared using a pharmaceutically acceptable "carrier" composed of materials that are
considered safe and effective and may be administered to an individual without causing
undesirable biological side effects or unwanted interactions. The "carrier" is all
components present in the pharmaceutical formulation other than the active ingredient
or ingredients. The term "carrier" includes but is not limited to diluents, binders,
lubricants, glidants, dissolution enhancing agents and rate controlling agents.
The rate-controlling agent(s) used in admixture with the active ingredient may be
selected from the group comprising hydrophilic release controlling agents, hydrophobic
release controlling agents, and mixtures thereof. More preferrabl are the hydrophobic
release controlling agents.
The hydrophilic release controlling agents are selected from but are not limited to
hydroxypropyl methyl cellulose (HPMC), hydroxypropyl cellulose (HPC), hydroxyethyl
cellulose (HEC) polyethylene oxide, polyvinyl alcohol, polyvinylpyrrolidone, xanthan
gum, guar gum, chitosan and its derivatives, carbomer, canageenan, carboxymethyl

cellulose, sodium alginate, polyglycolized glycerides, polyethylenglycol, or mixture
thereof.
The hydrophobic release controlling agents are selected from but are not limited to
polyvinyl acetate dispersion, ethyl cellulose, cellulose acetate, cellulose propionate
(lower, medium or higher molecular weight), cellulose acetate propionate, cellulose
acetate butyrate, cellulose acetate phthalate, cellulose triacetate, poly (methyl
methacrylate), poly (ethyl methacrylate), poly (butyl methacrylate), poly (isobutyl
methacrylate), and poly (hexyl methacrylate), poly (isodecyl methacrylate), poly (lauryl
methacrylate), poly (phenyl methacrylate), poly (methyl acrylate), poly (isopropyl
acrylate), poly (isobutyl acrylate), poly (octadecyl acrylate), waxes such as beeswax,
carnauba wax, paraffin wax, microcrystalline wax, and. ozokerite; fatty alcohols such as
cetostearyl alcohol, stearyl alcohol, cetyl alcohol and myristyl alcohol, and fatty acid
esters such as glyceryl monostearate; glycerol monooleate, acetylated monoglycerides,
tristearin, tripalmitin, cetyl esters wax, glyceryl paltnitostearate, glyceryl behenate, and
hydrogenated vegetable oils.
The amount of the rate-controlling agent that may be used in the composition of the
present invention is in the range from about 1% to about 80% by weight of the
composition, Pereferably from about 1% to about 70% by weight of the composition and
more preferebely from about 1% to about 60% by weight of the composition.
Diluents may be, for example, any pharmaceutically acceptable, non-toxic diluent.
Particular examples include lactose, dextrose, sucrose, maltose, microcrystalline
cellulose, starch, calcium hydrogen phosphate, mannitoi and the like.
Binders may be, for example, starch, sugars, gums, low molecular weight hydroxypropyl
mathylcellulose, hydroxypropyl cellulose, hydroxyethyl cellulose or the like.
Dissolution enhancing agents include pharmaceuticaily acceptable organic acids.
Examples include but not limited to ascorbic acid, succinic acid, malonic acid, oxalic
acid, tartaric acid, furnaric acid, adipic acid, glucono delta-lactone and malic acid.
Lubricants may be, for example, talc, magnesium stearate, calcium stearate, stearic
acid, sodium stearyl fumarate, sodium benzoate or the like.
Giidants may be, for example, colloidal silicon dioxide, talc or the like.
The term "controlled release pharmaceutical compositions" includes a pharmaceutical
composition that encompasses one or more individual units. The individual units may
be in form of granules, pellets, rninitablets or beads. Granules, pellets, minitablets or
beads of the present invention can be filled into a capsule or can be compressed into a
tablet.
In a more preferred embodiment of the invention individual units are tablet and more
preferably unit is a bilayer tablet.

The bilayer tablet composition of the present invention comprises first layer comprising
Milnacipran or pharmaceutically acceptable salts thereof and release controlling agent
which comprises hydrophobic control releasing agent, optionally other carrier material
and second layer comprises of other suitable carrier material and optionally
Milnacipran or pharmaceutically acceptable salts thereof.
Further the bilayer tablet composition of the present invention comprises first layer
comprising Milnacipran or pharmaceutically acceptable salts thereof and hydrogenated
vegetable oil optionally other carrier material and second layer which comprises
copolymer of methacrylic acid and methyl meth acrylate, other suitable carrier material
and optionally Milnacipran or pharmaceutically acceptable salts thereof.
A typical example of the pharmaceutical composition of the invention is Pseudo-geometric
Drug Delivery System which comprises a) first layer comprising effective amounts of the
Milnacipran or salts thereof and hydrophobic control releasing agent, and optionally other
carrier material having defined geometric form, b) a second layer or a support-platform
comprises of other suitable carrier material and optionally Milnacipran or pharmaceutically
acceptable salts thereof, wherein carrier material comprises methacrylate polymer
(Eudragit L or S).
Thus Pseudo-geometric Drug Delivery System comprises two layers wherein support
platform remains intact in stomach, therefore tablet structure remains intact and thus it
controls or prevents burst effect in stomach, which prevents dose dumping. Thus the
system provides less release of drug in stomach and reduces the adverse effect like
nausea and vomiting.
Solid oral dosage forms of the present invention may be prepared by any conventional
techniques for example dry granulation, direct compression, wet granulation, and
extrusion-spheronization, melt granulation, compression coating. Melt granulation is the
preferred technique.
In the preferred embodiment of the present invention bilayer tablet composition is
prepared my melt granulation, wherein a first tablet layer composition is prepared by
a) melting release controlling agent and dispersing Milnacipran or pharmaceutically
acceptable salts thereof in it;
b) cooling above melted mass to room temperature and passing solid mass through
suitable seive to obtain granules
c) lubricating the granules
and second layer composition is prepared by
a) mixing hydrophobic release controlling agent and other suitable carrier material
and optionally Milnacipran or pharmaceutically acceptable salts thereof.

b) granulating above mixture with purified water followed by drying the granules
and seiving through a suitable seive
c) lubricating the granules
introducing both the granules into a tablet press; compressing said tablet layer
composition to form different tablet layer; compressing both tablet layer compositions to
form a bilayer tablet
For direct compression, the second tablet layer composition may be prepared by dry-
mixing the constituent components, e.g. by means of a high-intensity mixer or a free-fall
blender.
For production of the bilayer tablet according to the present invention, the first and
second tablet layer compositions are compressed in a bilayer tablet press, e.g. a rotary
press in the bilayer tableting mode.
The invention provides a once daily controlled-release pharmaceutical composition
comprising Milnacipran or pharmaceutically acceptable salts thereof and hydrophobic
release controlling agent which is bioavailable to commercially available Milnacipran
hydrochloride (Savella®) Tablets administered twice daily. A study was carried out to
compare the rate and extent of absorption of single dose of two test formulations (T1
and T2) of Milnacipran and single dose of Savella(R) CO rng (containing Milnacipran HCI
50 mg) tablets bid. (one tablet each 12 hourly), administered under fed conditions. The
controlled release pharmaceutical composition of the invention exhibits mean Cmax in the
range of about 50-2000 ng/ml and AUC(0-1)in the range of 1000-8000 ng/mL*h.
In order to further illustrate the present invention, the following examples are given:



Brief Manufacturing Procedure:
1st Layer:
1. Weigh all ingredients.
2. Melt Sterotex & disperse Milnacipran HCI to it.
3. Cool above melted mass to room temperature.
4. Pass solid mass through 18 #.
5. Lubricate above granules with colloidal silicon dioxide and Magnesium Stearate.
2nd Layer:
1. Mix Lactose, Povidone K30 & Eudragit L100-55.
2. Granulate above with Purified Water.
3. Dry the granules and sift through 20#. Lubricate granules with Aerosil &
Magnesium stearate.
4. Compress above blend as bilayer tablet using suitable compression machine.
5. Optionally coated with Water permeable methacrylate polymer or Ethyl cellulose
& hydroxyl propyl methyl cellulose.(Water soluble or water insoluble polymer).

Brief manufacturing Procedure:
1st Layer:
1 Weigh all ingredients.

2. Melt Sterotex & Polyethylene Glycol, disperse Milnacipran HCI to it.
3. Cool above melted mass to room temperature.
4. Pass solid mass through 18 #.
5. Lubricate above granules with colloidal silicon dioxide and Magnesium Stearate.
2nd Layer:
1. Mix Lactose, Povidone K30 & Eudragit L100-55.
2. Granulate above with Purified Water.
3. Dry the granules and sift through 20#. Lubricate granules with silicon dioxide &
Magnesium stearate.
4. Compress above blend as bilayer tablet using suitable compression machine.
5. Optionally coated with suitable acrylate polymer or Ethyl cellulose & hydroxyl
propyl methylcellulose.

Brisf Manufacturing Procedure:
1st Layer:
1. Weigh all ingredients.
2. Melt Sterotex and Lactose & disperse Milnacipran HCI to it.
3. Cool above melted mass to room temperature.
4. Pass solid mass through 18 #.
5. Mix 40 # Lactose & sized granules of above step.
6. Lubricate above granules with colloidal silicon dioxide and Magnesium Stearate.
2nd Layer:

1. Mix Lactose, Povidone K30 & Eudragit L100-55.
2. Granulate above with Purified Water.
3. Dry the granules and sift through 20#. Lubricate granules with Aerosil &
Magnesium stearate.
4. Compress above blend as bilayer tablet using suitable compression machine.
5. Optionally coated with Eudragit RL/RS (Water permeable polymer) or Ethyl
cellulose & hydroxyl propyl methyl cellulose.(Water soluble or water insoluble
polymer).

Brief Manufacturing Procedure:
1st Layer:
1. Weigh all ingredients.
2. Melt Sterotex and Lactose & disperse Miinacipran HCI to it.
3. Cool above melted mass to room temperature.
4. Pass solid mass through 18 #.
5. Mix 40 # Lactose & sized granules of above step.
6. Lubricate above granules with colloidal silicon dioxide and Magnesium Stearate.
2nd Layer:
1. Mix Lactose, F ovidone K30 & Eudragit L100-55.
2. Granulate above with Purified Water.
3. Dry the granules and sift through 20#. Lubricate granules with Aerosil &
Magnesium stearate.
4. Compress above blend as bilayer tablet using 12 to 13 mm round .shape punch.

5. Optionally coated with Eudragit RL/RS (Water permeable polymer) or Ethyl
cellulose & hydroxyl propyl methyl cellulose (Water soluble or water insoluble
polymer).
The results of in-vitro dissolution of pharmaceutical compositions of examples 1-4 are
shown in Fig 1-4 respectively.
Pharmacokinetic Studies
An open label, balanced, randomized, three-treatment, three-sequence, three-period,
single dose, crossover relative bioavailability study was performed in 12 healthy, adult,
male, human volunteers who meet all inclusion under standard fed conditions. The
objective of the study was to compare the rate and extent of absorption of single dose
of two formulations (T1 and T2) of Milnacipran and single dose of Savella(R) 50 mg
(containing Milnacipran HCI 50 mg) tablets b.i.d. (one tablet each 12 hourly),
administered under fed conditions in healthy, adult, male, human subjects in a
randomized cross over study and also to improve adverse events like nausea and
vomiting. To avoid vomiting/nausea effects due to investigational products, all subjects
will also be administered with single dose of Granisetron HCI- 1 mg tablet b.i.d. with
sufficient quantity of water as required by subject (not more than 100 mL) as per
following schedule:
Subjects Receiving Test (T1 or T2) Product: One tablet at 1 hour before dosing in the
morning (i.e. at -1 hour of dosing) and one tablet at "11" hours post dose in the evening.
Subjects Receiving Reference (R) Product: One tablet at 1 hour before first dosing in
the morning (i.e., at -1 hour of dosing) and one tablet at 1 hour before second dosing in
the evening (i.e., at 11 hours).
Sampling Schedule:
A total of 19 blood samples were collected from each subject during each period at
1.00, 2.00, 3.00, 4.00, 4.50, 5.00, 5.50, 6.00, 7.00, 8.00, 10.00, 12.00, 16.00, 20.00,
24.00, 30.00, 36.00 and 48.00 hours post dose for reference as well as test product.
Washout Period:
A washout of at least 7 days was kept from the completion of dosing between two
consecutive periods.
Following Pharmacokinetic Parameters of Test & Reference Products were
compared:
Primary parameters: Cmax, AUC(0-t) and AUC(0-inf)
Results of Relative Bioavailability Assessment:
Table 1: Compilation of Pilot Bio Results ot T1 Formulation:

Brief Manufacturing Procedure:
A. Preparation of Active Layer:
1. Weigh all ingredients.
2. Pass Miinacipran HC! & Sterotex through 40# mesh. Melt Sterotex and disperse
Milnacipran HCI in this melted mass with continuous stirring. Cool the mass to room
temperature.
3. Pass the solid mass through 20 #. Lubricate above granules with Aerosil and
Magnesium Stearate.
B. Preparation of inactive Layer:
1. Pass Lactose Monohydrate, Povidone K-30 & Eudragit L100 through 40#. Mix
properly all ingredients.
2. Granulate this blend with Purified water. Dry granules & pass dried granules through
20 #.
3. Pass Aerosil & Magnesium Stearate through 60# mesh and lubricate with above 20 #
passed granules.
C. Compression:
Compress above blends (Ist & IInd Layer) using 9.6 mm round shape, bevelled edge
punches plain on both side.
D. Film Coating of Tablets
Dissolve Opadry Yellow in isopropyl alcohol & Dichloromethane mixture. Coat the
tablets of step C using Opadry Yellow solution in a suitable coating machine till the
desired weight gain is achieved. Cure the coated tablets for sufficient time in coating
pan.
Test Formulation (T2)



Brief.Manufacturing Procedure:
A. Preparation of Active Layer:
1. Weigh all ingredients.
2. Pass Milnacipran HCI, Polyethylene Glycol 4000, Sterotex (Hydrogenated Vegetable
Oil) and Lactose monohydrate through 40# mesh.
3. Melt Polyethylene Glycol 4000 and Sterotex and disperse Milnacipran HCI in this
melted mass with continuous stirring, then add DCL-11 (Lactose monohydrate) to it.
4. Cool the melted mass to room temperature. Pass the solid mass through 20 # and
add Mannitol extra granularly to it. Lubricate above granules with Aerosil and
Magnesium Stearate.
B. Preparation of Inactive Layer:

1. Pass DCL-11, Povidone K-90, Eudragit L100, DCP (A Tab) & Sterotex through 40#.
Mix-properly ail ingredients.
2. Granulate the blend with purified water. Dry granules & pass sized granules through
20 #.
3. Pass Aerosil & Magnesium Stearate through 60# mesh and lubricate 20 # passed
granules.
C. Compression:
Compress above blends (lst& IInd Layer) using 13.3 mm round shape, bevelled edge
punches plain on both side.
D. Film Coating of Tablets:
Dissolve Opadry Yellow in Isopropyl alcohol & Dichloromethane mixture. Coat the
tablets using Opadry Yellow solution in a suitable coating machine till the desired
weight gain is achieved. Cure the coated tablets for sufficient time in coating pan.

We Claim:
1. A controlled release pharmaceutical composition comprising Milnacipran or
pharmaceutically acceptable salts thereof and hydrophobic release controlling
agent.
2. A controlled release pharmaceutical composition of claim 1 wherein the amount
of Milnacipran or pharmaceuticaHy acceptable salts thereof ranges from about
25 mg to about 500 mg.
3. A controlled release pharmaceutical composition of claim 1, wherein the
hydrophobic release controlling agent is selected from polyvinyl acetate
dispersion, ethyl cellulose, cellulose acetate, cellulose propionate (lower,
medium or higher molecular weight), cellulose acetate propionate, cellulose
acetate butyrate, cellulose acetate phthalate, cellulose triacetate, poly (methyl
methacrylate), poly (ethyl methacrylate), poly (butyl methacrylate), poly (isobutyl
methacrylate), and poly (hexyl methacrylate), poly (isodecyl methacrylate), poly
(lauryi methacrylate), poly (phenyl methacrylate), poly (methyl acrylate), poly
(isopropyl acrylate), poly (isobutyl acrylate), poly (octadecyl acrylate), waxes
fatty alcohols, fatty acid esters or hydrogenated vegetable oil.
4. A controlled release pharmaceutical composition of claim 3, wherein the wax is
selected from beeswax, carnauba wax, paraffin wax, microcrystalline wax or
ozokerite.
5. A controlled release pharmaceutical composition of claim 3, wherein the fatty
alcohol is selected from cetostearyl alcohol, stearyl alcohol, cetyl alcohol or
myristyl alcohol.
6. A controlled release pharmaceutical composition of claim 3, wherein the fatty
acid esters is selected from glyceryl monostearate; glycerol monooleate,
acetylated monoglycerides, tristearin, tripalmitin, cetyl esters wax, glyceryl
palmitostearate or glyceryl behenate.
7. A controlled release pharmaceutical composition of claim 1 further comprising
hydrophilic release controlling agent.
8. A controlled release pharmaceutical composition of claim 1, wherein the
pharmaceutical composition is in form of granules, pellets, or beads, which can
be further filled into a capsule or can be compressed into minitablets or tablet.
9. A controlled release pharmaceutical composition of claim 8, in the form of a
multilayer tablet which comprises a) first layer comprising effective amounts of
the Milnacipran or salts thereof and hydrophobic release controlling agent, and
optionally pharmaceuticaHy acceptable carrier, b) a second layer comprises of

hydrophobic release controlling agent and optionally Milnacipran or
pharmaceutically acceptable salts thereof.
10. A controlled release pharmaceutical composition comprising Milnacipran or
pharmaceutically acceptable salts thereof and hydrophobic release controlling
agent wherein the composition releases 90% of the total amount of Milnacipran
or pharmaceutically acceptable salts thereof between 8 to 20 hours when
dissolution is carried out in 900 ml 0.1N HCI, USP apparatus Type I (Basket) at
100 rpm for 2 hrs, followed by 900 ml Phosphate buffer pH 6.8 USP apparatus
Type I (Basket) at 100 rpm.
11. A controlled release pharmaceutical composition of claim 10 wherein the
composition releases 90% of the total amount of Milnacipran or pharmaceutically
acceptable salts thereof between 8 to 12 hours.
12. A controlled release pharmaceutical composition of claim 10 wherein the
composition releases 90% of the total amount of Milnacipran or pharmaceutically
acceptable salts thereof between 12 to 14 hours.
13. A once daily controlled release pharmaceutical composition comprising
"Milnacipran or pharmaceutically acceptable salts "thereof and hydrophobic
release controlling agent which has substantially similar bioavailability under fed
condition to that of commercially available Milnacipran hydrochloride (Saveila®)
Tablets administered twice daily.
14. A controlled release pharmaceutical composition of claim 13, wherein the
composition exhibits a mean Cmax from about 50 to about 2000ng/ml.
15. A controlled release pharmaceutical composition of claim 13 wherein the
composition exhibits a mean Cmaxfrom about 50 to about 500 ng/ml.
16. A controlled release pharmaceutical composition of claim 13 wherein the
composition exhibits a mean AUC(0-1)from about 1000 to about 8000 ng/mL*h.
17. A controlled release pharmaceutical composition of claim 13 wherein the
composition exhibits a mean AUC(0-1) from about 1500 to about 5000 ng/mL*h.
18. A process of preparing a controlled release pharmaceutical composition of claim
9 comprises a) preparing a first layer comprising i) melting hydrophobic release
controlling agent and Milnacipran or pharmaceutically acceptable salts thereof in
it ii) cooling followed by sieving the melted mass to obtain granules and iii)
lubricating the granules b) preparing a second layer comprising granules which
comprises hydrophobic release controlling agent and optionally Milnacipran or
pharmaceutically acceptable salts thereof.

19. A once daily controlled release pharmaceutical composition of claims 1, 10, 13
comprising Milnacipran or pharmaceutically acceptable salts thereof and
hydrophobic release controlling agent for the management of fibromyalgia.
A controlled release pharmaceutical composition comprising Milnacipran or
pharmaceutically acceptable salts thereof and hydrophobic release controlling agent.
The composition releases 90% of the total amount of Milnacipran or pharmaceutically
acceptable salts thereof between 8 to 20 hours when dissolution is carried out in 900 ml
0.1N HCI, USP apparatus Type I (Basket) at 100 rpm for 2 hrs, followed by 900 ml
Phosphate buffer pH 6.8 USP apparatus Typo I (Basket) at 100 rpm. A process of
preparing a controlled release pharmaceutical composition comprises: a) preparing a
first layer comprising i) melting hydrophobic release controlling agent and Milnacipran or
pharmaceutically acceptable salts thereof in it ii) cooling followed by sieving the melted
mass to obtain granules and iii) lubricating the granules; and b) preparing a second
layer comprising granules which comprises hydrophobic release controlling agent and
optionally Milnacipran or pharmaceutically acceptable salts thereof.