FIELD OF THE INVENTION
The present invention relates to once daily sustained release pharmaceutical compositions
of Trimetazidine or a pharmaceutically acceptable salt(s), polymorph(s), solvate(s),
hydrate(s), enantiomer(s) thereof using dual retard release technique.
BACKGROUND OF THE INVENTION
Trimetazidine is an antianginal drug and was first disclosed in US patent 3262852.
Trimetazidine dihydrochloride [l-(2,3,4-trimethoxybenzyl)-piperazine dihydrochloride]
is freely soluble in water, about 80%. It has two pKa values 4.32 and 8.95. It regulates
ionic and extra cellular exchanges, correcting the abnormal flow of ions across the cell
membrane caused by ischemia and preventing cellular edema caused by anoxia. Thus it
ensures the functioning of the ion pumps and the sodium-potassium transmembrane flux
and maintains the cellular homeostasis.
Trimetazidine dihydrochloride is used therapeutically, as a coronary vasodilator for the
prophylactic treatment of anginal chest pain attack and during such attacks, during
chorioretinal attacks as well as for the treatment of giddiness of vascular origin (Vertigo
of Maniere, acouphenous).
Trimetazidine dihydrochloride is administered orally in doses of 60 to 70 mg daily in
divided doses as an immediate or modified release preparation. It is quickly absorbed and
eliminated by the organism with plasma half-life of around 6.0 ± 1.4 hours and Tmax of
around 1.8 ± 0.7 hours. Since it has a shorter plasma half life, in practice 20mg
preparation is given twice or thrice a day in order to ensure relatively constant plasma
levels but, due to the fact that it is absorbed quickly, these immediate release forms lead
to maximum plasma levels immediately after administration and to a very low plasma
level at the time of the next dose, resulting in great differences in peak and trough plasma
levels at steady state. Trimetazidine dihydrochloride is regarded as a safe drug in the long

treatment of chronic ischemic disorders. This compels the necessity of fabricating the
immediate release dosage form into a sustained release once-a-day preparation for
achieving regular and constant plasma levels, which is also favourable for compliance of
the patient to his treatment.
Trimetazidine is currently marketed as modified release tablets at the dosage of 35 mg
under the brand name "Vastarel®".
U.S. Patent 4,814,176 by Makino, Yuji; Matugi, Hideo; Suzuki, Yoshiki; describes a
sustained release preparation comprising a) chitin, chitosan or a mixture thereof or b)
non-anionic cellulose ether, and c) pharmaceutically effective amount of at least one
pharmaceutically active agent.
U.S. Patent 4,755,544 by Makino, Yuji; Matugi, Hideo; Suzuki, Yoshiki; describes a
sustained release preparation comprising (a) at least one non-anionic cellulose ether,
(b) at least one anionic polymer compound selected from the group consisting of
methoxyethylene-maleic anhydride copolymers and the hydrolyzates thereof, and (c) at
least one pharmaceutically active agent..
European Patent Application 0673649 by Huet de Barochez describes pharmaceutical
compositions for the prolonged release of trimetazidine or of one of its pharmaceutically
acceptable salts characterized in that prolonged release of trimetazidine is controlled by
the use of a mixture of water insoluble polymer and a plasticizer coated on a reservoir
system containing 80mg of trimetazidine dihydrochloride.
European Patent Application 1108424 Bl by Servier Lab describes matrix tablet for the
prolonged release of trimetazidine or a pharmaceutically acceptable salt thereof,
characterized in that the prolonged release is controlled by the use of a cellulose
derivative polymer present in the matrix, selected from hydroxypropylcellulose,
hydroxyethylcellulose, hydroxymethylcellulose, methylcellulose and hydroxypropyl
methylcellulose.

However, there are alternate means by which we can design a once daily pharmaceutical
compositions of trimetazidine which is bioequivalent to twice daily compositions
marketed under the brand name, Vastarel® 35mg.
Thus, the present invention provides a novel once daily sustained release formulations of
trimetazidine or its pharmaceutically acceptable salts thereof using dual retard technique,
which provide freedom from burst effect, associated with formulation of controlled
release of highly water-soluble drugs.
OBJECTS OF THE INVENTION
The object of the present invention is a once daily sustained release pharmaceutical
composition comprising a core comprising trimetazidine or a pharmaceutically
acceptable salt(s), polymorph(s), solvate(s), hydrate(s), enantiomer(s) thereof, one or
more sustained release polymer(s) in a matrix and one ore more pharmaceutically
acceptable excipient(s), wherein the core is further coated with a functional coating.
Another object of the present invention is a once daily sustained release pharmaceutical
composition comprising a core comprising trimetazidine or a pharmaceutically
acceptable salt(s), polymorph(s), solvate(s), hydrate(s), enantiomer(s) thereof, one or
more sustained release polymer(s) in a matrix and one ore more pharmaceutically
acceptable excipient(s), wherein the core is further coated with a functional coating,
wherein about 0-55% of drug released in about 4 hours, about 30-85% of drug released in
about 8 hours, and greater than about 75% of drug released in about 12 hours using 0.1 N
HC1 as dissolution medium.
Another object of the present invention is a once daily sustained release pharmaceutical
composition comprising a core comprising trimetazidine or a pharmaceutically
acceptable salt(s), polymorph(s), solvate(s), hydrate(s), enantiomer(s) thereof, one or
more sustained release polymer(s) in a matrix and one ore more pharmaceutically
acceptable excipient(s), wherein the core is further coated with a functional coating

characterized in that the once daily sustained release pharmaceutical composition is
bioequivalent to 35mg twice daily modified release formulation.
DETAILED DESCRIPTION OF THE INVENTION
The present invention relates to a once daily sustained release pharmaceutical
composition comprising a core comprising trimetazidine or a pharmaceutically
acceptable salt(s), polymorph(s), solvate(s), hydrate(s), enantiomer(s) thereof, one or
more sustained release polymer(s) in a matrix and one ore more pharmaceutically
acceptable excipient(s), wherein the core is further coated with a functional coating.
As used herein, "pharmaceutically acceptable salts" refer to derivatives of the
trimetazidine wherein trimetazidine is modified by reacting it with an acid or base as
needed to form an ionically bound pair. Examples of pharmaceutically acceptable salts
include conventional non- toxic salts or the quaternary ammonium salt of the parent
compound formed, for example, from non-toxic inorganic or organic acids. Suitable non-
toxic salts include those derived from inorganic acids such as hydrochloric, hydrobromic,
sulfuric, sulfamic, phosphoric, nitric, and others known to those of ordinary skill in the
art. The salts prepared from organic acids such as amino acids, acetic, propionic,
succinic, glycolic, stearic, lactic, malic, tartaric, citric, ascorbic, pamoic, maleic,
hydroxymaleic, phenylacetic, benzoic, salicylic, sulfanilic, fumaric, oxalic, isethionic,
and others known to those of ordinarily skilled in the art. List of other suitable salts are
found in Remington's Pharmaceutical Sciences, 17th edition. Mack Publishing Company,
Easton Pa., 1985. p. 1418, the relevant disclosure of which is hereby incorporated by
reference. The most preferred salt of Trimetazidine for the present invention is
dihydrochloride salt.
The term "sustained release pharmaceutical compositions " as used herein in relation to
the composition according to the invention or a rate controlling polymer or used in any
other context means release, which is not immediate release and is taken to encompass
controlled release, sustained release, prolonged release, timed release, retarded release,
extended release and delayed release. The term " sustained release pharmaceutical

compositions" as used herein can be described as pharmaceutical compositions whose
drug-release characteristics of time course and/or location are chosen to accomplish
therapeutic or convenience objectives not offered by conventional dosage forms such as a
solution or an immediate release dosage form. Modified release solid oral dosage forms
include both delayed and extended release drug products (as per US FDA guideline for
'SUPAC-MR: Modified Release Solid Oral Dosage Forms'). Sustained release can be
used interchangeably with prolonged release, programmed release, timed release,
extended release, controlled release and other such dosage forms.
By "pharmaceutically acceptable" is meant a carrier comprised of a material that is not
biologically or otherwise undesirable.
Presently, trimetazidine is administered 35 milligrams orally two times a day as modified
release dosage form. The therapeutic dose according to the present invention for once
daily formulation can vary from 50-100 mg per day, preferably 60-80mg per day and
most preferably 70mg once daily-
"Cmax" as used herein, means maximum plasma concentration of the trimetazidine.
"Tmax" as used herein, means time taken to achieve the maximum observed plasma
concentration.
"AUC" as used herein, means area under the plasma concentration-time curve.
The sustained release polymers in the core comprise one or more hydrophilic or
hydrophobic polymer(s) or combinations thereof.
The hydrophilic polymers include but are not limited to hydroxyethylcellulose,
hydroxypropyl cellulose, Hydroxypropyl Methylcellulose, sodium carboxymethyl
cellulose, sodium alginate, carbomer (Carbopol(TM)), xanthan gum, guar gum, locust
bean gum, poly vinyl acetate, polyvinyl alcohol. Swellable polymers include, but are not

limited to, a crosslinked poly (acrylic acid), crosslinked poly (alkylene oxide),
crosslinked polyvinyl alcohol, a crosslinked polyvinyl pyrrolidone; a polyurethane
hydrogel, a maleic anhydride polymer, such as a maleic anhydride copolymer, a cellulose
polymer, a polysaccharide, starch, and starch based polymers, alginates, alginic acid,
PVA, carbomer. The most preferred hydrophilic polymer in the core according to the
present invention is xanthan gum.
The hydrophobic polymers include but are not limited to hydrogenated vegetable oil,
purified grades of beeswax; fatty acids; long chain fatty alcohols, such as cetyl alcohol,
myristyl alcohol, and stearyl alcohol; glycerides such as glyceryl esters of fatty acids like
glyceryl monostearate, glyceryl distearate, glyceryl esters of hydrogenated castor oil and
the like; oils such as mineral oil and the like, or acetylated glycerides; ethyl cellulose,
stearic acid , paraffin, carnauba wax, talc; and the stearate salts such as calcium,
magnesium, zinc and other materials known to one of ordinary skill in the art.
Pharmaceutically acceptable excipients include but are not limited to binders, diluents,
lubricants, disintegrants, glidants and surface-active agents.
The amount of excipient employed will depend upon how much active agent is to be
used. One excipient can perform more than one function.
Binders include, but are not limited to, starches such as potato starch, wheat starch, corn
starch; microcrystalline cellulose such as products known under the registered trade
marks Avicel, Filtrak, Heweten or Pharmacel; celluloses such as hydroxypropyl
cellulose, hydroxyethyl cellulose, hydroxypropylmethyl cellulose (HPMC), ethyl
cellulose, sodium carboxy methyl cellulose; natural gums like acacia, alginic acid, guar
gum; liquid glucose, dextrin, povidone, syrup, polyethylene oxide, polyvinyl pyrrolidone,
poly-N-vinyl amide, polyethylene glycol, gelatin, poly propylene glycol, tragacanth,
combinations there of and other materials known to one of ordinary skill in the art and
mixtures thereof.

Fillers or diluents, which include, but are not limited to confectioner's sugar,
compressible sugar, dextrates, dextrin, dextrose, fructose, lactitol, mannitol, sucrose,
starch, lactose, xylitol, sorbitol, talc, microcrystalline cellulose, calcium carbonate,
calcium phosphate dibasic or tribasic, calcium sulphate, and the like can be used.
Lubricants may be selected from, but are not limited to, those conventionally known in
the art such as Mg, Al or Ca or Zn stearate, polyethylene glycol, glyceryl behenate,
mineral oil, sodium stearyl fumarate, stearic acid, hydrogenated vegetable oil and talc.
Glidants include, but are not limited to, silicon dioxide; magnesium trisilicate, powdered
cellulose, starch, talc and tribasic calcium phosphate, calcium silicate, magnesium
silicate, colloidal silicon dioxide, silicon hydrogel and other materials known to one of
ordinary skill in the art.
Disintegrants include but not limited to starches; clays; celluloses; alginates; gums; cross-
linked polymers, e.g., cross-linked polyvinyl pyrrolidone or crospovidone, e.g.,
POLYPLASDONE XL, cross-linked sodium carboxymethylcellulose or croscarmellose
sodium, e.g., AC-DI-SOL from FMC; and cross-linked calcium carboxymethylcellulose;
soy polysaccharides; and guar gum. Use of disintegrant according to the present
invention facilitates in the release of drug in the latter stage and thereby completely
releasing the drug from the dosage form.
The present compositions may optionally contain a surface-active agent. The preferred
agent is copolymers composed of a central hydrophobic chain of polyoxypropylene (poly
(propylene oxide)) and polyoxyethylene (poly (ethylene oxide)) that is well kown as
poloxamer. However, other agents may also be employed such as dioctyl sodium
sulfosuccinate (DSS), triethanolamine, sodium lauryl sulphate (SLS), polyoxyethylene
sorbitan and poloxalkol derivatives, quaternary ammonium salts or other
pharmaceutically acceptable surface-active agents known to one ordinary skilled in the
art.

The pharmaceutical dosage forms of the invention have one or more functional coatings
such as film coating, sugar coating, extended release coating, enteric coating, bioadhesive
coating and other coatings known in the art. These coatings help pharmaceutical
formulations to release the drug at and for the required time.
The functional coating comprises a hydrophilic or hydrophobic substance(s) or the
combinations thereof. Most preferably, a combination of hydrophilic and hydrophobic
substance(s) is used.
It has been found that a simple matrix composition of trimetazidine dihydrochloride using
one or more sustained release polymer(s) cannot sustain the release of the drug over the
desired time period, however it was found that a combination of sustained release matrix
core and a functional coating helps in release of the drug for the entire duration of release
required.
The pharmaceutical composition according to the present invention therefore uses the
dual release retard technique. The dual retard technique is a combination of matrix and
reservoir formulations. First the matrix particles of active ingredient and one or more
sustained release polymer(s) are formed and then, these are further coated with a
functional coating. Thus, the dual retard release technique presents the double barriers
and effectively controls the diffusion of the high dose, high solubility active ingredients
from the present invention in predictable manner.
The other advantages of the present invention are such as it reduces the chances of dose
dumping, unnecessary burst effects and failure of the system, which are otherwise usually
associated with simple matrix or reservoir systems.
The hydrophobic substance in the coating is selected from but are not limited to
Ammonio methacrylate copolymers type A and B as described in USP, methacrylic acid
copolymer type A, B and C as described in USP, Polyacrylate dispersion 30% as
described in Ph. Eur., Polyvinyl acetate dispersion, ethylcellulose, 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 actylate), poly(octadecyl acrylate), waxes such as
beeswax, carnauba 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 distearate; glycerol monooleate, acetylated
monoglycerides, tristearin, tripalmitin, cetyl esters wax, glyceryl palmitostearate, glyceryl
behenate, and hydrogenated castor oil.
The hydrophilic substance in the coating is selected from but are not limited to celluloses
or their salts or derivatives thereof, hydroxyethylcellulose, hydroxypropyl cellulose,
hydroxypropyl methylcellulose, sodium carboxymethyl cellulose, alginic acid or their
salts and derivatives thereof, carbomer (Carbopol(TM)), polyethyleneoxide, xanthan
gum, guar gum, locust bean gum, poly vinyl acetate, polyvinyl alcohol, lactose, PVA
these hydrophilic polymers also act as pore forming agent.
According to an especially preferred embodiment the functional coating contains a
combination of ethylcellulose and hydroxypropylmethylcellulose.
Pharmaceutical dosage forms of the invention can be coated by a wide variety of
methods. Suitable methods include compression coating, coating in a fluidized bed or a
pan and hot melt (extrusion) coating. Such methods are well known to those skilled in the
art.
These coating comprises one or more excipients selected from the group comprising
coating agents, opacifiers, fillers, plasticizers, polishing agents, colouring agents,
antitacking agents and the like.

The pharmaceutical formulation according to the present invention include but is not
limited to tablets (single layered tablets, multilayered tablets, mini tablets, bioadhesive
tablets, caplets, matrix tablets, tablet within a tablet, mucoadhesive tablets, modified
release tablets, pulsatile release tablets, timed release tablets), pellets, beads, granules,
sustained release formulations, capsules, microcapsules, tablets in capsules and
microspheres, matrix formulations, microencapsulation and powder/pellets/granules for
suspension.
The pharmaceutical composition of the invention can be formed by various methods
known in the art such as by dry granulation, wet granulation, melt granulation, direct
compression, double compression, extrusion spheronization, layering and the like.
The solvent(s) used in wet granulation in the present invention include all the solvents
well known in the art or their mixtures thereof.
Trimetazidine is basically absorbed from the upper part of the stomach which is its
primary site of absorption. Therefore the size of the punch which is used for compression
also plays a major role in the pharmaceutical composition of the present invention. It is
most preferred to use a bigger punch size for the tablets of the present invention and
thereby providing the retention of the drug in the upper part of the stomach.
Sustained release matrix tablet according to the present invention are manufactured
preferably as per the following procedure:
i) blend the trimetazidine and pharmaceutically acceptable additives,
ii) subjecting the blend to slugging/compaction to form a coprimate
iii) converting the coprimate to granules and
iv) Mixing the coprimate with other excipients
v) Compressing the granules to form the solid oral dosage form.
vi) The compressed granules are further coated with a functional coating.

The examples given below are illustrative embodiments of the invention and are merely
exemplary. A person skilled in the art may make variations and modifications without
deviating from the spirit and scope of the invention. All such modifications and variations
are intended to be included within the scope of the invention.

Procedure:
1) Sift the Lactose & Avicel along with Trimetazidine DiHCL.
2) Mix the materials of step 1 & granulate it with povidone water solution to produce
granules.
3) Sift together Xanthan Gum & Avicel mix well with granules of step 2.
4) Sift the Magnesium Stearate & Aerosil.
5) Lubricate the blend of step 3 with sifted material of step 4
6) Compress the blend of step 5.
Coating:
1) Take Sufficient qty of IP A & DCM
2) Add required quantity of HPMC, EC & Triethyl citrate, to above solvent under
continuous stirring to dissolve.
3) Coat the core tablets.


Procedure:
1. Melt Hydrogenated Vegetable Oil to the melted add Trimetazidine DiHCL &
lactose (intra)
2. Allow the materials of the step 1 to cool & solidify, mill it get granules
3. Mix the granules of step 2 & with extra granular materials, Avicel & lactose
4. Sift the Magnesium Stearate & Aerosil.
5. Lubricate the blend of step 3 with sifted material of step 4
6. Compress the blend of step 5.
Coating:
1. Take Sufficient qty of IPA & DCM
2. Add required quantity of HPMC, EC & Triethyl citrate, to above solvent under
continuous stirring to dissolve.
3. Coat the core tablets



Procedure:
1. Sift Trimetazidine dihydrochloride and sufficient quantity of lactose. To the
above mixture, add Magnesium Stearate.
2. Compress the slug of above blend using suitable punch & suitable hardness.
3. Deslug the slug of step 3 and sift it.
4. Sift the DCP, Xanthan gum, lactose, Avicel, Aerosil together. And mix well with
blend of step 4.
5. Sift the magnesium Stearate. And lubricate the blend of step. 5.
6. Compress the blend of step. 6 using suitable punch.
Coating:
1. Take Sufficient qty of IP A & DCM
2. Add required quantity of HPMC, EC & Triethyl citrate, to above solvent
under continuous stirring to dissolve.
3. Coat the core tablets.


Procedure:
1. Sift Trimetazidine dihydrochloride and sufficient quantity of lactose through
sieve.
2. To the above mixture add Magnesium Stearate.
3. Compress the slug of above blend using suitable punch & suitable hardness.
4. Deslug the slug of step 3 and sift it.
5. Sift the Croscarmellose Sodium, xanthan gum, lactose, Avicel, Aerosil together.
And mix well with blend of step 4.
6. Sift the magnesium stearate. And lubricate the blend of step 5.
7. Compress the blend of step 6 using 13.3 mm round shape punch with suitable
thickness & hardness.
Coating:
1. Take Sufficient qty of IP A & DCM
2. Add required quantity of HPMC, EC & Triethyl citrate, to above solvent under
continuous stirring to dissolve.
3. Coat the core tablets

Procedure:
1. Sift Trimetazidine dihydrochloride and sufficient quantity of Lactose through
sieve.
2. To the above mixture add Magnesium Stearate.
3. Compress the slug of above blend using suitable punch & suitable hardness.
4. Deslug the slug of step 3. and sift it.
5. Sift the Crosscarmellose Sodium, xanthan gum, lactose, microcrystalline
cellulose, Colloidal silicon dioxide together. And mix well with blend of step 4.
6. Sift the magnesium stearate. And lubricate the blend of step 5.

7. Compress the blend of step 6 using 13.3 mm round shape punch with suitable
thickness & hardness.
Coating:
1. Take Sufficient qty of IP A & Acetone
2. Add required quantity of Eudragit & Triethyl citrate, to above solvent
under continuous stirring to dissolve.
3. Coat the core tablets
In-vitro Dissolution Study
The compositions of the present invention have a prolonged in vitro release rate
compared to the marketed Vastarel® composition. The in vitro test used to measure
release rate of the active agent from a composition of the invention is as follows:
A solution of 900 ml of a 0.1N HC1 and the apparatus USP Dissolution Apparatus Type I.
The tablet composition was placed in the apparatus and dissolution was periodically
measured. The in vitro dissolution studies of Example 4 is such that about 30% to about
85 % of drug is released in about 8 hrs, and more than about 85% of drug is released in
12 hours.

In -vivo Bioeauivalence Study
Open Label, balanced, randomized, single-dose, two-treatment, two-sequence, two-
period crossover relative bioavilability study of Trimetazidine 70 mg MR Tablets
example 4 (once daily) of Lupin Limited, India Comparing with that of Vastarel®
(Trimetazidine) MR Tablets 35mg bid (one Tablets each 12 hourly) of Servier Industries,
France, in 12 healthy, adult, male, human subjects under fasting conditions.

The study was designed to demonstrate the similar clinical efficacy compared to
Vastarel®.
The plasma Trimetazidine concentration is shown in Figure: 1
The in-vivo bioequivalence study shows the results as shown in the table below:
Table 1: Comparative pharmacokinetic parameters of present invention vs Vastarel®


WE CLAIM:
1: A once daily sustained release pharmaceutical composition comprising a core
comprising trimetazidine or a pharmaceutically acceptable salt(s), polymorph(s),
solvate(s), hydrate(s), enantiomer(s) thereof, one or more sustained release polymer(s) in
a matrix and one ore more pharmaceutically acceptable excipient(s), wherein the core is
further coated with a functional coating.
2: A once daily sustained release pharmaceutical composition according to claim 1,
wherein one or more sustained release polymer(s) comprises hydrophilic and/or
hydrophobic polymer or combinations thereof.
3: A once daily sustained release pharmaceutical composition according to claim 1,
wherein trimetazidine is present in a dose selected from a range of 50-100mg.
4: A once daily sustained release pharmaceutical composition according to claim 1,
wherein trimetazidine is present in a dose selected from a range of 60-80mg.
5: A once daily sustained release pharmaceutical composition according to claim 1,
wherein trimetazidine is present in a dose of 70mg.
6: A once daily sustained release pharmaceutical composition according to claim 1,
wherein the functional coating comprises hydrophilic and/or hydrophobic substances or
combinations thereof.
7: A once daily sustained release pharmaceutical composition according to claim 6,
wherein the hydrophilic substance is hydroxypropylmethylcellulose and the hydrophobic
substance is ethyl cellulose.
8: A once daily sustained release pharmaceutical composition comprising a core
comprising trimetazidine or a pharmaceutically acceptable salt(s), polymorph(s),

solvate(s), hydrate(s), enantiomer(s) thereof, one or more sustained release polymer(s) in
a matrix and one ore more pharmaceutically acceptable excipient(s), wherein the core is
further coated with a functional coating, wherein about 0-55% of drug released in about 4
hours, about 30-85% of drug released in about 8 hours, and greater than about 75% of
drug released in about 12 hours using 0.1 N HC1 as dissolution medium.
9: A once daily sustained release pharmaceutical composition comprising a core
comprising trimetazidine or a pharmaceutically acceptable salt(s), polymorphs),
solvate(s), hydrate(s), enantiomer(s) thereof, one or more sustained release polymer(s) in
a matrix and one ore more pharmaceutically acceptable excipient(s), wherein the core is
further coated with a functional coating characterized in that the once daily sustained
release pharmaceutical composition is bioequivalent to 35mg twice daily modified
release formulation.

Pharmaceutical composition of Trimetazidine or a pharmaceutically acceptable salt(s), polymorph(s), solvate(s), hydrate(s), enantiomer(s) thereof using dual retard release technique. A once daily sustained release pharmaceutical composition comprising a core comprising trimetazidine or a pharmaceutically acceptable salt(s), polymorph(s), solvate(s), hydrate(s), enantiomer(s) thereof, one or more sustained release polymer(s) in a matrix and one ore more pharmaceutically acceptable excipient(s), wherein the core is further coated with a functional coating.