Prolonged release pharmaceutical composition of trimetazidine dihydrochloride

Abstract

The present invention relates to a prolonged-release pharmaceutical composition of trimetazidine dihydrochloride designed to provide controlled and sustained drug release over an extended period. The composition comprises trimetazidine dihydrochloride in combination with one or more pharmaceutically acceptable excipients selected to achieve a desired release profile, improved patient compliance, and enhanced therapeutic effectiveness. The invention further provides a process for preparing the prolonged-release composition, which includes blending, granulating, and compressing the active ingredient with release-modifying polymers and other formulation components. The composition demonstrates consistent in vitro release characteristics and offers a stable and efficient dosage form for the management of conditions requiring trimetazidine therapy.

Description

[0001] PROLONGED RELEASE PHARMACEUTICAL COMPOSITION OF TRIMETAZIDINE DIHYDROCHLORIDE

[0002] Field of Invention 1. The present invention relates to a prolonged release pharmaceutical composition of trimetazidine dihydrochloride. The invention further relates to a process for preparation of the said pharmaceutical composition.

[0003] Background 2. Trimetazidine is a piperazine compound. It is chemically l-(2,3,4- trimethoxybenzyl) piperazine dihydrochloride. 3. Vastarel® XR 80 mg has been approved in the form of prolonged-release hard capsule. It is indicated for the symptomatic treatment of stable angina pectoris in patients inadequately controlled or intolerant to first line therapies. 4. Trimetazidine prolonged or sustained release preparation for oral administration with different approaches is available in the prior art. 5. US10117838 describes a pharmaceutical composition for prolonged release of trimetazidine with an inner phase comprising trimetazidine dihydrochloride coated on a neutral core and an outer layer consisting of a retardant, an anti-agglomerant (talc), and a plasticizer. The anti-agglomerant (talc) used is 100% to 200% of the weight of the retardant. It further teaches that in industrial scale production, when the anti-agglomerant is absent in the outer phase of the pharmaceutical compositions, irregular shaped minigranules, numerous cracks in the minigranules coating and even amalgamations between the mini granules are produced. These coating defects cause major modifications to the in vitro dissolution kinetics, especially profiles of accelerated dissolution. In an industrial scale production, if the anti-agglomerant is in excess, then the minigranules obtained have an irregular and flaky surface due to the presence of excessive talc sticking to the surface of the minigranules. These minigranules have dissolution kinetics that are greatly accelerated and even immediate-release kinetics. 6. EP 1448173 describes a process for the preparation of trimetazidine dihydrochloride microbeads in three stages. Stage I involves preparation of drug core by spraying an aqueous solution of trimetazidine hydrochloride with binder, anti-tack agent and glidants on inert seeds such as sugar spheres. Stage II involves coating of the drug cores with water insoluble polymer, while stage III involves further coating with another polymer and antitack agent in fluid bed processor to produce sustained release microbeads. 7. CN102133195 discloses a sustained-release micro-pill composition comprising a core, a trimetazidine hydrochloride drug layer and a sustained-release coating layer. Talc is used during coating process to remove static charge and prevent adhesion. 8. EP2391353 describes a once daily sustained release pharmaceutical composition comprising a core comprising trimetazidine, one or more sustained release polymer and one or more pharmaceutically acceptable excipient including talc, wherein the core is further coated with a functional polymer. 9. EP0673649 describes a pharmaceutical composition for prolonged release of trimetazidine, wherein the prolonged release of the trimetazidine is controlled by waterinsoluble polymer and plasticizer.

[0004] Objects of Invention 0. The object of the invention is to provide a prolonged release pharmaceutical composition of trimetazidine dihydrochloride that exhibits desired in-vitro cumulative drug release profile of more than or equal to 80% of the labelled amount at the end of 24 hours. 1. Another object of the invention is to provide the said pharmaceutical composition comprising 80mg of trimetazidine dihydrochloride in prolonged release capsule dosage form and is bioequivalent to Vastarel® XR 80mg capsules. 2. Yet another object of the invention is to provide the said pharmaceutical composition, without the use of any anti-tacking agent in the prolonged release layer of the composition. 3. Yet another object of the invention is to provide the said pharmaceutical composition, without the use of any anti-tacking agent in the composition. It is pertinent to note that all the prior art compositions use anti-tacking agents. 4. Yet another object of the invention is to provide a process for the preparation of such pharmaceutical compositions.

[0005] Summary 5. The present invention relates to prolonged release pharmaceutical composition comprising trimetazidine dihydrochloride that exhibits desired in-vitro cumulative drug release profile of more than or equal to 80% of the labelled amount at the end of 24 hours. The prolonged release composition or the prolonged release layer of the composition is devoid of the anti-tacking agent such as talc. The present invention also provides a process for the preparation of such compositions.

[0006] Detailed Description 6. The present invention provides a prolonged release pharmaceutical composition comprising trimetazidine dihydrochloride, wherein the composition comprises: a drug layer; an intermediate coating layer; and a prolonged release layer. 7. Preferably, the trimetazidine dihydrochloride prolonged release pharmaceutical compositions of the present invention comprises: a drug layer from 15% to 85% by weight of composition; an intermediate coating layer from 2% to 30% by weight of composition; and a prolonged release layer from 8% to 30% by weight of composition. 8. In one of the embodiments of the present invention, the prolonged release pharmaceutical composition comprises: a) an inert core; b) a drug layer comprising of trimetazidine dihydrochloride and a binder; c) an intermediate coating layer (seal coating) comprising of a hydrophilic polymer or a hydrophilic ingredient; and d) a prolonged-release coating layer (prolonged release coating), comprising of one or more prolonged release polymers. 9. In another embodiment of the present invention, the prolonged release pharmaceutical composition comprises: a) an inert core; b) a drug layer comprising of trimetazidine dihydrochloride and a binder; c) an intermediate coating layer (seal coating) comprising of a hydrophilic polymer or a hydrophilic ingredient; and d) a prolonged-release coating layer (prolonged release coating), comprising of one or more prolonged release polymers; wherein the composition is free of anti-tacking agent. 0. In yet another embodiments of the present invention, the prolonged release pharmaceutical compositions comprise: a) an inert core; b) a drug layer comprising of trimetazidine dihydrochloride and a binder; c) an intermediate coating layer (seal coating) comprising of a hydrophilic polymer or a hydrophilic ingredient; and d) a prolonged-release coating layer (prolonged release coating) comprising of one or more prolonged release polymers and a plasticizer; wherein the composition is free of anti-tacking agent. 1. In yet another embodiment of the present invention, the prolonged release pharmaceutical compositions comprise: a) an inert core; b) a drug layer comprising of trimetazidine dihydrochloride and a binder; c) an intermediate coating layer (seal coating) comprising of a hydrophilic polymer or a hydrophilic ingredient; and d) a prolonged-release coating layer (prolonged release coating) comprising of one or more prolonged release polymers; wherein the prolonged release layer is free of anti-tacking agent. 2. In yet another embodiment of the invention, the prolonged release pharmaceutical compositions comprise: a) an inert core; b) a drug layer comprising of trimetazidine dihydrochloride and a binder; c) an intermediate coating layer (seal coating) comprising a hydrophilic polymer or a hydrophilic ingredient; and d) a prolonged-release coating layer (prolonged release coating), comprising of one or more prolonged release polymers and a plasticizer; wherein the prolonged release layer is free of anti-tacking agent. 3. In yet another embodiment of the invention, the prolonged release pharmaceutical compositions comprising trimetazidine dihydrochloride containing a prolonged release coating layer comprising of one or more prolonged release polymers and optionally, a plasticizer, wherein the prolonged release layer or the prolonged release composition is free of anti-tacking agent such as talc. 4. The present invention also provides a process for the preparation of the prolonged release pharmaceutical composition comprising trimetazidine dihydrochloride that comprise steps of:

[0007] 1) providing an inert core;

[0008] 2) applying a drug layer comprising trimetazidine dihydrochloride and a binder on the inert core to obtain drug core or drug pellets;

[0009] 3) applying an intermediate coating layer (seal coat) comprising a hydrophilic polymer or a hydrophilic ingredient on the drug pellets to obtain seal coated pellets;

[0010] 4) applying a prolonged-release coating layer (prolonged release coating) comprising of one or more polymers and optionally a plasticizer on the seal coated pellets; and

[0011] 5) optionally blending the pellets with a lubricating agent to obtain prolonged release pellets. 5. The prolonged release composition is preferably in the form of pellets or can be filled in capsule of desired size ‘00’ to size ‘5’, preferably capsule size ‘2’ or size ‘3’ to provide a dose of 80mg of trimetazidine dihydrochloride. 6. The capsule dosage form of the present invention is administered orally to a patient in need thereof for the symptomatic treatment of stable angina pectoris who are inadequately controlled by or intolerant to first-line antianginal therapies. 7. These prolonged release pellets or capsule when tested in-vitro in 900 ml phosphate buffer, pH 6.8 at 50 rpm at 37.0°C ± 0.5°C using USP type II apparatus (paddle method) exhibited cumulative drug release profile of more than or equal to 80% (80% to 100%) at the end of 24 hours. 8. The trimetazidine dihydrochloride prolonged release capsule (80mg) when tested in-vivo in human subjects under fed and fasting conditions was bioequivalent to the marketed product Vastarel® XR 80mg capsules. 9. Thus, in accordance with the present invention, the three essential stages of the manufacturing process, that can be continuously carried out in a single step, for the preparation of trimetazidine dihydrochloride prolonged release composition, preferably in the form of capsule, are as follows:

[0012] Stage I: Preparation of drug core (drug pellets)

[0013] Stage II: Preparation of Intermediate coating layer (seal pellets)

[0014] Stage III: Preparation of prolonged release coating layer (prolonged release pellets)

[0015] Stage I: Preparation of drug cores (drug pellets): 0. The first stage in manufacturing trimetazidine dihydrochloride prolonged release pellets is to prepare a drug core or drug pellets. This is carried out by applying a drug layer on inert cores to obtain drug cores. The process comprise steps of: dispersing and / or dissolving a binder in a suitable solvent to obtain binder dispersion / solution; adding trimetazidine dihydrochloride with stirring to obtain drug-binder dispersion / solution; optionally, filtering the resulting drug - binder dispersion / solution through a suitable mesh such as 100 mesh; spraying the drug - binder dispersion / solution on inert cores in a bottom spray fluid bed processor to obtain drug cores / drug pellets; drying the drug cores / drug pellets, preferably in the same equipment. 1. The drug layer is preferably from about 30% to about 80% by weight, more preferably from about 40% to about 70% by weight and most preferably from about 50% to about 60% by weight of the composition. 2. The content of trimetazidine dihydrochloride in drug core is about 20% to about 90% by weight, preferably from about 50% to about 80% by weight, and more preferably from about 60% to about 75% by weight of the drug core. 3. The "inert core” is selected from sugar spheres, microcrystalline cellulose pellets, dibasic calcium phosphate pellets, mannitol pellets, polyols pellets, glass beads, and the like. The particle sizes of the inert cores may vary from about 100 pm to about 1400 pm, preferably from about 200 pm to about 1100 pm, most preferably, from about 500 pm to about 750 pm. The inert core is from about 10% and about 30% by weight of the composition, preferably from about 15% to about 25%, more preferably from about 17.5% to about 22.5% by weight of the composition. 4. The binder is selected from hydroxypropyl methylcellulose (HPMC), hydroxypropyl cellulose (HPC), carboxymethylcellulose sodium, methylcellulose, hydroxyethyl cellulose, povidone, sugar, microcrystalline cellulose or mixtures thereof, preferably selected from hydroxypropyl methylcellulose and povidone. The binder is from about 0.5% to about 15% by weight of the composition, preferably from about 1% to about 12%, more preferably from about 2% to about 8%, most preferably from about 3% to about 6% by weight of the composition. 5. Hydroxypropyl methylcellulose used as binder is available in various viscosity grades. HPMC of very low viscosity grade which has a nominal viscosity of less than or equal to about 50 mPas (as measured by the method disclosed in USP) are preferred. Examples of very low viscosity HPMC include HPMC of viscosity grade of 3mPas, 5mPas, 6mPas, lOmPas, 15 mPas and 50mPas. 6. In an embodiment of the present invention, the drug core (drug pellets) comprises sugar sphere (inert core) from about 12% to about 30% by weight composition; trimetazidine dihydrochloride from about 40% to about 75% by weight of composition, and hydroxypropyl methylcellulose (binder) from about 1% to about 10% by weight of the composition.

[0016] Stage II: Preparation of Intermediate coating layer (seal pellets) 7. The second stage in manufacturing trimetazidine dihydrochloride prolonged release pellets is to apply a coat as intermediate coating layer on drug core or drug pellets to obtain intermediate layer coated pellets (seal coated pellets). The process comprises steps of: dispersing and / or dissolving a hydrophilic polymer or a hydrophilic ingredient in a suitable solvent to obtain a dispersion / solution; optionally, filtering the resulting dispersion / solution through a suitable mesh such as 100 mesh; spraying the said dispersion / solution on drug cores in a bottom spray fluid bed processor to obtain intermediate layer coated drug cores / pellets (seal coated drug cores / pellets); drying the intermediate layer coated drug cores / pellets, preferably in the same equipment. 8. The hydrophilic polymer or the hydrophilic ingredient is selected from hydroxypropyl methylcellulose (HPMC), hydroxyethyl cellulose, hydroxypropyl cellulose, hydroxyethyl methylcellulose, carboxymethylcellulose, polyethylene glycol, polyethylene oxides, povidone, sucrose, lactose, microcrystalline cellulose, gums, starch, polyalcohols or mixtures thereof, preferably selected from hydroxypropyl methylcellulose (HPMC) and povidone. The hydrophilic polymer or the hydrophilic ingredient is from about 1% to about 18% by weight of the composition, preferably from about 2% to about 16%, more preferably from about 3% to about 14%, most preferably from about 4% to about 12% by weight of the composition. 9. In an embodiment of the present invention, the hydrophilic polymer or the hydrophilic ingredient is soluble in water. 0. Very low viscosity grade of HPMC having viscosity (as measured by method disclosed in USP) less than or equal to about 50 mPas (cps) for example 3mPas, 5mPas, 6mPas, lOmPas, 15 mPas and 50mPas are preferred as hydrophilic polymer or hydrophilic ingredient. 1. The intermediate coating layer is preferably from about 1% to about 20% by weight, more preferably from 3% to 15% by weight, most preferably from 6% to 12% by weight of the composition.

[0017] Stage III: Preparation of prolonged release coating layer (prolonged release pellets)2. The third stage in manufacturing trimetazidine dihydrochloride prolonged release pellets is to apply a prolonged release coating layer on intermediate layer coated pellets (seal coated pellets) to obtain prolonged release coated pellets (prolonged release pellets). The process comprises steps of: dispersing and / or dissolving one or more prolonged release polymers (release controlling polymers) in a suitable solvent to obtain polymer dispersion / solution; optionally, adding plasticizer with stirring; optionally, filtering the resulting mixture through a suitable mesh such as 100 mesh; spraying the resulting mixture on intermediate layer coated pellets (seal coated pellets) in a bottom spray fluid bed processor to obtain prolonged release pellets; drying the prolonged release pellets, preferably in the same equipment. 3. Prolonged release polymer is selected from one or more cellulose derivatives, acrylates, polymethacrylates (methacrylic acid co-polymers), waxes, or mixtures thereof. 4. Preferably, the prolonged release polymer is selected form ethyl cellulose, low viscosity HPMC, polymethacrylates (e.g. Eudragit RL, Eudragit RS, Eudragit NE), cellulose acetate, cellulose acetate butyrate, cellulose acetate propionate, cellulose acetate phthalate, hydroxypropyl methylcellulose acetate succinate, hydroxypropyl methylcellulose phthalates or mixtures thereof. 5. HPMC of low viscosity grade which has a nominal viscosity of (as measured by method disclosed in USP) greater than 50 mPas (cps) are preferred. Examples of low viscosity HPMC include HPMC of viscosity grade of lOOmPas, 250 mPas, 400mPas, and 750 mPas. 6. The prolonged release coating layer comprises one or more prolonged release polymers from about 8% to about 30%, preferably from about 8.5% to about 25%, more preferably from about 10% to 20%, most preferably from 12% to 16% by weight of the composition. 7. In an embodiment of the invention, the one or more polymers in the prolonged release layer is a mixture of ethyl cellulose and hydroxypropyl methylcellulose preferably from about 9% to 15% by weight of the composition. 8. In another embodiment of the invention, the prolonged release polymer is a mixture of ethyl cellulose and low viscosity HPMC (Methocel K100LV). 9. In yet another embodiment of the invention, the prolonged release polymer is a mixture of ethyl cellulose and low viscosity HPMC (Methocel K100LV) in the ratio of about 90: 10 to about 50:50, preferably about 85: 15 to 60:40, more preferably about 80:20 to 70:30, most preferably from about 74:26 to 78:22. 0. Plasticizer in the prolonged release layer is selected from triethyl citrate, tributyl acetyl citrate, acetyl triethyl citrate, triacetin, polyethylene glycol, miglyol, cetyl alcohol, diethyl phthalate, dibutyl phthalate, propylene glycol, or mixtures thereof. 1. Plasticizers in the prolonged release layer is from about 5% to about 40%, preferably from about 7.5% to about 30%, more preferably from about 10% to about 20%, most preferably from about 12.5% to about 17.5% by weight of prolonged release polymer(s). 2. In an embodiment of the invention the preferred plasticizer is tributyl acetyl citrate from 0.1% to 5%, preferably from 1% to 4%, more preferably from 2% to 3%, and most preferably from 2.25% to 2.75% by weight of composition. 3. In another embodiment of the invention, the prolonged release coating layer comprises ethyl cellulose from about 9% to about 13% by weight of composition, low viscosity hydroxypropyl methyl cellulose (HPMC K100LV) from about 2% to about 4% by weight of composition, and tributyl acetyl citrate from about 1.5% to about 3% by weight of composition. 4. Solvent used in the preparation of drug cores / intermediate coated pellets / prolonged release pellets is selected from water, methanol, ethanol, isopropanol, acetone, dichloromethane, or mixtures thereof. Preferable solvent is selected from water, isopropanol, or mixtures thereof. 5. Pellets from stage 111 are optionally blended with a lubricating agent selected from calcium stearate, magnesium stearate, or stearic acid. These prolonged release pellets are filled into capsules, preferably of size ‘2’ or size ‘3’ for a dose of 80 mg of trimetazidine dihydrochloride. 6. The prolonged release pellets or capsules are analyzed in-vitro in phosphate buffer pH 6.8, Type II USP Paddle with PTFE Filter, RPM-50, Temperature 37.0°C ± 0.5°C, Media Volume: 900 mL 7. The filled capsules when analyzed in-vitro comply with the following specifications: i) not more than 10%, preferably not more than 5% of the labelled amount (80mg) of trimetazidine dihydrochloride is released at the end of 2 hours; ii) more than or equal to 80%, preferably more than or equal to 85% of the of the labelled amount (80mg) of trimetazidine dihydrochloride is released at the end of 24 hours. 8. Intermediate coating layer of the present invention which is coated on the drug cores surprisingly helps to achieves the desired in-vitro drug release profile thereby meeting desired specifications. 9. It is important to note that prior art US10117838 teaches the essential use of antitacking agent (talc) in the outer layer to achieve uniform minigranules. US10117838 teaches that in the absence of anti-agglomerant in the outer phase of the pharmaceutical compositions, irregular minigranules, numerous cracks in the minigranules' coating and even amalgamations between the minigranules are observed. These coating defects cause major modifications to the in vitro dissolution kinetics, especially profiles of accelerated dissolution. US 10117838 further teaches that excess of anti-agglomerant in the outer phase of the pharmaceutical compositions in industrial scale production, results in minigranules with irregular and flaky surface. 0. The present invention teaches away from the prior art US10117838. The present invention does not use anti-agglomerant in the outer layer and yet achieves the desired results. In an embodiment of the present invention, the prolonged release composition does not contain talc i.e. the composition is free anti-agglomerant. Intermediate coating layer of the present invention which is coated on the drug cores surprisingly helps to achieves the desired in-vitro drug release profile of the above-mentioned specifications and the desired results. 1. The invention is described with non-limiting examples. 2. Examples 1 to 3:

[0018] Prolonged Release Capsule Comprising Trimetazidine dihydrochloride

[0019] Stage - Preparation of drug cores:

[0020] HPMC 6cps (mPas) was dispersed and dissolved in a mixture of water and isopropyl alcohol. Trimetazidine dihydrochloride was added to it with stirring. The resulting drug solution was sprayed on sugar sphere in a fluid bed bottom spray processor followed by drying to obtain drug cores.

[0021] Stage - Preparation of seal coated pellets

[0022] HPMC 6cps (mPas) was dispersed and dissolved in a mixture of water and isopropyl alcohol. The resulting solution was sprayed on drug cores in a fluid bed bottom spray processor followed by drying to obtain seal coated pellets.

[0023] Stage III - Preparation of prolonged release pellets:

[0024] Ethyl cellulose was dispersed and dissolved in a mixture of water and isopropyl alcohol. HPMC K100LV was slowly added to the above mixture under stirring, followed by addition of tributyl acetyl citrate. The resultant mixture was sprayed on seal coated pellets in a fluid bed bottom spray processor followed by drying to obtain prolonged release pellets. These pellets were blended with magnesium stearate and filed into size ‘2’ capsule for a dose of 80mg of trimetazidine dihydrochloride. 3. Comparative example 4:

[0025] Prolonged Release Capsule Comprising Trimetazidine dihydrochloride

[0026] Stage - Preparation of drug cores:

[0027] HPMC 6cps (mPas) was dispersed and dissolved in a mixture of water and isopropyl alcohol. Trimetazidine dihydrochloride was added to it with stirring. The resulting drug solution was sprayed on sugar sphere in a fluid bed bottom spray processor followed by drying to obtain drug cores.

[0028] Stage - Preparation of prolonged release pellets:

[0029] Ethyl cellulose was dispersed and dissolved in a mixture of water and isopropyl alcohol. HPMC K100LV was slowly added to the above mixture under stirring, followed by addition of tributyl acetyl citrate. The resultant mixture was sprayed on seal coated pellets in a fluid bed bottom spray processor followed by drying to obtain prolonged release pellets. These pellets were blended with magnesium stearate and filed into size ‘2’ capsule for a dose of 80mg of trimetazidine dihydrochloride. 4. Example 5:

[0030] Dissolution Studies:

[0031] The prolonged release pellets or capsules prepared as per examples 1-3 and comparative 4 were analyzed in-vitro in phosphate buffer pH 6.8, Type II USP Paddle with PTFE Filter, RPM-50, Temperature 37.0°C ± 0.5°C, Media Volume: 900 mL Table I: Drug Release profile for prolonged release capsules of examples 1 - 4

[0032] It is evident from table 1 that the prolonged release capsules of examples 1 - 3, in accordance with the present invention, exhibits the desired in-vitro drug release profile, wherein not more than 10% of the labelled amount (80mg) of trimetazidine dihydrochloride is released at the end of 2 hours and more than or equal to 80% of the of the labelled amount (80mg) of trimetazidine dihydrochloride is released at the end of 24 hours.

[0033] In distinct contrast, the prolonged release capsules of the comparative example 4 which do not contain an intermediate coating layer, thereby not in accordance with the present invention, does not exhibit the desired in-vitro drug release profile i.e. more than 10% of the labelled amount (80mg) of trimetazidine dihydrochloride is released at the end of 2 hours and less than 80% of the of the labelled amount (80mg) of trimetazidine dihydrochloride is released at the end of 24 hours. 5. Example 6:

[0034] Stability Studies:

[0035] The prolonged release capsules prepared as per example 3 for a dose of 80 mg were packed in Alu- Alu blister. These blisters were subjected to accelerated stability condition at 40°C / 75 %RH and long-term condition at 25 °C / 60 % RH. The capsules were found to be stable as per ICH guidelines at least for a period of 3 months. Dissolution:

[0036] Impurity:

[0037] NMT - Not More Than

[0038] NDT - Not Detected

[0039] BQL - Below quantification limit

[0040] 0066. Example ?:

[0041] Comparative In-Vivo Bioequivalence studies

[0042] An open label, balanced, randomized, single dose, crossover bioequivalence studies of trimetazidine dihydrochloride capsules 80mg (test product) of example 3 of the present invention was carried out in normal healthy human subject using Vastarel® XR capsules (Trimetazidine Dihydrochloride Extended-Release Hard Capsules 80mg) distributed by Laboratories Servier (reference product).

[0043] The bioequivalence studies were carried out under fasting (n=15) and fed conditions (n=15). The % ratio of the geometric mean and the 90 % CI for log transformed data are presented in table 2.

[0044] 0067. Table 2: Bioequivalence Data

[0045] Based on the results of the bioequivalence studies, the trimetazidine capsules were found to be bioequivalent to commercially available Vastarel® XR 80mg capsules.

[0046] 0068. Thus, the composition of the present invention provides the desired prolonged release of trimetazidine dihydrochloride and was found to be bioequivalent to Vastarel® XR 80mg capsules. The composition was also found to be stable under accelerated conditions (40°C / 75%RH) at least for a period of 3 months.

Claims

Claims1. A dual-layer coated modified-release pharmaceutical composition comprising: a. a core comprising trimetazidine or a pharmaceutically acceptable salt thereof and one or more pharmaceutically acceptable excipients; b. a first coating layer, comprising one or more pH-dependent polymer(s) or one or more time -dependent polymer(s), and one or more plasticizer(s); and c. a second coating layer, comprising one or more pH-dependent polymer(s) or one or more time -dependent polymer(s), and one or more plasticizer(s); wherein, when first layer comprises one or more pH-dependent polymer(s), second layer comprises one or more time -dependent polymer(s), and vice versa.

2. The composition according to claim 1, wherein first layer comprises one or more pH- dependent polymer(s) and one or more plasticizer(s), and second layer comprises one or more time-dependent polymer(s) and one or more plasticizer(s).

3. The composition according to claim 1, wherein the pH-dependent polymer(s) of first layer are selected from: methacrylic acid-methacrylate copolymers, polyvinyl acetate phthalate, cellulose acetate phthalate, hydroxypropyl methylcellulose phthalate, and hydroxypropyl methylcellulose acetate succinate.

4. The composition according to claim 1, wherein the time-dependent polymer(s) of second layer are selected from: ammonio methacrylate copolymers type A or B, ethyl cellulose, poly(methyl methacrylate), poly(butyl methacrylate), methacrylic acid copolymer types A, B or C, polyvinyl acetate, cellulose acetate, cellulose triacetate, poly(ethyl acrylate), poly(butyl methacrylate), poly(isobutyl methacrylate), poly(hexyl methacrylate), poly(octadecyl acrylate), and waxes including carnauba wax, beeswax, microcrystalline wax, fatty alcohols, ozokerite, and ceresin.

5. The composition according to claim 1, wherein the pH-dependent polymer in first layer is methacrylic acid-methyl methacrylate copolymer (1:2).

6. The composition according to claim 1, wherein the time-dependent polymer in second layer is an ammonio methacrylate copolymer.

7. The composition according to claim 1, wherein the plasticizer(s) of first layer and second layer are selected from: acetyl tributyl citrate, glycerol triacetate, acetyl triethyl citrate, acetyl ethyl citrate, diethyl sebacate, dibutyl sebacate, diethyl or dibutyl phthalate, polyethylene glycol, glycerol, and propylene glycol.

8. The composition according to claim 1, wherein the plasticizer(s) in first layer and second layer are the same.

9. The composition according to claim 1, wherein the plasticizer(s) in first layer and second layer are different.

10. The composition according to claim 1, wherein the plasticizer in first layer and second layer is triethyl citrate.

11. The composition according to claim 1, wherein the core comprises trimetazidine dihydrochloride.

12. The composition according to claim 1, wherein the core comprises particles, granules, pellets, tablets, or capsules.

13. The composition according to claim 1, wherein the core comprises pellets.

14. The composition according to claim 1, wherein the pellets are compressed into tablets.

15. The composition according to claim 1, wherein the core comprises 20-80% w / w of trimetazidine dihydrochloride, based on the total weight of the core.

16. The composition according to claim 1, wherein the first coating layer is present in an amount of 3-8% w / w of the total composition.

17. The composition according to claim 1, wherein the second coating layer is present in an amount of 5-12% w / w of the total composition.

18. The composition according to claim 2, wherein the pH-dependent polymer in first layer has a dissolution threshold pH of 5.0-6.8.

19. The composition according to claim 2, wherein the time-dependent polymer in second layer has a permeability suitable for releasing 40-70% drug between 6-10 hours.

20. The composition according to claim 1, wherein first layer comprises methacrylic acid- methyl methacrylate copolymer (1 :2) in an amount of 30-70% w / w of the total weight of first layer.

21. The composition according to claim 1, wherein second layer comprises ammonio methacrylate copolymer type B in an amount of 40-80% w / w of the total weight of second layer.

22. The composition according to claim 1, wherein the plasticizer content in each coating layer is 5-20% w / w relative to the polymer content.

23. The composition according to claim 1, wherein the core comprises microcrystalline cellulose, lactose monohydrate, and povidone as excipients.

24. The composition according to claim 1, wherein the dual-layer coating provides a lag time of 2-4 hours followed by sustained release up to 18-24 hours.

25. The composition according to claim 1, wherein the in-vitro dissolution profile meets: a. Not more than 10% drug release in first 2 hours, b. 20-40% drug release at 6 hours, and c. >80% drug release by 24 hours.

26. The composition according to claim 14, wherein the pellets have aparticle size of 300-800 pm.

27. The composition according to claim 15, wherein the compressed tablets have a hardness of 8-14 kp and a friability less than 1%.

28. The composition according to claim 1, wherein the dual coating is applied using a fluid bed coater with bottom-spray (Wurster) technology.

29. The composition according to claim 1, wherein the pharmaceutical composition is formulated as a modified-release capsule containing coated pellets.

30. The composition according to claim 1, wherein the composition is free of anti-tacking agent.

31. A dual-layer coated modified-release pharmaceutical composition comprising: a. a core comprising trimetazidine dihydrochloride; b. a first coating layer comprising one or more time-dependent polymers; and c. a second coating layer comprising one or more pH-dependent polymers; wherein the order of the two coating layers is selected to achieve a controlled release profile up to 24 hours wherein the composition is free of anti-tacking agent.Dated this 01stDay of December 2025Ajendu Digitally signed by Ajendu Pradeep Pradeep Sohani Date: 2025.12.01 So ha p i 14:23:33 +05'30'Ajendu P SohaniIntellectual Property Rights,Inventia Healthcare Limited

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