A novel extended release pharmaceutical composition of trimetazidine or salt thereof

Abstract

The present invention relates to a novel extended release composition of trimetazidine or salt thereof in the form of pellet which are prepared by matrix technology in the treatment of angina pectoris. The pellet according to present invention are prepared by matrix technology comprising one or more extended release polymers along with one or more pharmaceutically acceptable excipients.

Description

[0001] A NOVEL EXTENDED RELEASE PHARMACEUTICAL COMPOSITION OF TRIMETAZIDINE OR SALT THEREOF

[0002] FIELD OF THE INVENTION

[0003] The present invention relates to novel extended release pharmaceutical compositions of trimetazidine or salt thereof. The present invention also relates to process of manufacturing thereof.

[0004] BACKGROUND OF THE INVENTION

[0005] Trimetazidine is a piperazine derivative indicated for the symptomatic treatment of stable angina pectoris and ischemic heart disease. Trimetazidine is an anti-ischemic (antianginal) metabolic agent of the fatty acid oxidation inhibitor class. It improves myocardial glucose utilization through inhibition of fatty acid metabolism.

[0006] Trimetazidine is l-(2, 3, 4-Trimethoxybenzyl) piperazine with a molecular weight of 266.34 g / mol, and a molecular formula of C14H22N2O3. Trimetazidine is represented by compound of structural formula I.

[0007] Formula I.

[0008] The salt form commonly used is Trimetazidine dihydrochloride (molecular formula C14H24CI2N2O3; relative molecular weight 339.3 g / mol). Trimetazidine dihydrochloride is white to off-white powder, freely soluble in water, sparingly soluble in alcohol. Trimetazidine dihydrochloride is having melting point between 231-235°C and boiling point 364°C at 760 mmHg.

[0009] Trimetazidine 80mg Capsules was approved in Brazil under the tradename VASTAREL around February 2020. Trimetazidine 80mg capsule contain trimetazidine dihydrochloride as the active ingredient and inactive ingredients like sugar spheres (sucrose and com starch), hypromellose, ethylcellulose, acetyl tributyl citrate, talc, Magnesium stearate. Capsule composition contains gelatin, titanium dioxide and red iron oxide.

[0010] Trimetazidine Capsules was approved and used in the treatment of ischemic heart disease and angina pectoris.

[0011] EP2623096B1 discloses pharmaceutical composition for prolonged release of trimetazidine comprising an inner and an outer layer, wherein said inner layer comprises a neutral core coated with trimetazidine, an outer layer comprises a retardant and an anti- agglomerant. The said patent document discloses composition of prolonged release of trimetazidine prepared by layering method; however, said patent document does not disclose prolonged release composition prepared by matrix method.

[0012] W02006123073 discloses sustained release composition of Trimetazidine. Further, said PCT application does not discloses or teaches pellet formulation, steps of extrusion speheronization.

[0013] W02010084397 discloses modified release solid pharmaceutical composition comprising Trimetazidine and polyethylene oxide. The said patent document does not teach or discloses pellet formulation, steps of extrusion speheronization.

[0014] W02009066315 discloses sustained release pharmaceutical composition comprising one or more water soluble materials and one or more water insoluble materials. However, said patent document does not disclose or teaches pellet formulation, steps of extrusion speheronization.

[0015] The product known in the prior art for Trimetazidine does not provide adequate and desired release of drug from dosage form; therefore, lacks efficacy and result in non-patient compliance in the treatment of angina pectoris and ischemic heart disease. Also the product known in the prior art made up with neutral core and followed by coating with Trimetazidine. The products known in the prior art made up of neutral core pellets exhibit variability in drug release due to less uniformity in the core structure. Neutral core pellets might require additional step or additives to achieve desired release characteristics; therefore, which is cumbersome.

[0016] Therefore, there is need in the art to prepare extended release composition of trimetazidine in the form of capsule comprising pellets which are prepared by matrix technology, which comprises extended release polymer in the core as well in the coating of Trimetazidine pellets and which provides desired release in the treatment of angina pectoris and ischemic heart disease.

[0017] Accordingly, applicant of the present invention invented extended release composition of trimetazidine in the form of capsule comprising pellets which are prepared by matrix technology and which comprises extended release polymer in the core as well in the coating of Trimetazidine pellets. The trimetazidine pellet prepared by matrix technology provides uniform and desired release from the dosage form require in the treatment of angina pectoris and ischemic heart disease. The process of manufacturing trimetazidine pellet prepared by matrix technology is simple, cost effective and does not involve more processing time. Therefore, extended release composition of trimetazidine according to present invention are safe, effective and provides patient compliance in the treatment of angina pectoris.

[0018] SUMMARY OF THE INVENTION

[0019] A first aspect of the present invention is to provide a novel extended release composition of trimetazidine or salt thereof in the form of pellet which are prepared by matrix technology.

[0020] In another aspect of the present invention is to provide extended release composition of trimetazidine or salt thereof along with one or more extended release polymer in the form of pellet and the said composition is prepared by matrix technology.

[0021] In another aspect of the present invention is to provide extended release composition of trimetazidine or salt thereof in the form of pellet; wherein pellet comprises a) a core comprising trimetazidine or salt thereof b) coating comprising extended release polymer over the core; wherein the core of composition is manufactured by matrix technology.

[0022] In another aspect of the present invention is to provide extended release composition of trimetazidine or salt thereof in the form of pellet; wherein pellet comprises a) a core comprising trimetazidine or salt thereof b) optionally seal coating comprising polymer c) coating comprising extended release polymer; wherein the core of composition is manufactured by matrix technology.

[0023] In another aspect of the present invention is to provide extended release composition of trimetazidine or salt thereof in the form of pellet; wherein pellet comprises a) a core comprising trimetazidine or salt thereof along with one or more extended release polymer b) coating comprising extended release polymer over the core; wherein the core of composition is manufactured by matrix technology.

[0024] In another aspect of the present invention is to provide extended release composition of trimetazidine or salt thereof in the form of pellet; wherein pellet comprises a) a core comprising trimetazidine or salt thereof along with one or more extended release polymer b) optionally seal coating comprising polymer c) coating comprising extended release polymer over the core; wherein the core of composition is manufactured by matrix technology.

[0025] In another aspect of the present invention is to provide extended release composition of trimetazidine or salt thereof in the form of pellet; wherein pellet comprises a) a core comprising trimetazidine or salt thereof along with one or more extended release polymer b) optionally seal coating comprising polymer c) coating comprising extended release polymer over the core; wherein the core of composition is manufactured by matrix technology and involves extrusion spheronization method.

[0026] In another aspect of the present invention is to provide extended release composition of trimetazidine or salt thereof manufactured by matrix technology may be in the form of pellet, capsule, tablet, sachet, granules or beads.

[0027] In another aspect of the present invention is to provide process of manufacturing extended release composition of trimetazidine or salt thereof in the form of pellet wherein the process steps involves a) Mixing the trimetazidine or salt thereof along with one or more pharmaceutically acceptable excipient to form the Trimetazidine core b) Optionally coating the core with seal coating polymer to form the seal coated core c) Coating the seal coated core with coating comprising extended release polymer.

[0028] In another aspect of the present invention is to provide process of manufacturing extended release composition of trimetazidine or salt thereof in the form of pellet wherein the process steps involves a) Mixing the trimetazidine or salt thereof, extended release polymer optionally along with one or more pharmaceutically acceptable excipient to form the Trimetazidine core b) Optionally coating the core with seal coating polymer to form the seal coated core c) Coating the seal coated core with coating comprising extended release polymer.

[0029] In another aspect of the present invention is to provide process of manufacturing extended release composition of trimetazidine or salt thereof in the form of pellet wherein the process steps involves a) Mixing the trimetazidine or salt thereof, extended release polymer optionally along with one or more pharmaceutically acceptable excipient b) Mixing binder along with solvent to form the binder solution c) Mixing mixture formed in step a) with binder solution formed in step b) to form the dump mass d) Extrusion spheronzation of the dump mass formed in step c) to form the pellets of trimetazidine or salt therefore. e) Optionally coating the core with seal coating polymer to form the seal coated core f) Coating the seal coated core with coating comprising extended release polymer.

[0030] In another aspect of the present invention is to provide extended release pellet of trimetazidine or salt thereof in the treatment of ischemic heart disease and angina pectoris wherein said pellet comprises a) a core comprising trimetazidine or salt thereof b) coating comprising extended release polymer over the core and wherein the core of composition is manufactured by matrix technology.

[0031] DETAIL DESCRIPTION OF THE INVENTION

[0032] The present invention relates to novel extended release pharmaceutical compositions of trimetazidine or salt thereof.

[0033] The extended release composition of trimetazidine or salt thereof according to present invention means composition provides gradual release over an extended period.

[0034] The trimetazidine according to present invention may be present in the form of pharmaceutically acceptable salt. The salt of trimetazidine according to present invention may be trimetazidine dihydrochloride, trimetazidine hydrochloride, trimetazidine hemimalate, trimetazidine hemiadipate, trimetazidine hemitartrate, trimetazidine hemiphosphate, trimetazidine hemisulfate, trimetazidine hemisuccinate, trimetazidine hemifumarate and salts of trimetazidine with phenyl sulphonyl urea. Preferably, trimetazidine is present in the form dihydrochloride salt.

[0035] The extended release composition of trimetazidine or salt thereof according to present invention is used in the treatment of angina pectoris and ischemic heart disease.

[0036] Angina pectoris is the medical term for chest pain or discomfort due to coronary heart disease. It occurs when the heart muscle doesn't get as much blood as it needs. This usually happens because one or more of the heart's arteries is narrowed or blocked, also called ischemia.

[0037] Ischemic means that an organ (e.g., the heart) is not getting enough blood and oxygen. Ischemic heart disease, also called coronary heart disease (CHD) or coronary artery disease, is the term given to heart problems caused by narrowed heart (coronary) arteries that supply blood to the heart muscle.

[0038] A first aspect of the present invention is to provide a novel extended release composition of trimetazidine or salt thereof in the form of pellet which are prepared by matrix technology. The extended release composition of trimetazidine or salt thereof in the form of pellet according to present invention wherein core of pellet is manufactured by matrix technology.

[0039] The matrix technology of pellet formation according to present invention means “Trimetazidine or salt thereof may be mixed with one or more pharmaceutically acceptable excipient” and undergo direct compression or dry granulation or wet granulation; further said mixture undergo extrusion and spheronization to form the core of trimetazidine pellet.

[0040] In another aspect of the present invention is to provide extended release composition of trimetazidine or salt thereof along with one or more extended release polymer in the form of pellet and wherein the core of pellet is prepared by matrix technology.

[0041] The extended release composition of trimetazidine or salt thereof in the form of pellet according to present invention may comprises a) a core comprising trimetazidine or salt thereof b) coating comprising Extended release polymer over the core; wherein the core of composition is manufactured by matrix technology.

[0042] The extended release polymer according to present invention may be selected from but not limited to ethyl cellulose, polyethylene oxide, acrylates, cellulose acetate, glyceryl dibehenate, methyl cellulose (methocel), stearic acid, cellulose derivatives such as hydroxyethyl cellulose, hydroxypropyl cellulose, hydroxypropylmethyl cellulose, carboxymethyl cellulose and sodium carboxymethyl cellulose, carnauba wax, cetyl alcohol, hydrogenated vegetable oil, hydrogenated castor oil or mixture thereof.

[0043] The extended release composition of trimetazidine or salt thereof in the form of pellet according to present invention may comprises a) a core comprising Trimetazidine or salt thereof b) optionally seal coating comprising polymer c) coating comprising extended release polymer; wherein the core of composition is manufactured by matrix technology.

[0044] The extended release composition of trimetazidine or salt thereof; wherein seal coating present in the composition separates the core of trimetazidine with extended release coating.

[0045] The extended release composition of trimetazidine or salt thereof in the form of pellet according to present invention may comprises a) a core comprising trimetazidine or salt thereof along with one or more extended release polymer b) coating comprising Extended release polymer over the core; wherein the core of composition is manufactured by matrix technology.

[0046] The extended release composition of trimetazidine or salt thereof in the form of pellet wherein core and extended release coating may comprise same extended release polymer.

[0047] The extended release composition of trimetazidine or salt thereof in the form of pellet wherein core and extended release coating may comprise ethyl cellulose as extended release polymer.

[0048] The extended release composition of trimetazidine or salt thereof in the form of pellet wherein core and extended release coating may comprise different extended release polymer.

[0049] The extended release composition of trimetazidine or salt thereof in the form of pellet according to present invention may comprises a) a core comprising trimetazidine or salt thereof along with one or more extended release polymer b) optionally seal coating comprising polymer c) coating comprising Extended release polymer; wherein the core of composition is manufactured by matrix technology.

[0050] The extended release composition of trimetazidine or salt thereof according to present invention may be in the form of pellet, capsule, tablet, sachet, granules or beads.

[0051] In another embodiment of the present invention is to provide a pharmaceutical composition comprising Trimetazidine or salt thereof; wherein the percentage of Trimetazidine or salt thereof in the pharmaceutical composition is between 10% to 60% preferably 15% to 55% and more preferably 25% and 35% of the total weight of the composition.

[0052] The percentage of extended release polymer in the pharmaceutical composition is between 5% and 60% of the total weight of the composition.

[0053] In another embodiment of the present invention is to provide a pharmaceutical composition comprising Trimetazidine or salt thereof; wherein the drug to polymer ratio may ranges from 0.05: 1 to 4: 1, preferably 0.1: 1 to 3: 1, more preferably 0.3: 1 to 2.5: 1.

[0054] The one or more pharmaceutically acceptable excipient according to present invention may be selected from extend release polymer, diluent, binder, plasticizer, anti-tacking agent, lubricant, glidant, coating polymer, alkalizer, processing solvent. The examples of extended release polymer according to present invention may be selected from but not limited to ethyl cellulose, polyethylene oxide, acrylates, cellulose acetate, glyceryl dibehenate, methocel, stearic acid, cellulose derivatives such as hydroxyethyl cellulose, hydroxypropyl cellulose, hydroxypropylmethyl cellulose, carboxymethyl cellulose and sodium carboxymethyl cellulose, carnauba wax, cetyl alcohol, hydrogenated vegetable oil, hydrogenated castor oil or mixture thereof. The extended release polymer according to present invention may be preferably ethyl cellulose, polyethylene oxide, acrylate polymers.

[0055] The examples of diluent according to present invention may be selected from but not limited to lactose monohydrate, microcrystalline cellulose, cellulose powder, dicalcium phosphate, sucrose, starch or a starch derivatives, carbonates including calcium or sodium or magnesium carbonate, bicarbonates including calcium or sodium bicarbonate, mannitol, sucrose, xylitol, sorbitol, maltose, glucose, dibasic calcium phosphate, calcium phosphate, tribasic calcium, calcium sulphate, dextrate, dextrin, fructose, kaolin, lactitol, dextrose, glyceryl palmitostearate and combination thereof.

[0056] The examples of binder according to present invention may be selected from but not limited to polyvinylpyrrolidones, a polyvinylpyrrolidonevinyl acetate copolymer, hydroxy propyl methyl cellulose, acacia, gum arabic, hydrocolloids, dextrins, gelatin, glucose, guar gum, starch, starch pregelatinized, maltose, maltodextrin, and combinations thereof.

[0057] The examples of plasticizer according to present invention may be selected from but not limited to triethyl citrate, triacetin, waxes, propylene glycol, polyethylene glycol, or combination thereof and alike.

[0058] The examples of anti-tacking agent according to present invention may include but not limited to purified talc, silicon dioxide, glycerol monosterate, simethicone or combination thereof and alike.

[0059] The examples of lubricant according to present invention may include but not limited to magnesium stearate, zinc stearate, stearic acid, calcium stearate, sodium stearyl fumarate, polyethylene glycols, silicone dioxide, talc, hydrogenated vegetable oil or combination thereof.

[0060] The examples of glidant according to present invention may include but not limited to colloidal silicon dioxide (Aerosil), talc, magnesium stearate, and silica. Preferably, glidant is talc. The examples of alkalizer according to present invention may include but not limited to dibasic calcium phosphate, calcium carbonate, sodium bicarbonate, potassium carbonate, magnesium hydroxide, sodium carbonate.

[0061] The examples of solvents according to present invention may include but not limited to isopropyl alcohol, dichloromethane, acetone and purified water or combination thereof and alike.

[0062] In another aspect of the present invention is to provide process of manufacturing extended release composition of trimetazidine or salt thereof in the form of pellet wherein the process steps involves a) Mixing the trimetazidine or salt thereof along with one or more pharmaceutically acceptable excipient to form the Trimetazidine pellet core b) Optionally coating the core with seal coating polymer to form the seal coated core c) Coating the seal coated core with coating comprising extended release polymer.

[0063] The process of manufacturing extended release composition of trimetazidine or salt thereof according to present invention wherein core of the trimetazidine pellet is manufactured by matrix technology and which involves mixing Trimetazidine or salt thereof along with one or more pharmaceutically acceptable excipient and may undergo direction compression, dry granulation or wet granulation; further said mixture undergo extrusion and spheronization to form the pellet core of the Trimetazidine or salt thereof.

[0064] The process of manufacturing extended release composition of trimetazidine or salt thereof in the form of pellet wherein the process steps may involve a) Mixing the trimetazidine or salt thereof, extended release polymer optionally along with one or more pharmaceutically acceptable excipient to form the Trimetazidine core b) Optionally coating the core with seal coating polymer to form the seal coated core c) Coating the seal coated core with coating comprising extended release polymer

[0065] Wherein the core of the composition is manufactured by extrusion and spheronization.

[0066] The process of manufacturing extended release composition of trimetazidine or salt thereof in the form of pellet wherein the process steps may involve a) Mixing the trimetazidine or salt thereof, ethyl cellulose, optionally along with one or more pharmaceutically acceptable excipient to form the Trimetazidine core b) Optionally coating the core with seal coating polymer to form the seal coated core c) Coating the seal coated core with coating comprising ethyl cellulose. The process of manufacturing extended release composition of trimetazidine or salt thereof in the form of pellet wherein the process steps may involve a) Mixing the trimetazidine or salt thereof, extended release polymer optionally along with one or more pharmaceutically acceptable excipient b) Mixing binder along with solvent to form the binder solution c) Mixing mixture formed in step a) with binder solution formed in step b) to form the dump mass d) Extrusion spheronization of the dump mass formed in step c) to form the core of trimetazidine pellets. e) Optionally coating the core with seal coating polymer to form the seal coated core f) Coating the seal coated core with coating comprising extended release polymer.

[0067] The process of manufacturing extended release composition of trimetazidine or salt thereof in the form of pellet wherein the process steps may involve a) Mixing the trimetazidine or salt thereof, ethyl cellulose optionally along with one or more pharmaceutically acceptable excipient b) Mixing binder along with solvent to form the binder solution c) Mixing mixture formed in step a) with binder solution formed in step b) to form the dump mass d) Extrusion spheronization of the dump mass formed in step c) to form the pellets of trimetazidine or salt therefore. e) Optionally coating the core with seal coating polymer to form the seal coated core f) Coating the seal coated core with coating comprising ethyl cellulose.

[0068] The process of manufacturing novel pharmaceutical composition of Trimetazidine or salt thereof, percentage of Trimetazidine, extended release polymer and other excipients is optimized in such way that composition of Trimetazidine or salt thereof according to present invention provides uniform and desired release from the dosage form which is required in the treatment of angina pectoris and ischemic heart disease.

[0069] The extended release pellet according to present invention may be filled in to the capsule or compressed in to the tablet.

[0070] The novel pharmaceutical composition of Trimetazidine or salt thereof undergone stability study as per ICH guideline at 25°C / 60%RH, 30°C / 75%RH, 40°C / 75%RH and composition found to be stable and in compliance.

[0071] The novel pharmaceutical composition of Trimetazidine or salt thereof according to present invention is in the form of pellets, capsule and tablet can be packaged in suitable airtight containers and moisture proof packs. Packaging may include but not limited to high- density polyethylene bottle, aluminum blister package. The container material or packaging material of the present invention does not affect the quality of the preparation or does not allow diffusion of any kind into or across the material of the container into the preparation.

[0072] EXAMPLES:

[0073] Some illustrative non-limiting example of the present invention are described below

[0074] Table 1: Example 1

[0075] Manufacturing Procedure:

[0076] 1. Sift Trimetazidine Dihydrochloride, microcrystalline cellulose, polyethylene oxide (Polyox WSR 1105 LEO NF), and polyethylene oxide (Polyox WSR NK 60 LEO NF) through 30#.

[0077] 2. Prepare binder solution of povidone (PVP K30) in purified water and isopropyl alcohol.

[0078] 3. Prepare the wet mass in rapid mixer granulator by using mixture of step 1 and binder solution in step 2.

[0079] 4. Granulate the wet mass in rapid mixer granulator. Extrude material using extruder and 1.2 mm screen at suitable speed and suitable time and spheronize extrudes using spheronizer at suitable speed (200 - 800 rpm) and time (3 to 5 minutes), dry spheronized material at 55- 65°C, and sift material using 12# and 30# (1700 micron to 600 micron) to form the pellets of Trimetazidine

[0080] 5. Fill pellets in capsule size “1”. Table 2: Example 2

[0081] Manufacturing Procedure:

[0082] 1. Sift Trimetazidine Dihydrochloride, microcrystalline cellulose, through 30#, 2. Add polymethacrylates (Eudragit NM30 D) in purified water and granulate the wet mass in rapid mixer granulator.

[0083] 3. Extrude material using extruder and 1.2 mm screen at suitable speed and suitable time and spheronize extrudes using spheronizer at suitable speed ( 200 - 800 rpm) and time (3 to 5 minutes), dry spheronized material at 55- 65°C, and sift material using 12# and 30# (1700 micron to 600 micron),

[0084] 4. Fill pellets in capsule size “1”.

[0085] Table 3: Example 3

[0086] Manufacturing Procedure: 1. Sift Trimetazidine Dihydrochloride, microcrystalline cellulose, and polymethacrylates

[0087] (Eudragit RSPO) through 30#.

[0088] 2. Prepare binder solution of povidone K-30 in purified water and 3. Granulate the wet mass in rapid mixer granulator by using mixture of step 1 and binder solution in step 2.

[0089] 4. Extrude material using extruder and 1.2 mm screen at suitable speed and suitable time and spheronize extrudes using spheronizer at suitable speed (200 - 800 rpm) and time (3 to 5 minutes), dry spheronized material at 55- 65°C, and sift material using 12# and 30# (1700 micron to 600 micron),

[0090] 5. Fill pellets in capsule size “1”.

[0091] Table 4: Example 4

[0092] Manufacturing Procedure:

[0093] 1. Core Preparation:

[0094] • Sift Trimetazidine Dihydrochloride, microcrystalline cellulose, lactose, through 30#

[0095] • And prepare binder solution of Povidone K30 in purified water. • Granulate above material in Rapid mixer granulator. Check the integrity of screen before and after use and assemble the screen of 1.00 mm to extruder. • Collect extrudes in SS container (Stainless steel) having in-process stage label as extrudes ready for the spheronization. Assemble the spheronizer and spheronize extrudes at speed 300 RPM for 1-3 mins. Gradually increase speed to 700-1500 RPM and continue the process till round shaped pellets observed, discharge and collect the spheronized pellets in SS container (Stainless steel) having in-process stage label as wet pellets - ready for drying, Set the inlet temperature 55 - 60°C of FBC (Fluidized Bed Coater) and dry the pellets for 2 Hrs, check the LOD (Loss on Drying) and continue drying intermittently till target LOD (Loss on Drying) achieve (NMT: 1.0% at 105°C).

[0096] • Sift the pellets through 14# / 25# sieve and label as sifted material ready for seal coating.

[0097] 2. Seal Coating:

[0098] • Disperse hydroxy propyl methyl cellulose 5 cps in isopropyl alcohol under stirring. Add dichloromethane in it and continue stirring to get clear solution, add homogenized talc and stir for 10 - 20 minutes then add triethyl citrate under stirring.

[0099] • Spray the above coating solution till desired weight gain achieved, dry the seal coated pellets in FBC (Fluidized Bed Coater) with inlet temperature of 45 °C for 20 min.

[0100] • Sift the dried pellets through 14# / 25# sieve. Collect the sifted pellets in double polythene lined HDPE (High-density polyethylene) drums and label as sifted seal coated pellets- ready for extended release coating.

[0101] 3. Extended Release Coating:

[0102] • Add ethyl cellulose 7 cps in Isopropyl alcohol under stirring then add dichloromethane under continue stirring to get uniform dispersion. Then add purified talc under stirring then add triethyl citrate until homogenous solution is formed.

[0103] • Load the sifted material in FBC (Fluidized Bed Coater) and dry the pellets with Inlet temperature of 45°C for 30 mins.

[0104] • Sift the dried pellets through 14# / 25# sieve, Collect the sifted pellets in double polythene lined HDPE (High-density polyethylene) drums and label as extended release coated pellets.

[0105] • Fill pellets in capsule size “1”. Table 5: Example 5

[0106] Manufacturing Procedure:

[0107] 1. Core Preparation: • Sift Trimetazidine Dihydrochloride, microcrystalline cellulose, glyceryl dibehenate through 30#

[0108] • And prepare binder solution of povidone K30 in purified water.

[0109] • Granulate above material using binder in Rapid mixer granulator. Check the integrity of screen before and after use and assemble the screen of 1.00 mm to extruder. Collect extrudes in SS container (stainless steel) having in-process stage label as extrudes ready for the spheronization. Discharge and collect the spheronized pellets in SS container (stainless steel) having in-process stage label as wet pellets - ready for drying, Set the inlet temperature 55 - 60°C of FBC (fludized bed coater) and dry the pellets for 2 Hrs, check the LOD (loss on drying) and continue drying intermittently till target LOD (loss on drying) achieve (NMT: 1.0% at 105°C), • Sift the pellets through 14# / 25# sieve and label as sifted material ready for seal coating.

[0110] 2. Seal Coating:

[0111] • Disperse hydroxy propyl methyl cellulose 5 cps in isopropyl alcohol under stirring. Add dichloromethane in it and continue stirring to get clear solution, add homogenized talc and stir for 10 - 20 minutes then add triethyl citrate under stirring.

[0112] • Spray the coating solution till desired weight gain achieved, dry the seal coated pellets in FBC (fludized bed coater) with inlet temperature of 45°C for 20 min.

[0113] • Sift the dried pellets through 14# / 25# sieve. Collect the sifted pellets in double polythene lined HDPE (High-density polyethylene) drums and label as sifted seal coated pellets- ready for extended release coating.

[0114] 3. Extended Release Coating:

[0115] • Add hydroxyl propyl methyl cellulose in isopropyl alcohol under stirring then add ethyl cellulose 7 cps under stirring then add dichloromethane under continue stirring to get uniform dispersion. Then add Purified talc under stirring and add triethyl citrate until homogenous solution formed.

[0116] • Load the sifted material in FBC (fluidized bed coater) and dry the pellets with inlet temperature of 45°C for 30 mins,

[0117] • Sift the dried pellets through 12# and 30# (1700 micron to 600 micron) sieve, collect the sifted pellets in double polythene lined HDPE (High-density polyethylene) drums and label as seal coated pellets.

[0118] • Fill pellets in capsule size “1”.

[0119] Table 6: Example 6, 7, 8 & 9

[0120] Manufacturing Procedure:

[0121] Formulation example 6 to example 9 developed using wet granulation method.

[0122] 1. All the ingredients from serial no. 1 to 7 from above table were weighed and passed through 40#. The said ingredients were blended in planetary mixer for 20 min.

[0123] 2. Prepare binder solution of polyvinyl pyrrolidone in isopropyl alcohol.

[0124] 3. By using mixture of step 1 and binder solution in step 2 to form a wet mass.

[0125] 4. The wet mass was passed through multi mill having 8 mm screen. The wet granules dried in fluidized bed dryer at 40°C for 30 min. Dried granules were then passed through multi mill having 2 mm screen.

[0126] 5. The dried granules were finally passed through 20#. The dried granules are lubricated using talc and magnesium stearate in a blender for 5 min.

[0127] 6. The granules were then compressed using 11 mm round flat faced punches with beveled edges. Tablet weight was set at 250 mg with hardness of 5-6 kg / cm2. Table 7: Example 10

[0128] Manufacturing Procedure:

[0129] 1. Core Preparation:

[0130] • Sift Trimetazidine Dihydrochloride, microcrystalline cellulose, ethyl cellulose through 30#.

[0131] • Prepare binder solution of povidone K30 in purified water. Granulate core material using binder.

[0132] • Extrude material using 1.2 mm screen at suitable speed and suitable time, spheronize extrudes at suitable speed and time. Dry material at 50-60°C, and sift through 12# and 30# (1700 micron to 600 micron) sieve; sifted material ready for seal coating. . Seal Coating:

[0133] • Disperse hydroxy propyl methyl cellulose 5 cps in isopropyl alcohol under stirring. Add dichloromethane in it and continue stirring to get clear solution, add homogenized talc and stir for 10 - 20 minutes then add triethyl citrate under stirring.

[0134] • Spray the coating solution till desired weight gain achieved, dry the seal coated pellets in FBC (fluidized bed coater) with inlet temperature of 45°C for 20 min.

[0135] • Sift the dried pellets through 14# / 25# sieve. Collect the sifted pellets in double polythene lined HDPE (High-density polyethylene) drums and label as sifted seal coated pellets- ready for extended release coating.

[0136] 4. Extended Release Coating:

[0137] • Add hydroxyl propyl cellulose in isopropyl alcohol under stirring then add ethyl cellulose 20 cps under stirring then add dichloromethane under continue stirring to get uniform dispersion. Then add purified talc under stirring then add triethyl citrate until homogenous solution formed. • Load the sifted material in FBC (fludised bed coater) and dry the pellets with inlet temperature of 45°C for 30 mins,

[0138] • Sift the dried pellets through 12# and 30# (1700 micron to 600 micron) sieve, collect the sifted pellets in double polythene lined HDPE (High-density polyethylene) drums and label as seal coated pellets.

[0139] • Fill pellets in capsule size “2”.

Claims

We Claim1) An extended release composition of Trimetazidine or salt thereof in the form of pellet, wherein pellet comprises a) A core comprising Trimetazidine or salt thereof along with one or more pharmaceutical acceptable excipients b) Optionally seal coating c) Extended release coating of polymer over the core.2) The extended release composition of Trimetazidine or salt thereof as claimed in claim 1, wherein core comprises one or more extended release polymer.3) The extended release polymer as claimed in claim 1, may be selected from the group consisting of ethyl cellulose, polyethylene oxide, acrylates, methyl cellulose, cellulose acetate, or stearic acid.4) The extended release composition as claimed in claim 1, wherein core of the composition is manufactured by matrix technology using extrusion and spheronization method.5) The extended release composition as claimed in claim 1; wherein percentage ofTrimetazidine or salt thereof is in the range of 15 to 55 % and percentage of extended release polymer is in the range of 5 to 60% by weight of composition.6) The extended release composition as claimed in claim 1; wherein the ratio ofTrimetazidine or salt thereof to extended release polymer is ranges from 0.3: 1 to2.5: 1.7) The extended release composition of Trimetazidine or salt thereof as claimed in claim 1 may be in the form of pellet, capsule, tablet, sachet, granules or beads.8) The extended release composition as claimed in claim 1 wherein composition comprising one or more pharmaceutically acceptable excipient is selected from the group consisting of Extend release polymer, Diluent, Binder, Plasticizer, Antitacking agent, Lubricant, Glidant, Coating polymer, Alkalizer and Processing solvent.9) The extended release composition as claimed in claim 1 wherein Extend release polymer are selected from ethyl cellulose, polyethylene oxide, Polyacrylate polymer, cellulose ethers polymer, stearic acid, glyceryl dibehenate or mixture thereof; Diluents are microcrystalline cellulose, lactose or mixture thereof; Binders arePovidone, Hydroxy propyl methyl cellulose; Plasticizer is triethyl citrate; Antitacking agent is talc; Lubricant is magnesium stearate; Glidant is talc; Coating polymers are ethyl cellulose, hydroxyl propyl cellulose; Alkalizer is dibasic calcium phosphate and Processing solvents are isopropyl alcohol, methylene dichloride.10) The process of manufacturing extended release composition of Trimetazidine involve steps of a) Mixing the Trimetazidine or salt thereof, extended release polymer optionally along with one or more pharmaceutically acceptable excipient b) Mixing binder along with solvent to form the binder solution c) Mixing mixture formed in step a) with binder solution formed in step b) to form the dump mass. d) Extrusion spheronization of the dump mass formed in step c) to form the core of Trimetazidine pellet. e) Optionally coating the core with seal coating polymer to form the seal coated core f) Coating the seal coated core with coating comprising extended release polymer.