MODIFIED RELEASE COMPOSITIONS OF TRIMETAZIDINE
DIHYDROCHLORIDE

FIELD OF THE INVENTION

The present invention relates to modified release pharmaceutical composition of Trimetazidine dihydrochloride. The present invention also relates to process for preparing modified release pharmaceutical composition of Trimetazidine dihydrochloride.

BACKGROUND OF THE INVENTION

Trimetazidine dihydrochloride [l-(2,3,4-trimethoxybenzyl)-piperazine
dihydrochloride] composed of formula

Trimetazidine dihydrochloride is freely soluble in water and sparingly soluble in alcohol.

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 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 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 favorable for compliance of the patient to his treatment.

U.S. Patent 4,814,176 describes a sustained release preparation comprising a) chitin, chitosan or a mixture thereof and b) anionic polymer compounds such as those having a carboxyl group, a sulfonic group or a group capable of providing the same. It mentions trimetazidine as one of the examples in the description which can be included in such systems but does not provide any detailed study on trimetazidine as a sustained release preparation

European Patent Application No. 0 673 649 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. However the in-vivo bioavailability study conducted on 12 volunteers shows steady state plasma concentration (Css) at around 1 lng/ml with 80mg dose.

European Patent Application No. 1108424B 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 hydroxyl propylcellulose, hydroxyethylcellulose, hydroxymethyl cellulose, methylcellulose and hydroxypropyl methyl cellulose.

International Patent Application WO2002/51417 describes solid pharmaceutical composition for the controlled release of trimetazidine or its pharmaceutically acceptable salts, characterized in that it comprises a mixture of trimetazidine thermoformable or its pharmaceutically acceptable salts and one or more polymers selected from the group of polymethacrylates, the release of trimetazidine is only controlled by the nature of the polymethacrylates used, their relative amount compared to the trimetazidine, and the technique used in the manufacture of the composition.

European Patent Application No. EP1195160 describes a sustained release matrix pharmaceutical tablet compositions containing 60 mg of TMZ HCI and hydrocolloid forming materials and or hydrophobic polymers and or other hydrophobic materials as a retardant, which release TMZ HCI in a sustained and reproducible manner over a prolonged period of time to achieve the sustained effect of trimetazidine over a 24 hour period after oral administration. Sustained release matrix tablets are prepared by hot melt granulation comprising the following steps:

a) granulating trimetazidine dihydrochloride with at least one of a hydrophobic polymer and/or other hydrophobic material to form a granulate mass;

b) characterized in that granulation of the mixture is carried out by hot melt granulation at a temperature of 40°C to 120°C.

This invention makes use of multi-step process involving multiple equipments that is laborious, time consuming with potential of cross contamination.

European Patent Application No. EP1448173A describes process for the preparation of drug delivery system containing trimetazidine dihydrochloride (TMZ HCI) in novel compositions for 'once a day' dosing for 60mg of TMZ HCI exhibiting pH independent invitro release with no latent period, the process comprising: 'Dissolving TMZ HCI in aqueous or hydroalcoholic media, Dispersing and/or dissolving binder in aqueous or hydroalcoholic media, Mixing of TMZ HCI solution with binder dispersion, Adding antitack agent and/or glidants to TMZ HCI-binder dispersion. Spraying the dispersion on inert seeds such as sugar spheres followed by drying to obtain drug core, Sequential coating with one or more water insoluble polymer (s) in aqueous or organic solvents with or without plasticizers and antitack agents followed by drying carried out in a single equipment such as fluid bed processor in a continuous manner followed by curing when necessary to obtain sustained release of TMZ HCI from the formed un-agglomerated microbeads that of uniform shape and size.

Again this invention also makes use of f multi-step process involving multiple equipments that is laborious, time consuming with potential of cross contamination.

EP1881831A Solid pharmaceutical composition in sustained release comprising trimetazidine or a pharmaceutically acceptable salt, in association with at least one polyethylene oxide and at least one lubricant, possibly in combination with one or more pharmaceutically acceptable excipients.

The above patents/applications describes various technologies/processes for preparing Trimetazidine Dihydrochloride modified release dosage forms like reservoir system, matrix delivery system, hot-melt granulation process, non-pearl coating technology. All these technology/process are laborious, time consuming with potential of cross contamination. Trimetazidine Dihydrochloride is highly water soluble molecule and requires high quantity of Polyethylene oxide for controlling the release from the dosage from for maintaining the prolonged release of the drug. Use of high quantity of Polyethylene oxide is toxic and also not acceptable by the regulatory agencies. Also use of high quantity of polysaccharide gums for controlling the release of Trimetazidine dihydrochloride produces instability of formulation during stability. Hence, there is need to develop simple cost effective process/technology for preparing modified release dosage form of Trimetazidine Dihydrochloride, which is non toxic and as well as stable, complying with all regulatory agencies. The inventors of the present invention during their continuous effort to develop a cost effective and stable modified release composition of Trimetazidine dihydrochloride developed a composition comprising of polyethylene oxide and polysaccharide gums as releasing polymers for Trimetazidine dihydrochloride, which is non toxic, stable and maintains prolonged release of Trimetaizdine dihydrochloride.

OBJECTIVE OF PRESENT INVENTION

The main objective of the present invention is to provide stable modified release composition of Trimetazidine Dihydrochloride.

In another objective of the present invention is to provide simple cost effective stable modified release composition of Trimetazidine Dihydrochloride.

SUMMARY OF THE INVENTION

One embodiment of the present invention relates to stable modified release composition of Trimetazidine Dihydrochloride.

In another embodiment of the present invention relates to stable modified release composition of Trimetazidine Dihydrochloride, comprising polyethylene oxide and polysaccharide gum as release polymers and one or more pharmaceutically acceptable excipients.

In another embodiment of the present invention relates to process for preparing stable modified release composition of Trimetazidine Dihydrochloride.

SUMMARY OF THE INVENTION

The present invention provides stable modified release composition of Trimetazidine Dihydrochloride.

The present invention also provides stable modified release composition of Trimetazidine Dihydrochloride, wherein the composition comprises polyethylene oxide and polysaccharide gum as release polymers and one or more pharmaceutically acceptable excipients.

Polyethylene oxide used according to the present invention comprises molecular weight ranging from 100, 000 to 7,000,000 can be used for purpose of release polymer. More particularly Polyethylene oxide having molecular weight ranging from 5,000, 000 to 7,000,000 can be used for purpose of release polymer. It may include using a polyethylene oxide with a concentrated solution of 1% has a viscosity at 25°C between 7,500mPa/s and 10,000 mPa/s.

Modified release composition according to the present invention comprises 25-45% by weight of polyethylene oxide, to the total weight of the dosage form.

Modified release composition according to the present invention comprises 8-20% by weight of polysaccharide gum, to the total weight of the dosage form.

The ratio of polyethylene oxide to polysaccharide gum used in the present invention ranges from 1:10 to 10:1, specifically 2:1 to 3:1 and more specifically 2.5:1.

Polysaccharide gums according to the present invention may be selected from the group consisting of xanthan gum, guar gum, agar gum, tragacanth, locust bean gum, and combinations thereof. More specifically the polysaccharide gum is xanthan gum.

One or more pharmaceutically acceptable excipients according to the present invention are selected from diluents, binders, disintegrants, lubricants, glidant and combinations thereof.

Suitable diluents used according to the present invention may be selected from microcrystalline cellulose, mannitol, lactose, starch, maize starch, wheat starch, potato starch, calcium hydrogen phosphate anhydrous, sorbitol, sucrose, dicalcium phosphate and combinations thereof.

Suitable binders used according to the present invention may be selected from povidone, alginic acid, starch, potato starch, wheat starch, corn starch, hydroxypropyl methylcellulose, hydroxypropyl cellulose, hydroxyethyl cellulose, gelatin and combinations thereof.

Suitable disintegrants used according to the present invention may be selected from sodium starch glycolate, crospovidone, microcrystalline cellulose, low substituted hydroxypropyl cellulose, croscarmellose sodium, croscarmellose potassium, starch, and combinations thereof.

Suitable lubricants used according to the present invention may be selected from stearic acid, magnesium stearate, sodium stearyl fumarate, fumaric acid, calcium stearate, hydrogenated vegetable oil, stearic acid, glyceryl behenate, and combinations thereof.

Suitable glidants used according to the present invention may be selected from calcium phosphate tribasic, powdered cellulose, colloidal silicon dioxide, magnesium oxide, magnesium silicate, magnesium trisilicate, starch, talc and combinations thereof.

The modified release dosage form according to the present invention may be tablet, capsule, granule or nonpareil seeds.

The tablets may be coated with film coating agents like hydroxypropyl methylcellulose, hydroxypropyl cellulose, polyvinyl alcohol and combination thereof along with processing aids.

Stable modified release composition of Trimetazidine dihydrochloride according to the present invention may be prepared by direct compression, wet granulation and dry granulation.

Preferably Stable modified release composition of Trimetazidine dihydrochloride according to the present invention is prepared by direct compression process.

Direct compression according to the present invention comprising the following steps:

a) sifting of all materials

b) blending of all sifted materials

c) optionally lubrication

d) Compression.

The invention is illustrated by the following non limiting examples: Example 1: Composition with only polyethylene oxide

Brief description of the manufacturing process;

• Sifted separately Trimetazidine dihydrochloride, Calcium hydrogen phosphate anhydrous, polyethylene oxide, Colloidal silicon dioxide, povidone K90 through #30mesh and magnesium stearate through #40mesh.

• Mixed sifted Trimetazidine dihydrochloride, Calcium hydrogen phosphate anhydrous, polyethylene oxide, Colloidal silicon dioxide, povidone K90 and blended for 20 minutes

• The above blend is lubricated with sifted magnesium stearate for 5 minutes.

• The lubricated blend was compressed into Tablets.

The above compressed tablets was analyzed for dissolution using 900 ml of 0.1N hydrochloric acid as dissolution medium and USP Type II apparatus, 50rpm and compared with Reference Product VASTAREL 35 (B.No. 832868)

The results from the above data indicates that the release of drug is comparable with the reference product however, which contains high amount of Polyethylene oxide and is reaching the toxic level and also during stability the physical appearance of tablets is changed.

Example 2: Composition with only Polysaccharide gum
Brief description of the manufacturing process:

• Sifted separately Trimetazidine dihydrochloride, Calcium hydrogen phosphate anhydrous, Xanthan gum, colloidal silicon dioxide, povidone K90 through #30mesh and magnesium stearate through #40mesh.

• Mixed sifted Trimetazidine dihydrochloride, Calcium hydrogen phosphate anhydrous, xanthan gum, Colloidal silicon dioxide, povidone K90 in a blender, and blended for 20 minutes

• The above blend is lubricated with sifted magnesium stearate for 5 minutes.

• The lubricated blend is compressed into Tablets.

The above compressed tablets were analyzed for dissolution using 900 ml of 0.1N hydrochloric acid as dissolution medium and USP Type II apparatus, 50rpm and compared with Reference Product VASTAREL 35 (B.No. 832868)

The results from the above data indicate that the release of drug is comparable with the reference product. Then the above tablets were charged for stability testing along with reference Product at 40°C/75RH. After three months the tablets were analyzed for Related Substances and the results were given below:

Comparative Related substances data for Example 2 and Reference Product (Vastarel® 35 mg~)

During stability the related substances values are increased compared to initial values particularly Impurity C is crossed above the ICH limits.

Example3: Composition with Polysaccharide gum and Polyethylene oxide as per the present invention

Brief description of the manufacturing process:

• Sifted separately Trimetazidine dihydrochloride, Calcium hydrogen phosphate anhydrous, Xanthan gum, Polyethylene oxide, Colloidal silicon dioxide, povidone K90 and magnesium stearate through #30mesh.

• Mixed sifted Trimetazidine dihydrochloride, Calcium hydrogen phosphate anhydrous, Polyethylene oxide, xanthan gum, Colloidal silicon dioxide, povidone K90 and blended for 20 minutes.

• The above blend is lubricated with sifted magnesium stearate for 5 minutes.

• The lubricated blend was compressed into Tablets.

• Compressed tablets were coated with film coating agent

The above compressed tablets are analyzed for dissolution using 900 ml of 0.1N hydrochloric acid as dissolution medium and USP Type II apparatus, 50rpm and compared with Reference Product VASTAREL 35 (B.No. 832868)

The results from the above data indicate that the release of drug is comparable with the reference product. Then the above tablets were charged for stability testing along with reference Product at 40°C/75RH and 25°C/60RH. After six months at 40°C/75RH and 18 months at 25°C/60RH the tablets were analyzed for Related Substances and the results were given below:

Comparative Related substances data for Example 3 and Reference Product (Vastarel®
35 mg)

During stability studies the related substances values are well within the specifications as well as within the ICH limits.

CLAIMS

1. Stable modified release composition of Trimetazidine Dihydrochloride, wherein the composition comprises polyethylene oxide and polysaccharide gum as release polymers and one or more pharmaceutically acceptable excipients.

2. Stable modified release composition of claim 1, wherein ratio of polyethylene oxide to polysaccharide gum is in the ratio of 1:10 to 10:1.

3. Stable modified release composition of claim 1, wherein ratio of polyethylene oxide to polysaccharide gum is in the ratio of 2:1 to 3:1, more specifically 2.5: 1.

4. Stable modified release composition of claim 1, 2 or 3, wherein polysaccharide gum is selected from the group consisting of xanthan gum, guar gum, agar gum, tragacanth, locust bean gum, and combinations thereof, and more specifically xanthan gum.

5. Stable modified release composition of claim 1, wherein one or more pharmaceutically acceptable excipients are selected from diluents, binders, disintegrants, lubricants, glidant and combinations thereof.

6. Stable modified release composition of claim 1, may be in the form of tablets or capsules or granules.

7. Stable modified release composition of claim 6, wherein tablets are prepared by direct compression, wet granulation and dry granulation and more specifically direct compression process.