Form 2
THE PATENTS ACT, 1970
(39 of 1970)
&
THE PATENTS RULE 2003
PROVISIONAL SPECIFICATION
[See section 10 and rule 13]
1. TITLE OF THE INVENTION
"Sustained release compositions of Trimetazidine and process of preparation"
2. APPLICANT
(a) NAME: USV LIMITED
(b) NATIONALITY: Indian Company incorporated under the
Companies ACT 1956
(c) ADDRESS: B.S.D. Marg, Govandi, Mumbai 400 088,
Maharashtra, India
3. PREAMBLE TO THE DESCRIPTION
The following specification describes the invention.

Technical field of the invention:
The present invention relates to novel sustained release pharmaceutical compositions used for the treatment of angina pectoris comprising:
(i) Trimetazidine or a pharmaceutically acceptable salt thereof;
(ii) at least one of the release modifying agents selected from;
(a) one or more water soluble materials;
(b) one or more water insoluble materials;
(c) one or more water swellable materials;
along with other suitable pharmaceutically acceptable excipients and characterized by the absence of cellulose and/or their derivatives as release modifying agents.
Particularly, said compositions are in the form of solid dosage forms. The present invention further relates to a process for preparation of said sustained release compositions.
Background and Prior art:
Trimetazidine is used in the treatment of angina pectoris. 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. Angina pectoris, also known as angina, is chest pain due to ischemia of the heart muscle which inturn is caused due to obstruction or spasm of the coronary arteries.
Trimetazidine is chemically l-[(2,3,4-trimethoxyphenyl)methyl]piperazine with
molecular formula C14H22N2O3 and molecular weight 266.34. Trimetazidine is freely soluble in water. It has two pKa values 4.32 and 8.95. Trimetazidine regulates ionic and extra cellular exchanges, correcting the abnormal flow of ions
2

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 administered orally in doses of 40 to 60mg daily in divided doses as an immediate release preparation. It is quickly absorbed and eliminated by the organism with plasma half life of around 6.0 +/- 1.4 hours and T max 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 term treatment of chronic ischemic disorders. A need therefore arises for compositions which could provide a sustained effect so as to achieve regular and constant plasma levels and which provides patient compliance.
There are various marketed preparations containing Trimetazidine. The brand VASTAREL from Servier is also marketed as CARDAPTAN, PREDUCTAL MR, IDAPTAN, FLAVEDON MR, TRIZEDON, VASTINAN, VASOREL. VASTAREL prolonged release film-coated tablets 35 mg contain calcium hydrogen phosphate dihydrate, hypromellose, povidone, anhydrous colloidal silica, magnesium stearate, macrogol, titanium dioxide (El71), glycerol, red iron oxide(E172).
US3262852 discloses a novel vasodilative substance, dihydrochloride of 1-(2,3,4-trimethoxybenzyl)piperazine i.e. Trimetazidine dihyrochloride.
US4814176 discloses a sustained release preparation comprising: (a) chitin,
3

chitosan, or a mixture thereof (b) anionic polymer compounds such as those having a carboxyl group, a sulfonic acid group, or a group capable of providing the same, and (c) pharmaceutically active agents. It however, do not provide any detailed study on Trimetazidine compositions.
EP0613686 discloses use of Trimetazidine for the preparation of medicaments for the treatment of troubles due to the therapeutic use of immuno-suppressants.
CN1864680 discloses orally disintegrated Trimetazidine hydrochloride tablet for treating angina pectoris and its process of preparation.
US3950508 discloses delayed action pharmaceutical tablets prepared from admixtures of active ingredient with talc, ethyl cellulose and magnesium stearate tableting lubricant, with twice as much talc present as ethyl cellulose.
EP0673649 discloses compositions for prolonged liberation of Trimetazidine (II) or its salts by making use of a mixture of water insoluble polymer and a plasticizer coated on a reservoir to control liberation. However, EP0673649 discloses compositions containing dose of 80mg of Trimetazidine dihydrochloride which is very high when compared to total conventional dose of 40mg to 60mg, in divided doses.
EP1108424 discloses a matrix tablet for prolonged release of Trimetazidine where the prolonged release is controlled by the use of a cellulose derivative polymer present in the matrix, selected from hydroxypropyl cellulose, hydroxymethyl cellulose, methylcellulose and hydroxypropyl methyl cellulose.
EP 1195160 discloses a pharmaceutical composition for sustained release of Trimetazidine dihydrochloride, comprising Trimetazidine dihydrochloride as the active substance and at least one of: (a) one or more hydrocolloid forming
4

materials; (b) one or more hydrophobic polymers; and (c) one or more other categories of hydrophobic materials.
JP61212517 discloses a long-acting tablet of a basic water-soluble medicine, enabling the proper and slow release of the medicine independent to the pH of the gastric or intestinal juice, by using ultrafine powder of an enteric polymer base as a polymeric matrix and using a hardened oil as an agent for controlling the release of the medicine.
RU2281772 discloses a medicinal formulation where the release of Trimetazidine dihydrochloride in the body from the formulation is carried out for 8 hr that provides the constant level of the preparation in blood.
WO02051417 discloses a novel solid pharmaceutical composition, with controlled release, obtained by hot-process thermoforming of a mixture based on polymers belonging to the polymethacrylate family, and Trimetazidine or one of its pharmaceutically acceptable salts.
WO03043610 discloses novel compositions and process for manufacturing of novel pharmaceutical compositions in the form of microbeads comprising of Trimetazidine dihydrochloride and further coating of the beads with polymeric membrane to tailor the drug release characteristics enabling "once a day" dosing for 60 mg dose of Trimetazidine dihydrochloride per unit dose.
While various Trimetazidine compositions are available commercially, there still exists a need for sustained release compositions which are effective and could be used for long term treatment of angina and with better patient compliance.
5

Object of the Invention:
The main object of the invention is to provide novel sustained release pharmaceutical compositions comprising (i) Trimetazidine or a pharmaceutically acceptable salt thereof; (ii) at least one of the release modifying agents selected from; (a) one or more water soluble materials; (b) one or more water insoluble materials; (c) one or more water swellable materials; along with other suitable pharmaceutically acceptable excipients.
Another object of the invention is to provide compositions which are characterized by the absence of cellulose and/or their derivatives as release modifying agents.
Yet another object of the invention is to provide a process for preparation of sustained release pharmaceutical compositions.
Another object of the invention is to provide sustained release compositions which has better patient compliance and used in the treatment of angina pectoris.
Further object of the invention is to provide compositions which releases Trimetazidine in a sustained and reproducible manner over a prolonged period of time to achieve a sustaining effect of Trimetazidine over 12 hours period after oral administration.
Further object of the invention is to provide compositions of Trimetazidine that demonstrates reliable release rate and facilitated in-vivo absorbtion for desired period of time.
6

Summary of the invention:
The invention discloses novel sustained release pharmaceutical compositions used
for the treatment of angina pectoris comprising:
(i) Trimetazidine or a pharmaceutically acceptable salt thereof;
(ii) at least one of the release modifying agents selected from;
(a) one or more water soluble materials;
(b) one or more water insoluble materials;
(c) one or more water swellable materials;
along with other suitable pharmaceutically acceptable excipients and characterized by the absence of cellulose and/or their derivatives as release modifying agents.
Further, the invention discloses a process for preparation of said Trimetazidine sustained release compositions comprising the steps of:
(1) preparing an intra-granular composition by,
a) mixing Trimetazidine or a pharmaceutically acceptable salt thereof and diluents with one or more release modifying agents to form a blend;
b) preparing the binder solution by dissolving the binder in a suitable solvent;
c) granulating the blend of step(a) with binder solution of step(b) to form desired wet mass;
d) screening the wet mass of step(c) to form granules;
e) drying the granules of step(d) till loss on drying in the range of 1.0% to 7.0% is achieved;
f) sizing the dried granules of step(e).

(2) mixing intra-granular composition of step(l) with an extra-granular composition containing anti-adherants and optionally one or more release modifying agents to form a granule blend;
(3) lubricating the granule blend of step(2) with suitable lubricants;
(4) compressing the lubricated granules of step(3) into tablets using suitable compression machine or filling the lubricated granule of step(3) into hard
7

gelatin capsules;
(5) coating the tablets of step(4) with a polymer based coating.
Detailed Description:
The present invention describes novel sustained release pharmaceutical compositions used for the treatment of angina pectoris comprising: (i) Trimetazidine or a pharmaceutically acceptable salt thereof; (ii) at least one of the release modifying agents selected from;
(a) one or more water soluble materials;
(b) one or more water insoluble materials;
(c) one or more water swellable materials;
along with other suitable pharmaceutically acceptable excipients and characterized by the absence of cellulose and/or their derivatives as release modifying agents.
The present invention further describes a process for preparation of said sustained release compositions.
According to the invention, release modifying agents may be selected from one or more water soluble materials and/or water insoluble materials and/or water swellable materials. Water soluble materials which may be employed for the sustained release compositions include , but is not limited to polyethylene oxide (average molecular weight 6,00,000 to 50,00,000) , sodium alginate, calcium ammonium alginate, potassium alginate, calcium alginate, propylene glycol alginate, polyvinyl alcohol, povidone, carbomer, xanthan gum, triethyl citrate and the like. Water soluble materials may be present in an amount from 20% to 80% by weight of the total composition.
Water insoluble materials which may be employed for the sustained release compositions include , but is not limited to stearic acid, glyceryl monostearate,
8

glyceryl behenate, glyceryl palmitostearate, microcrystalline wax, polymethacrylate, stearyl alcohol, cetyl alcohol, cetostearyl alcohol, hydrogenated castor oil, polyvinyl acetate phthalate, waxes, shellac, magnesium aluminium silicates and the like and may be present in an amount from 20% to 80% by weight of the total composition.
Water swellable materials which may be employed for the sustained release compositions include , but is not limited to alginic acid, guar gum and the like and may be present in an amount from 20% to 80% by weight of the total composition.
Mixtures of water soluble/water swellable material with water insoluble material may be employed in a weight ratio of about 10:1 to 1:10, preferably 10:5 to 5:10.
According to one aspect of the invention, Trimetazidine is present in an amount from 8.0% to 50% by weight of the total composition; preferably in an amount from 10% to 30% by weight of the total composition.
Sustained release compositions according to the present invention contains Trimetazidine in a dose range from 20mg to 60mg. According to a preferred aspect, the sustained release compositions may contain Trimetazidine in doses such as 35mg, 60mg. Sustained release Trimetazidine compositions having dose of 35mg are recommended for twice-a-day administration in order to achieve a sustained effect of the drug.
According to another aspect of the invention, the ratio of Trimetazidine to release modifying agents is in the range of about 1:1 to 1:10; preferably 1:1 to 1:5.
According to one aspect, there is provided a method for treating angina by administering sustained release compositions comprising Trimetazidine to patients in need thereof.
9

The present invention further describes a process for preparation of Trimetazidine sustained release compositions comprising the steps of:
(1) preparing an intra-granular composition by,
a) mixing Trimetazidine or a pharmaceutically acceptable salt thereof and diluents with one or more release modifying agents to form a blend;
b) preparing the binder solution by dissolving the binder in a suitable solvent;
c) granulating the blend of step(a) with binder solution of step(b) to form desired wet mass;
d) screening the wet mass of step(c) to form granules;
e) drying the granules of step(d) till loss on drying in the range of 1.0% to 7.0% is achieved;
f) sizing the dried granules of step(e).
(2) mixing intra-granular composition of step(l) with an extra-granular
composition containing anti-adherants and optionally one or more release
modifying agents to form a granule blend;
(3) lubricating the granule blend of step(2) with suitable lubricants;
(4) compressing the lubricated granules of step(3) into tablets using suitable compression machine or filling the lubricated granules of step(3) into hard gelatin capsules;
(5) coating the tablets of step(4) with a polymer based coating.
Solid dosage forms such as tablets, capsules or any other solid dosage form can be formulated using the process as described herein. Further, the compositions of the present invention provide a reliable in vitro-dissolution profile for sustained effect of Trimetazidine.
According to another embodiment of the invention, the sustained release compositions may also be prepared by hot melt granulation technique, the process involving the steps of: granulating the active ingredient and water insoluble material by hot melt granulation or by extrusion, followed by sizing and mixing
10

with suitable pharmaceutical^ acceptable excipients.
Suitable pharmaceutical^ acceptable excipients that can be used for formulation include, but are not limited to, diluents/fillers, binders, glidants, lubricants, antiadherants, and the like.
Diluents which can be used as per the invention include, but are not limited to dihydrogen calcium phosphate, tribasic calcium phosphate, calcium carbonate, lactose, microcrystalline cellulose or mixtures thereof and is present in an amount from 10% to 70% by weight of the total composition.
Binders which can be used as per the invention include, but are not limited to polyvinylpyrrolidone, gelatin, polyvinyl alcohol, gum acacia and the like and is present in an amount 1.0% to 15% by weight of the total composition.
Solvents which can be used as per the invention include, isopropyl alcohol, water or mixtures thereof in an amount sufficient to dissolve the binder.
Anti-adherents which can be used as per the invention include, but are not limited to colloidal silicon dioxide, talc, starch and the like and is present in an amount up to 3.0% by weight of the total composition.
Lubricants which can be used as per the invention include, but are not limited to magnesium stearate, calcium stearate, zinc stearate and the like and is present in an amount up to 3.0% by weight of the total composition.
Sustained release compositions prepared by the process as described herein is further film coated using any of the conventional coating techniques known in the prior art like pan coating, spray coating etc. Tablet coat of 2-20% with respect to total weight can be employed to have desired release.
11

Functional coating may be carried out using functional coating polymers other than cellulose and/or cellulose derivatives. Functional coating polymers may be selected from polymethacrylates, polyvinylacetate phthalates, polyvinyl acetate and the like.
Non-functional film coating may be carried out using one or more excipients selected from the group comprising film formers, opacifiers, coating agents, taste-masking agents, colouring agents, antitacking agents and the like. Film formers such as hydroxypropyl cellulose or hydroxypropyl methyl celluloses or the like can be used. Opacifying agents that can be used include titanium dioxide, ferric oxide, sunset yellow and the like. Plasticizers such as polyethylene derivatives, polyethylene glycol, propylene glycol, triethyl citrate and the like can be used. Antitacking agents include talc, stearic acid, magnesium stearate, colloidal silicon dioxide and the like. Excipients for non functional film coating can be used in concentrations which are well known to a person skilled in the art. Non-functional film coating serves the purpose of taste neutralization and provides elegance to the tablets.
The present invention is further illustrated by reference to the following examples which does not limit the scope of the invention in any way. It will be apparent to those skilled in the art that many modifications, both to the materials and methods, can be practiced without departing from the purpose and scope of the disclosure.
Examples
Example 1
Trimetazidine dihydrochloride (175 gm), dicalcium phosphate dihydrate (359 gm) and polyethylene oxide (Polyox WSR N303) (150 gm) were mixed and granulated using binder solution containing polyvinyl pyrrolidone (30 gm)
12

dissolved in isopropyl alcohol (675 gm). The resultant mass was dried at 60°C and the agglomerates were milled to required size. Sized granules were blended with colloidal silicon dioxide (5.5 gm) and magnesium stearate (5.5 gm). Compress the blended granules into tablets.
Compressed tablets can be seal coated by dispersing 1000 gm of opadry white (HPMC based) in 9000 gm of purified water to get uniform surface for sustained release polymer coat. Polymethacrylate (Eudragit RS30D/RL 30D) (3925 gm), talc (117.75 gm), triethyl citrate (233 gm), titanium dioxide (100 gm) and FDC yellow no.6 (50 gm) were dispersed in 5574.25 gm of purified water and homogenized and coated on above seal coated tablets. Tablets are coated till a weight gain of about 2-20% is achieved so as to get the desired in-vitro dissolution profile.
Example 2
Trimetazidine dihydrochloride(175 gm), dicalcium phosphate dihydrate (388 gm) and polymethacrylate (Eudragit RSPO) (150 gm) were mixed and granulated using binder solution containing polyvinyl pyrrolidone (50 gm) dissolved in isopropyl alcohol (596 gm). Resultant mass was dried at 60°C and the agglomerates were milled to required size. Sized granules were blended with colloidal silicon dioxide (6.0 gm) and magnesium stearate (6.0 gm). Compress the blended granules into tablets. Compressed tablets are coated by the procedure as described in Example 1.
Example 3
Trimetazidine dihydrochloride(175 gm) and dicalcium phosphate dihydrate (354gm) were mixed and granulated using binder solution containing polyvinyl pyrrolidone (25 gm) dissolved in isopropyl alcohol (115 gm). Resultant mass was dried at 60°C and agglomerates were milled to required size. Sized granules were blended with Kollidone SR (560gm) (Kollidone SR is a physical mixture of
13

polyvinyl acetate and polyvinyl pyrrolidone), colloidal silicon dioxide (5.5 gm) and magnesium stearate (5.5 gm). Compress the blended granules into tablets. Compressed tablets are coated by the procedure as described in Example 1.
Example 4
Trimetazidine dihydrochloride(175 gm), dicalcium phosphate dihydrate (584gm) and polyvinyl pyrrolidone (30 gm) were mixed and granulated using binder solution containing polyvinyl alcohol (250 gm) dissolved in water (475 gm). Resultant mass was dried at 60°C and the agglomerates were milled to required size. Sized granules were blended with colloidal silicon dioxide (5.5 gm) and magnesium stearate (5.5 gm). Compress the blended granules into tablets. Compressed tablets are coated by the procedure as described in Example 1.
Example 5
Trimetazidine dihydrochloride (175 gm), dicalcium phosphate dihydrate (400.5gm) and xanthan gum (400 gm) were mixed and granulated using binder solution containing polyvinyl pyrrolidone (37.5gm) dissolved in isopropyl alcohol (215 gm). Resultant mass was dried at 60°C and agglomerates were milled to required size. Sized granules were blended with colloidal silicon dioxide (6.0 gm) and magnesium stearate (6.0 gm). Compress the blended granules into tablets. Compressed tablets are coated by the procedure as described in Example 1.
Example 6
Glyceryl monostearate (116.67 gm) was melted at 60°C. Trimetazidine dihydrochloride (175 gm) and lactose monohydrate (300gm) were mixed and heated to 60°C in a jacketed rapid mixer granulator and granulated with the melted stearate at 60°C. After granulation the granulated mass was mixed continuously till it cools to room temperature. Shellac (29.77 gm) and polyvinyl pyrrolidone (14.58 gm) were dissolved in isopropyl alcohol (73 gm). This solution was gradually added to the above granulated mass and the resultant mass was dried at
14

45°C and then milled to required size. Sized granules were blended with colloidal silicon dioxide (3.0 gm) and magnesium stearate (6.0 gm). Compress the blended granules into tablets. Compressed tablets are coated by the procedure as described in Example 1.
Sustained release compositions prepared according to above examples show the following in-vitro drug release characteristics when tested in gastric fluid pH 1.2 for the first hour and then in phosphate buffer pH 6.8.

Time in hours % Release
1 30-45%
4 50-80%
8 60-85%
12 > 85%
While the present invention is described above in connection with preferred or illustrative embodiments, these embodiments are not intended to be exhaustive or limiting of the invention. Rather, the invention is intended to cover all alternatives, modifications and equivalents included within its spirit and scope, as defined by the appended claims.
Dated this the 08th day of August 2007

Dr K G Rajendran
Head-Knowledge Cell USV Limited
15