EP2187874A2 - Sustained release compositions of trimetazidine and process for preparation thereof - Google Patents

Sustained release compositions of trimetazidine and process for preparation thereof

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Publication number
EP2187874A2
EP2187874A2 EP08852448A EP08852448A EP2187874A2 EP 2187874 A2 EP2187874 A2 EP 2187874A2 EP 08852448 A EP08852448 A EP 08852448A EP 08852448 A EP08852448 A EP 08852448A EP 2187874 A2 EP2187874 A2 EP 2187874A2
Authority
EP
European Patent Office
Prior art keywords
composition
weight
trimetazidine
pharmaceutically acceptable
tablets
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Withdrawn
Application number
EP08852448A
Other languages
German (de)
French (fr)
Inventor
Deepak Anant Hegde
Sandhya Rajendra Shenoy
Harish Tulsidutt Bhatt
Ashok Omray
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
USV Pvt Ltd
Original Assignee
USV Pvt Ltd
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by USV Pvt Ltd filed Critical USV Pvt Ltd
Publication of EP2187874A2 publication Critical patent/EP2187874A2/en
Withdrawn legal-status Critical Current

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Classifications

    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/20—Pills, tablets, discs, rods
    • A61K9/2004—Excipients; Inactive ingredients
    • A61K9/2022—Organic macromolecular compounds
    • A61K9/2031—Organic macromolecular compounds obtained otherwise than by reactions only involving carbon-to-carbon unsaturated bonds, e.g. polyethylene glycol, polyethylene oxide, poloxamers
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/20—Pills, tablets, discs, rods
    • A61K9/2004—Excipients; Inactive ingredients
    • A61K9/2009—Inorganic compounds
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/20—Pills, tablets, discs, rods
    • A61K9/2004—Excipients; Inactive ingredients
    • A61K9/2022—Organic macromolecular compounds
    • A61K9/2027—Organic macromolecular compounds obtained by reactions only involving carbon-to-carbon unsaturated bonds, e.g. polyvinyl pyrrolidone, poly(meth)acrylates
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/20—Pills, tablets, discs, rods
    • A61K9/2004—Excipients; Inactive ingredients
    • A61K9/2022—Organic macromolecular compounds
    • A61K9/205—Polysaccharides, e.g. alginate, gums; Cyclodextrin
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00—Drugs for disorders of the cardiovascular system
    • A61P9/10—Drugs for disorders of the cardiovascular system for treating ischaemic or atherosclerotic diseases, e.g. antianginal drugs, coronary vasodilators, drugs for myocardial infarction, retinopathy, cerebrovascula insufficiency, renal arteriosclerosis

Definitions

  • the present invention relates to sustained release pharmaceutical compositions useful for the treatment of angina pectoris comprising:
  • compositions are in the form of solid dosage forms.
  • the present invention further relates to a process for preparation of said sustained release pharmaceutical compositions.
  • 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 Q 4 H 22 N 2 O 3 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 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 Tmax of around 1.8 +/- 0.7 hours. Since it has a shorter plasma half life, in practice 20mg preparation is given twice or thrice a day in order to ensure relatively constant plasma levels but, due to the fact that it is absorbed quickly, these immediate release forms lead to maximum plasma levels immediately after administration and to a very low plasma level at the time of the next dose, resulting in great differences in peak and trough plasma levels at steady state.
  • Trimetazidine dihydrochloride is regarded as a safe drug in the long-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.
  • Trimetazidine dihyrochloride There are various marketed preparations containing Trimetazidine.
  • the brand VASTAREL from Sender is also marketed as CARDAPTAN, PREDUCTAL MR, IDAPTAN, FLAVEDON MR, TRIZEDON, VASTINAN and VASOREL.
  • VASTAREL prolonged release film-coated tablets 35 mg contain calcium hydrogen phosphate dihydrate, hypromellose, povidone, anhydrous colloidal silica, magnesium stearate, macrogol, titanium dioxide (E171), glycerol, red iron oxide (E172).
  • US3262852 discloses a vasodilative substance, dihydrochloride of 1 -(2,3,4- trimethoxybenzyl) piperazine i.e. Trimetazidine dihyrochloride.
  • US4814176 discloses a sustained release preparation comprising: (a) chitin, 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, does 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.
  • CNl 864680 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 as 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.
  • 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.
  • EP 1108424 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, methyl cellulose 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 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 ultra fine powder of an enteric polymer base as a polymeric matrix and using 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 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 compositions and process for manufacturing of 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.
  • the main object of the invention is to provide 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; together with suitable pharmaceutically acceptable excipients.
  • Another object of the invention is to provide pharmaceutical 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.
  • compositions which releases Trimetazidine in a sustained and reproducible manner over a prolonged period of time to achieve a sustaining effect of Trimetazidine over 10-12 hours period after oral administration.
  • Further object of the invention is to provide compositions of Trimetazidine that demonstrate reliable release rate and facilitated in-vivo absorption for desired period of time.
  • Another object of the invention is to provide sustained release compositions which are useful for the treatment of angina pectoris and has better patient compliance.
  • Another object of the invention is to provide a method of treating a patient suffering from angina pectoris, comprising administering to a patient in need thereof a therapeutically effective amount of sustained release pharmaceutical compositions as described herein.
  • the present invention discloses sustained release pharmaceutical compositions useful for the treatment of angina pectoris comprising Trimetazidine; wherein the compositions are characterized by the absence of cellulose and/or cellulose derivatives as release modifying agents.
  • the present invention provides sustained release pharmaceutical compositions comprising:
  • the present invention provides a process for preparation of 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; together with suitable pharmaceutically acceptable excipients; the said process comprising the steps of : i. preparing an intra-granular composition of Trimetazidine dihydrochloride, release modifying agent/(s) and suitable pharmaceutically acceptable excipients; ii.
  • Fig. 1 shows comparative dissolution profile of Vastarel and tablets prepared according to Example 1. Dissolution was carried out in 0.1N HCL for the first hour and then in pH 6.8 phosphate buffer.
  • Fig. 2 shows comparative dissolution profile of Vastarel and tablets prepared according to Example 2. Dissolution was carried out in 0.1N HCL for the first hour and then in pH 6.8 phosphate buffer.
  • the present invention describes sustained release pharmaceutical compositions useful for the treatment of angina pectoris comprising:
  • the present invention further describes a process for preparation of said sustained release pharmaceutical compositions.
  • Sustained release solid dosage forms such as tablets, capsules or any other solid dosage form may be formulated using the process as described herein.
  • compositions of the present invention releases Trimetazidine in a sustained and reproducible manner over a prolonged period of time to achieve a sustaining effect of Trimetazidine over 10-12 hours period after oral administration.
  • the present invention provides sustained release pharmaceutical compositions useful for the treatment of angina pectoris comprising Trimetazidine; wherein the compositions are characterized by the absence of cellulose and/or cellulose derivatives as release modifying agents.
  • Trimetazidine is present in an amount from about 8.0% to about 50.0% by weight of the total composition.
  • Trimetazidine is present in an amount from 10.0% to 30.0% by weight of the total composition.
  • the preferred pharmaceutically acceptable salt of Trimetazidine is Trimetazidine dihydrochloride.
  • the release modifying agents may be present in an amount from 10.0% to 80.0% by weight of the total composition.
  • the sustained release pharmaceutical compositions of the present invention comprises release- modifying agents that may be selected from at least one of (a) one or more water- soluble materials and/or (b)one or more water insoluble materials and/or (c) one or more water swellable materials; wherein the said compositions are characterized by the absence of cellulose and/or cellulose derivatives as release modifying agents.
  • the ratio of Trimetazidine to release modifying agents is in the range of about 1:0.5 to 1:10; preferably 1:1 to 1:5.
  • the water soluble materials that may be employed include, but are not limited to polyethylene oxide, sodium alginate, calcium ammonium alginate, potassium alginate, calcium alginate, propylene glycol alginate, polyvinyl alcohol, povidone, carbomer, xanthan gum, triethyl citrate or mixtures thereof.
  • Water-soluble materials may be present in an amount from 10.0% to 80.0% by weight of the total composition.
  • the water- soluble materials may be present in an amount from 15.0% to 70.0% by weight of the total composition.
  • the preferred water soluble materials being polyethylene oxide having average molecular weight 4,00,000 to 60,00,000; more preferably having average molecular weight 6,00,000 to 50,00,000.
  • the water insoluble materials that may be employed include, but are not limited to stearic acid, glyceryl monostearate, glyceryl behenate, glyceryl palmitostearate, microcrystalline wax, polymethacrylate, stearyl alcohol, cetyl alcohol, cetostearyl alcohol, hydrogenated castor oil, polyvinyl acetate, polyvinyl acetate phthalate, waxes, shellac, magnesium aluminium silicates or mixtures thereof.
  • Kollidone SR a physical mixture of polyvinyl acetate and polyvinyl pyrrolidone is the preferred water insoluble material. Water insoluble materials may be present in an amount from 10.0% to 80.0% by weight of the total composition.
  • the water insoluble materials may be present in an amount from 20.0% to 70.0% by weight of the total composition.
  • the water swellable materials that may be employed include, but are not limited to alginic acid, guar gum or mixtures thereof.
  • Water swellable materials may be present in an amount from 10.0% to 80.0% by weight of the total composition.
  • the water swellable materials may be present in an amount from 20.0% to 70.0% by weight of the total composition.
  • the sustained release compositions of the present invention may contain release modifying agents selected from one or more water soluble material employed together with one or more water insoluble material in a weight ratio of about 10:1 to 1:10.
  • one or more water soluble material may be employed together with one or more water insoluble material in a weight ratio of about 10:5 to 5:10.
  • the sustained release compositions of the present invention may contain release modifying agents selected from one or more water swellable material employed together with one or more water insoluble material in a weight ratio of about 10:1 to 1:10.
  • one or more water swellable material may be employed together with one or more water insoluble material in a weight ratio of about 10:5 to 5:10.
  • Sustained release compositions according to the present invention contain Trimetazidine in a dose range from 20mg to 60mg.
  • 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.
  • the sustained release pharmaceutical compositions of the present invention comprises 8.0% to 50.0% by weight of Trimetazidine dihydrochloride, 10.0% to 80.0% by weight of release modifying agent/(s), 10.0% to 70.0% by weight of diluent, 1.0% to 15.0% by weight of binder, 0.1% to 5.0% by weight of lubricant, 0.1% to 5.0% by weight of anti-adherant and 2.0% to 10.0% by weight of coating agents.
  • the sustained release pharmaceutical compositions of the present invention comprises 8.0% to 50.0% by weight of Trimetazidine dihydrochloride, 10.0% to 80.0% by weight of water soluble material/(s), 10.0% to 70.0% by weight of diluent, 1.0% to 15.0% by weight of binder, 0.1% to 5.0% by weight of lubricant, 0.1% to 5.0% by weight of anti- adherant and 2.0% to 10.0% by weight of coating agents.
  • the sustained release pharmaceutical compositions of the present invention comprises 10.0% to 30.0% by weight of Trimetazidine dihydrochloride, 15.0% to 70.0% by weight of water soluble material/(s), 20.0% to 60.0% by weight of diluent, 2.0% to 10.0% by weight of binder, 0.1% to 3.0% by weight of lubricant, 0.1% to 3.0% by weight of anti- adherant and 2.0% to 8.0% by weight of coating agents.
  • the sustained release pharmaceutical compositions of the present invention comprises 10.0% to 30.0% by weight of Trimetazidine dihydrochloride, 15.0% to 70.0% by weight of polyethylene oxide, 20.0% to 60.0% by weight of lactose monohydrate, 2.0% to 10.0% by weight of povidone, 0.1% to 3.0% by weight of magnesium stearate, 0.1% to 3.0% by weight of colloidal silicon dioxide and 2.0% to 8.0% by weight of coating agents.
  • the sustained release pharmaceutical compositions of the present invention comprises 10.0% to 30.0% by weight of Trimetazidine dihydrochloride, 15.0% to 70.0% by weight of xanthan gum, 20.0% to 60.0% by weight of lactose monohydrate, 2.0% to 10.0% by weight of povidone, 0.1% to 3.0% by weight of magnesium stearate, 0.1% to 3.0% by weight of colloidal silicon dioxide and 2.0% to 8.0% by weight of coating agents.
  • the sustained release pharmaceutical compositions of the present invention comprises 8.0% to 50.0% by weight of Trimetazidine dihydrochloride, 10.0% to 80.0% by weight of water insoluble material/(s), 10.0% to 70.0% by weight of diluent, 1.0% to 15.0% by weight of binder, 0.1% to 5.0% by weight of lubricant, 0.1% to 5.0% by weight of anti-adherant and 2.0% to 10.0% by weight of coating agents.
  • the sustained release pharmaceutical compositions of the present invention comprises 10.0% to 30.0% by weight of Trimetazidine dihydrochloride,20.0% to 70.0% by weight of water insoluble materials), 20.0% to 60.0% by weight of diluent, 2.0% to 10.0% by weight of binder, 0.1% to 3.0% by weight of lubricant, 0.1% to 3.0% by weight of anti- adherant and 2.0% to 8.0% by weight of coating agents.
  • the sustained release pharmaceutical compositions of the present invention comprises 10.0% to 30.0% by weight of Trimetazidine dihydrochloride, 20.0% to 60.% by weight of polymethacrylate, 20.0% to 60.0% by weight of dicalcium phosphate dihydrate, 2.0% to 10.0% by weight of povidone, 0.1% to 3.0% by weight of magnesium stearate, 0.1% to 3.0% by weight of colloidal silicon dioxide and 2.0% to 7.0% by weight of coating agents.
  • the sustained release pharmaceutical compositions of the present invention comprises 8.0% to 50.0% by weight of Trimetazidine dihydrochloride, 10.0% to 80.0% by weight of water swellable material/(s), 10.0% to 70.0% by weight of diluent, 1.0% to 15.0% by weight of binder, 0.1% to 5.0% by weight of lubricant, 0.1% to 5.0% by weight of anti-adherant and 2.0% to 10.0% by weight of coating agents.
  • the sustained release pharmaceutical compositions of the present invention comprises 10.0% to 30.0% by weight of Trimetazidine dihydrochloride, 20.0% to 70.0% by weight of water swellable material/(s), 20.0% to 60.0% by weight of diluent, 2.0% to 10.0% by weight of binder, 0.1% to 3.0% by weight of lubricant, 0.1% to 3.0% by weight of anti- adherant and 2.0% to 8.0% by weight of coating agents.
  • the sustained release pharmaceutical compositions of the present invention comprises 10.0% to 30.0% by weight of Trimetazidine dihydrochloride, 20.0% to 60.% by weight of guar gum, 20.0% to 60.0% by weight of dicalcium phosphate dihydrate, 2.0% to 10.0% by weight of povidone, 0.1% to 3.0% by weight of magnesium stearate, 0.1% to 3.0% by weight of colloidal silicon dioxide and 2.0% to 8.0% by weight of coating agents.
  • the process for preparation of Trimetazidine sustained release compositions comprises the steps of: i. preparing intra-granular composition of Trimetazidine dihydrochloride, release modifying agent/(s) and suitable pharmaceutically acceptable excipients; ii. mixing the intra-granular composition with extra granular composition comprising suitable pharmaceutically acceptable excipients and optionally one or more release modifying agents to form a granule blend; iii. lubricating the granule blend with suitable lubricants; iv. compressing the lubricated blend to form tablets; v. coating the compressed tablets with polymer based coating.
  • the process for preparation of Trimetazidine sustained release compositions comprises the steps of: i. preparing an intra-granular composition of Trimetazidine dihydrochloride, release modifying agent/(s) and suitable pharmaceutically acceptable excipients; ii. mixing the intra-granular composition with extra granular composition comprising suitable pharmaceutically acceptable excipients and optionally one or more release modifying agents to form a granule blend; iii. mixing the intra-granular composition with extra granular composition to form a granule blend; iv. lubricating the granule blend with suitable lubricants; v. filling the lubricated blend into hard gelatin capsules;
  • the intra-granular composition is prepared by the process comprising the steps of:
  • the process of preparation of Trimetazidine compositions comprises the steps of: i. preparing the intra-granular composition comprising multi-particulates by extrusion or spheronisation of Trimetazidine, release modulating agents and diluents; ii. mixing the intra-granular composition with extra-granular composition comprising suitable pharmaceutically acceptable excipients and optionally release modifying agents to form a granule blend; iii. further lubricating the granule blend; iv. compressing the lubricated blend into tablets; v. coating the compressed tablets.
  • the process of preparation of Trimetazidine compositions comprises the steps of: i. preparing the intra-granular composition by granulating Trimetazidine dihydrochloride with release modifying agents by hot melt granulation or by extrusion; ii. mixing the intra-granular composition with extra-granular composition comprising suitable pharmaceutically acceptable excipients to form granule blend; iii. further lubricating the granule blend; iv. compressing the lubricated blend into tablets; v. coating the compressed tablets.
  • the process of preparation of Trimetazidine compositions comprises the steps of: i. preparing an intra-granular composition of Trimetazidine dihydrochloride, release modifying agent/(s) and suitable pharmaceutically acceptable excipients; ii. mixing the intra-granular composition with extra granular composition comprising suitable pharmaceutically acceptable excipients to form granule blend; iii. lubricating the granule blend with lubricants; iv. compressing the lubricated blend into minitablet; v. coating the mini-tablets with/without release modifying agent and suitable pharmaceutically acceptable excipients. vi. mixing the coated mini-tablets with suitable pharmaceutical acceptable excipients and finally compressing into tablets vii. coating the compressed tablets.
  • Another embodiment of the invention is to provide a method of treating a patient suffering from angina pectoris, comprising administering to a patient in need thereof a therapeutically effective amount of sustained release pharmaceutical compositions as described herein.
  • compositions of the present invention provide a reliable in vitro- dissolution profile for sustained effect of Trimetazidine.
  • Suitable pharmaceutically acceptable excipients that can be used for formulation include, but are not limited to, diluents/fillers, binders, anti-adherants, lubricants, and the like.
  • Diluents that may 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 are present in an amount from 10% to 70% by weight of the total composition.
  • Binders that may 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 that may be used as per the invention include isopropyl alcohol, water or mixtures thereof in an amount sufficient to dissolve the binder.
  • Anti-adherents that may be used as per the invention include, but are not limited to colloidal silicon dioxide, talc, starch and the like and are present in an amount from 0.1% to 5.0% by weight of the total composition.
  • Lubricants that may 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 from 0.1% to 5.0% 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%-10% with respect to total weight may be employed to have desired release.
  • Functional coating may be carried out using release modifying agents (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 methylcellulose or the like may be used.
  • Opacifying agents that may 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 may be used.
  • Antitacking agents include talc, stearic acid, magnesium stearate, colloidal silicon dioxide and the like.
  • Excipients for non-functional film coating may 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.
  • compositions of the present invention are stable physically as well as chemically at accelerated conditions of stability.
  • sustained release compositions of the present invention shows the following in- vitro drug release characteristics when tested in 0.1N HCl for the first hour and then in phosphate buffer pH 6.8; which is comparable to the dissolution profile of Vastarel tablets.
  • release modifying agent refers to formulation excipients that sustain the release of the drug from the dosage form.
  • excipients refers to a pharmaceutically acceptable ingredient that is commonly used in the pharmaceutical technology for preparing granules and/or solid oral dosage compositions.
  • tablette refers and is intended to encompass compressed pharmaceutical dosage formulations of all shapes and sizes, whether coated or uncoated.
  • Trimetazidine dihydrochloride (175 gm), lactose monohydrate (359 gm) and polyethylene oxide (Polyox WSR N303) (150 gm) were mixed and granulated using binder solution containing polyvinyl pyrrolidone (30 gm) dissolved in isopropyl alcohol (675 gm). The resultant mass was dried at 60 0 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). Compressed the blended granules into tablets. Finally tablets were coated using non functional coating composition.
  • Trimetazidine dihydrochloride (175 gm), lactose monohydrate (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 0 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). Compressed the blended granules into tablets. Finally tablets were coated using non functional coating composition.
  • 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 0 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). Compressed the blended granules into tablets. Finally tablets were coated using non functional coating composition.
  • 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 0 C and agglomerates were milled to required size. Sized granules were blended with Kollidone SR (560gm) (Kollidone SR is a physical mixture of polyvinyl acetate and polyvinyl pyrrolidone), colloidal silicon dioxide (5.5 gm) and magnesium stearate (5.5 gm). Compressed the blended granules into tablets. Finally tablets were coated using non functional coating composition.
  • 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 0 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). Compressed the blended granules into tablets. Finally tablets were coated using non functional coating composition.
  • Glyceryl monostearate (116.67 gm) was melted at 60 0 C.
  • AUCo-t Area under the plasma concentration versus time curve, from time zero to the last measurable concentration.
  • AUCo-i nf Area under the plasma concentration versus time curve, from time zero to infinity.
  • Example 1 is bio-equivalent to reference product (Vastarel) when tested in-vivo on healthy, adult, human subjects under fasted and fed conditions. Results on in-vivo study of compositions prepared according to Example 1 is as shown in Table 3. Table 3
  • Example 2 is bio-equivalent to reference product (Vastarel) when tested in-vivo on healthy, adult, human subjects under fasted and fed conditions. Results on in-vivo study of compositions prepared according to Example 2 is as shown in Table 4.

Abstract

Disclosed herein are sustained release pharmaceutical compositions comprising Trimetazidine or a pharmaceutically acceptable salt thereof and release modifying agents together with suitable pharmaceutically acceptable excipients. The sustained release pharmaceutical compositions of the present invention are characterized by the absence of cellulose and/or their derivatives as release modifying agents.

Description

Sustained release compositions of Trimetazidine and process for preparation thereof
Related application:
This application claims the benefit of Indian Provisional Application No.
1533/MUM/2007 filed on August 08, 2007.
Technical field of the invention:
The present invention relates to sustained release pharmaceutical compositions useful 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; together with 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 pharmaceutical 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 Q4H22N2O3 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 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 Tmax of around 1.8 +/- 0.7 hours. Since it has a shorter plasma half life, in practice 20mg preparation is given twice or thrice a day in order to ensure relatively constant plasma levels but, due to the fact that it is absorbed quickly, these immediate release forms lead to maximum plasma levels immediately after administration and to a very low plasma level at the time of the next dose, resulting in great differences in peak and trough plasma levels at steady state.
Trimetazidine dihydrochloride is regarded as a safe drug in the long-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 Sender is also marketed as CARDAPTAN, PREDUCTAL MR, IDAPTAN, FLAVEDON MR, TRIZEDON, VASTINAN and VASOREL. VASTAREL prolonged release film-coated tablets 35 mg contain calcium hydrogen phosphate dihydrate, hypromellose, povidone, anhydrous colloidal silica, magnesium stearate, macrogol, titanium dioxide (E171), glycerol, red iron oxide (E172). US3262852 discloses a vasodilative substance, dihydrochloride of 1 -(2,3,4- trimethoxybenzyl) piperazine i.e. Trimetazidine dihyrochloride.
US4814176 discloses a sustained release preparation comprising: (a) chitin, 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, does 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.
CNl 864680 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 as 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.
EP 1108424 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, methyl cellulose 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 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 ultra fine powder of an enteric polymer base as a polymeric matrix and using 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 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 compositions and process for manufacturing of 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 that are effective and could be used for long term treatment of angina and with better patient compliance. Object of the Invention:
The main object of the invention is to provide 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; together with suitable pharmaceutically acceptable excipients.
Another object of the invention is to provide pharmaceutical 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.
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 10-12 hours period after oral administration.
Further object of the invention is to provide compositions of Trimetazidine that demonstrate reliable release rate and facilitated in-vivo absorption for desired period of time.
Another object of the invention is to provide sustained release compositions which are useful for the treatment of angina pectoris and has better patient compliance.
Another object of the invention is to provide a method of treating a patient suffering from angina pectoris, comprising administering to a patient in need thereof a therapeutically effective amount of sustained release pharmaceutical compositions as described herein.
Summary of the invention:
The present invention discloses sustained release pharmaceutical compositions useful for the treatment of angina pectoris comprising Trimetazidine; wherein the compositions are characterized by the absence of cellulose and/or cellulose derivatives as release modifying agents.
According to one aspect, the present invention provides 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; together with suitable pharmaceutically acceptable excipients and characterized by the absence of cellulose and/or their derivatives as release modifying agents.
According to another aspect, the present invention provides a process for preparation of 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; together with suitable pharmaceutically acceptable excipients; the said process comprising the steps of : i. preparing an intra-granular composition of Trimetazidine dihydrochloride, release modifying agent/(s) and suitable pharmaceutically acceptable excipients; ii. mixing the intra-granular composition with extra granular composition comprising suitable pharmaceutically acceptable excipients and optionally one or more release modifying agents to form a granule blend; iii. lubricating the granule blend with suitable lubricants; iv. compressing the lubricated blend to form tablets or filling the lubricated blend into hard gelatin capsules; v. further coating the compressed tablets with polymer based coating.
Brief description of the drawings:
Fig. 1 shows comparative dissolution profile of Vastarel and tablets prepared according to Example 1. Dissolution was carried out in 0.1N HCL for the first hour and then in pH 6.8 phosphate buffer.
Fig. 2 shows comparative dissolution profile of Vastarel and tablets prepared according to Example 2. Dissolution was carried out in 0.1N HCL for the first hour and then in pH 6.8 phosphate buffer.
Detailed Description:
The present invention describes sustained release pharmaceutical compositions useful 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; together with 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 pharmaceutical compositions. Sustained release solid dosage forms such as tablets, capsules or any other solid dosage form may be formulated using the process as described herein.
The pharmaceutical compositions of the present invention releases Trimetazidine in a sustained and reproducible manner over a prolonged period of time to achieve a sustaining effect of Trimetazidine over 10-12 hours period after oral administration.
According to one general aspect, the present invention provides sustained release pharmaceutical compositions useful for the treatment of angina pectoris comprising Trimetazidine; wherein the compositions are characterized by the absence of cellulose and/or cellulose derivatives as release modifying agents.
According to one aspect of the invention, Trimetazidine is present in an amount from about 8.0% to about 50.0% by weight of the total composition.
According to a preferred aspect, Trimetazidine is present in an amount from 10.0% to 30.0% by weight of the total composition.
According to another aspect, the preferred pharmaceutically acceptable salt of Trimetazidine is Trimetazidine dihydrochloride.
In the practice of the present invention, the release modifying agents may be present in an amount from 10.0% to 80.0% by weight of the total composition.
According to one embodiment of the invention, the sustained release pharmaceutical compositions of the present invention comprises release- modifying agents that may be selected from at least one of (a) one or more water- soluble materials and/or (b)one or more water insoluble materials and/or (c) one or more water swellable materials; wherein the said compositions are characterized by the absence of cellulose and/or cellulose derivatives as release modifying agents.
According to the present invention, the ratio of Trimetazidine to release modifying agents is in the range of about 1:0.5 to 1:10; preferably 1:1 to 1:5.
In the practice of the present invention, the water soluble materials that may be employed include, but are not limited to polyethylene oxide, sodium alginate, calcium ammonium alginate, potassium alginate, calcium alginate, propylene glycol alginate, polyvinyl alcohol, povidone, carbomer, xanthan gum, triethyl citrate or mixtures thereof. Water-soluble materials may be present in an amount from 10.0% to 80.0% by weight of the total composition. Preferably, the water- soluble materials may be present in an amount from 15.0% to 70.0% by weight of the total composition. The preferred water soluble materials being polyethylene oxide having average molecular weight 4,00,000 to 60,00,000; more preferably having average molecular weight 6,00,000 to 50,00,000.
In the practice of the present invention, the water insoluble materials that may be employed include, but are not limited to stearic acid, glyceryl monostearate, glyceryl behenate, glyceryl palmitostearate, microcrystalline wax, polymethacrylate, stearyl alcohol, cetyl alcohol, cetostearyl alcohol, hydrogenated castor oil, polyvinyl acetate, polyvinyl acetate phthalate, waxes, shellac, magnesium aluminium silicates or mixtures thereof. Kollidone SR a physical mixture of polyvinyl acetate and polyvinyl pyrrolidone is the preferred water insoluble material. Water insoluble materials may be present in an amount from 10.0% to 80.0% by weight of the total composition. Preferably, the water insoluble materials may be present in an amount from 20.0% to 70.0% by weight of the total composition. In the practice of the present invention, the water swellable materials that may be employed include, but are not limited to alginic acid, guar gum or mixtures thereof. Water swellable materials may be present in an amount from 10.0% to 80.0% by weight of the total composition. Preferably, the water swellable materials may be present in an amount from 20.0% to 70.0% by weight of the total composition.
According to one embodiment of the invention, the sustained release compositions of the present invention may contain release modifying agents selected from one or more water soluble material employed together with one or more water insoluble material in a weight ratio of about 10:1 to 1:10. Preferably, one or more water soluble material may be employed together with one or more water insoluble material in a weight ratio of about 10:5 to 5:10.
According to another embodiment of the invention, the sustained release compositions of the present invention may contain release modifying agents selected from one or more water swellable material employed together with one or more water insoluble material in a weight ratio of about 10:1 to 1:10. Preferably, one or more water swellable material may be employed together with one or more water insoluble material in a weight ratio of about 10:5 to 5:10.
Sustained release compositions according to the present invention contain 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 one embodiment, the sustained release pharmaceutical compositions of the present invention comprises 8.0% to 50.0% by weight of Trimetazidine dihydrochloride, 10.0% to 80.0% by weight of release modifying agent/(s), 10.0% to 70.0% by weight of diluent, 1.0% to 15.0% by weight of binder, 0.1% to 5.0% by weight of lubricant, 0.1% to 5.0% by weight of anti-adherant and 2.0% to 10.0% by weight of coating agents.
According to another embodiment, the sustained release pharmaceutical compositions of the present invention comprises 8.0% to 50.0% by weight of Trimetazidine dihydrochloride, 10.0% to 80.0% by weight of water soluble material/(s), 10.0% to 70.0% by weight of diluent, 1.0% to 15.0% by weight of binder, 0.1% to 5.0% by weight of lubricant, 0.1% to 5.0% by weight of anti- adherant and 2.0% to 10.0% by weight of coating agents.
According to a preferred embodiment, the sustained release pharmaceutical compositions of the present invention comprises 10.0% to 30.0% by weight of Trimetazidine dihydrochloride, 15.0% to 70.0% by weight of water soluble material/(s), 20.0% to 60.0% by weight of diluent, 2.0% to 10.0% by weight of binder, 0.1% to 3.0% by weight of lubricant, 0.1% to 3.0% by weight of anti- adherant and 2.0% to 8.0% by weight of coating agents.
According to a more preferred embodiment, the sustained release pharmaceutical compositions of the present invention comprises 10.0% to 30.0% by weight of Trimetazidine dihydrochloride, 15.0% to 70.0% by weight of polyethylene oxide, 20.0% to 60.0% by weight of lactose monohydrate, 2.0% to 10.0% by weight of povidone, 0.1% to 3.0% by weight of magnesium stearate, 0.1% to 3.0% by weight of colloidal silicon dioxide and 2.0% to 8.0% by weight of coating agents.
According to another preferred embodiment, the sustained release pharmaceutical compositions of the present invention comprises 10.0% to 30.0% by weight of Trimetazidine dihydrochloride, 15.0% to 70.0% by weight of xanthan gum, 20.0% to 60.0% by weight of lactose monohydrate, 2.0% to 10.0% by weight of povidone, 0.1% to 3.0% by weight of magnesium stearate, 0.1% to 3.0% by weight of colloidal silicon dioxide and 2.0% to 8.0% by weight of coating agents.
According to one embodiment, the sustained release pharmaceutical compositions of the present invention comprises 8.0% to 50.0% by weight of Trimetazidine dihydrochloride, 10.0% to 80.0% by weight of water insoluble material/(s), 10.0% to 70.0% by weight of diluent, 1.0% to 15.0% by weight of binder, 0.1% to 5.0% by weight of lubricant, 0.1% to 5.0% by weight of anti-adherant and 2.0% to 10.0% by weight of coating agents.
According to a preferred embodiment, the sustained release pharmaceutical compositions of the present invention comprises 10.0% to 30.0% by weight of Trimetazidine dihydrochloride,20.0% to 70.0% by weight of water insoluble materials), 20.0% to 60.0% by weight of diluent, 2.0% to 10.0% by weight of binder, 0.1% to 3.0% by weight of lubricant, 0.1% to 3.0% by weight of anti- adherant and 2.0% to 8.0% by weight of coating agents.
According to a more preferred embodiment, the sustained release pharmaceutical compositions of the present invention comprises 10.0% to 30.0% by weight of Trimetazidine dihydrochloride, 20.0% to 60.% by weight of polymethacrylate, 20.0% to 60.0% by weight of dicalcium phosphate dihydrate, 2.0% to 10.0% by weight of povidone, 0.1% to 3.0% by weight of magnesium stearate, 0.1% to 3.0% by weight of colloidal silicon dioxide and 2.0% to 7.0% by weight of coating agents.
According to one embodiment, the sustained release pharmaceutical compositions of the present invention comprises 8.0% to 50.0% by weight of Trimetazidine dihydrochloride, 10.0% to 80.0% by weight of water swellable material/(s), 10.0% to 70.0% by weight of diluent, 1.0% to 15.0% by weight of binder, 0.1% to 5.0% by weight of lubricant, 0.1% to 5.0% by weight of anti-adherant and 2.0% to 10.0% by weight of coating agents.
According to a preferred embodiment, the sustained release pharmaceutical compositions of the present invention comprises 10.0% to 30.0% by weight of Trimetazidine dihydrochloride, 20.0% to 70.0% by weight of water swellable material/(s), 20.0% to 60.0% by weight of diluent, 2.0% to 10.0% by weight of binder, 0.1% to 3.0% by weight of lubricant, 0.1% to 3.0% by weight of anti- adherant and 2.0% to 8.0% by weight of coating agents.
According to a more preferred embodiment, the sustained release pharmaceutical compositions of the present invention comprises 10.0% to 30.0% by weight of Trimetazidine dihydrochloride, 20.0% to 60.% by weight of guar gum, 20.0% to 60.0% by weight of dicalcium phosphate dihydrate, 2.0% to 10.0% by weight of povidone, 0.1% to 3.0% by weight of magnesium stearate, 0.1% to 3.0% by weight of colloidal silicon dioxide and 2.0% to 8.0% by weight of coating agents.
According to one embodiment, the process for preparation of Trimetazidine sustained release compositions comprises the steps of: i. preparing intra-granular composition of Trimetazidine dihydrochloride, release modifying agent/(s) and suitable pharmaceutically acceptable excipients; ii. mixing the intra-granular composition with extra granular composition comprising suitable pharmaceutically acceptable excipients and optionally one or more release modifying agents to form a granule blend; iii. lubricating the granule blend with suitable lubricants; iv. compressing the lubricated blend to form tablets; v. coating the compressed tablets with polymer based coating.
According to one embodiment, the process for preparation of Trimetazidine sustained release compositions comprises the steps of: i. preparing an intra-granular composition of Trimetazidine dihydrochloride, release modifying agent/(s) and suitable pharmaceutically acceptable excipients; ii. mixing the intra-granular composition with extra granular composition comprising suitable pharmaceutically acceptable excipients and optionally one or more release modifying agents to form a granule blend; iii. mixing the intra-granular composition with extra granular composition to form a granule blend; iv. lubricating the granule blend with suitable lubricants; v. filling the lubricated blend into hard gelatin capsules;
In the practice of the present invention, the intra-granular composition is prepared by the process comprising the steps of:
(a) mixing Trimetazidine dihydrochloride 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 with the binder solution to form desired wet mass;
(d) screening the wet mass to form granules;
(e) drying the granules till 'loss on drying' value in the range of 1.0% to 7.0% is achieved;
(f) sizing the dried granules.
According to another embodiment, the process of preparation of Trimetazidine compositions comprises the steps of: i. preparing the intra-granular composition comprising multi-particulates by extrusion or spheronisation of Trimetazidine, release modulating agents and diluents; ii. mixing the intra-granular composition with extra-granular composition comprising suitable pharmaceutically acceptable excipients and optionally release modifying agents to form a granule blend; iii. further lubricating the granule blend; iv. compressing the lubricated blend into tablets; v. coating the compressed tablets.
According to another embodiment, the process of preparation of Trimetazidine compositions comprises the steps of: i. preparing the intra-granular composition by granulating Trimetazidine dihydrochloride with release modifying agents by hot melt granulation or by extrusion; ii. mixing the intra-granular composition with extra-granular composition comprising suitable pharmaceutically acceptable excipients to form granule blend; iii. further lubricating the granule blend; iv. compressing the lubricated blend into tablets; v. coating the compressed tablets.
According to another embodiment, the process of preparation of Trimetazidine compositions comprises the steps of: i. preparing an intra-granular composition of Trimetazidine dihydrochloride, release modifying agent/(s) and suitable pharmaceutically acceptable excipients; ii. mixing the intra-granular composition with extra granular composition comprising suitable pharmaceutically acceptable excipients to form granule blend; iii. lubricating the granule blend with lubricants; iv. compressing the lubricated blend into minitablet; v. coating the mini-tablets with/without release modifying agent and suitable pharmaceutically acceptable excipients. vi. mixing the coated mini-tablets with suitable pharmaceutical acceptable excipients and finally compressing into tablets vii. coating the compressed tablets.
Another embodiment of the invention is to provide a method of treating a patient suffering from angina pectoris, comprising administering to a patient in need thereof a therapeutically effective amount of sustained release pharmaceutical compositions as described herein.
Further, the compositions of the present invention provide a reliable in vitro- dissolution profile for sustained effect of Trimetazidine.
Suitable pharmaceutically acceptable excipients that can be used for formulation include, but are not limited to, diluents/fillers, binders, anti-adherants, lubricants, and the like.
Diluents that may 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 are present in an amount from 10% to 70% by weight of the total composition.
Binders that may 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 that may be used as per the invention include isopropyl alcohol, water or mixtures thereof in an amount sufficient to dissolve the binder.
Anti-adherents that may be used as per the invention include, but are not limited to colloidal silicon dioxide, talc, starch and the like and are present in an amount from 0.1% to 5.0% by weight of the total composition.
Lubricants that may 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 from 0.1% to 5.0% 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%-10% with respect to total weight may be employed to have desired release.
Functional coating may be carried out using release modifying agents (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 methylcellulose or the like may be used. Opacifying agents that may 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 may be used. Antitacking agents include talc, stearic acid, magnesium stearate, colloidal silicon dioxide and the like. Excipients for non-functional film coating may 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 pharmaceutical compositions of the present invention are stable physically as well as chemically at accelerated conditions of stability.
The sustained release compositions of the present invention shows the following in- vitro drug release characteristics when tested in 0.1N HCl for the first hour and then in phosphate buffer pH 6.8; which is comparable to the dissolution profile of Vastarel tablets.
As used herein, the term "release modifying agent" refers to formulation excipients that sustain the release of the drug from the dosage form.
As used herein, the term "excipients" refers to a pharmaceutically acceptable ingredient that is commonly used in the pharmaceutical technology for preparing granules and/or solid oral dosage compositions.
As used herein, the term "tablet" refers and is intended to encompass compressed pharmaceutical dosage formulations of all shapes and sizes, whether coated or uncoated.
As used herein, the terms "comprise," "comprising," and "include" are intended to be open, non-limiting terms, unless the contrary is expressly indicated. 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), lactose monohydrate (359 gm) and polyethylene oxide (Polyox WSR N303) (150 gm) were mixed and granulated using binder solution containing polyvinyl pyrrolidone (30 gm) dissolved in isopropyl alcohol (675 gm). The resultant mass was dried at 600C 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). Compressed the blended granules into tablets. Finally tablets were coated using non functional coating composition.
Example 2
Trimetazidine dihydrochloride (175 gm), lactose monohydrate (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 600C and agglomerates were milled to required size. Sized granules were blended with colloidal silicon dioxide (6.0 gm) and magnesium stearate (6.0 gm). Compressed the blended granules into tablets. Finally tablets were coated using non functional coating composition.
Example 3
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 600C 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). Compressed the blended granules into tablets. Finally tablets were coated using non functional coating composition.
Example 4
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 600C and agglomerates were milled to required size. Sized granules were blended with Kollidone SR (560gm) (Kollidone SR is a physical mixture of polyvinyl acetate and polyvinyl pyrrolidone), colloidal silicon dioxide (5.5 gm) and magnesium stearate (5.5 gm). Compressed the blended granules into tablets. Finally tablets were coated using non functional coating composition.
Example 5
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 600C 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). Compressed the blended granules into tablets. Finally tablets were coated using non functional coating composition.
Example 6
Glyceryl monostearate (116.67 gm) was melted at 600C. Trimetazidine dihydrochloride (175 gm) and lactose monohydrate (300gm) were mixed and heated to 600C in a jacketed rapid mixer granulator and granulated with the melted stearate at 600C. After granulation the granulated mass was mixed continuously till it cools to room temperature. Shellac (29.77 gm) and polyvinyl pyrrolidine (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 450C and then milled to required size. Sized granules were blended with colloidal silicon dioxide (3.0 gm) and magnesium stearate (6.0 gm). Compressed the blended granules into tablets. Finally the tablets were coated using non functional coating composition.
In-vitro dissolution study
In- vitro dissolution rate studies of the Trimetazidine tablets prepared according to Example 1 of the present invention and which when tested in 0.1N HCl for the first hour and then in phosphate buffer pH 6.8. shows the results as shown in Table 1.
Table 1
In- vitro dissolution rate studies of the Trimetazidine tablets prepared according to Example 2 of the present invention and which when tested in 0.1N HCl for the first hour and then in phosphate buffer pH 6.8. shows the results as shown in Table 2.
Table 2
Bioequivalence study
A bioequivalence study was conducted on healthy, adult, human subjects under fasted and fed conditions.
AUCo-t = Area under the plasma concentration versus time curve, from time zero to the last measurable concentration.
AUCo-inf = Area under the plasma concentration versus time curve, from time zero to infinity.
Cmax — maximum plasma concentration.
Example 1 is bio-equivalent to reference product (Vastarel) when tested in-vivo on healthy, adult, human subjects under fasted and fed conditions. Results on in-vivo study of compositions prepared according to Example 1 is as shown in Table 3. Table 3
Example 2 is bio-equivalent to reference product (Vastarel) when tested in-vivo on healthy, adult, human subjects under fasted and fed conditions. Results on in-vivo study of compositions prepared according to Example 2 is as shown in Table 4.
Table 4
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.

Claims

We claim,
1. A sustained release pharmaceutical composition 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; together with suitable pharmaceutically acceptable excipients and characterized by the absence of cellulose and/or their derivatives as release modifying agents.
2. The composition as claimed in claim 1, wherein the ratio of Trimetazidine to the release modifying agents is in the range of 1 :0.5 to 1 :10.
3. The composition as claimed in claim 2, wherein the ratio of Trimetazidine to the release modifying agents is in the range of 1 : 1 to 1:5.
4. The composition as claimed in claim 1, wherein Trimetazidine is from about 8.0% to about 50.0% by weight of the total composition.
5. The composition as claimed in claim 1, wherein the release modifying agent is from 10.0% to 80.0% by weight of the total composition.
6. The composition as claimed in claim 1, wherein Trimetazidine is present as Trimetazidine dihydrochloride.
7. The composition as claimed in claim I3 wherein the water soluble materials are selected from the group consisting of polyethylene oxide, sodium alginate, calcium alginate, propylene glycol alginate, polyvinyl alcohol, povidone, carbomer, xanthan gum, triethyl citrate or mixtures thereof.
8. The composition as claimed in claim 1, wherein the water insoluble materials are selected from the group consisting of stearic acid, glyceryl monostearate, glyceryl behenate, glyceryl palmitostearate, microcrystalline wax, polymethacrylate, stearyl alcohol, cetyl alcohol, cetostearyl alcohol, hydrogenated castor oil, polyvinyl acetate, polyvinyl acetate pthalate, waxes, shellac, magnesium aluminium silicates or mixtures thereof.
9. The composition as claimed in claim 1, wherein the water swellable materials are selected from the group consisting of alginic acid, guar gum or mixtures thereof.
10. The composition as claimed in claim 1, wherein the excipients are selected from diluents, binders, lubricants, anti-adherants and coating agents.
11. The composition as claimed in claim 10, wherein the diluents are selected from the group consisting of dihydrogen calcium phosphate, tribasic calcium phosphate, calcium carbonate, lactose monohydrate and microcrystalline cellulose and is present in an amount from 10% to 70% by weight of the total composition.
12. The composition as claimed in claim 10, wherein the binders are selected from the group consisting of gelatin, polyvinyl alcohol, polyvinyl pyrrolidone and gum acacia and is present in an amount from 1.0% to 15% by weight of the total composition.
13. The composition as claimed in claim 10, wherein the lubricants are selected from the group consisting of magnesium stearate, calcium stearate and zinc stearate and is present in an amount from 0.1% to 5.0% by weight of the total composition.
14. The composition as claimed in claim 10, wherein the anti-adherants are selected from the group consisting of colloidal silicon dioxide, talc and starch and is present in an amount from 0.1% to 5.0% by weight of the total composition.
15. The composition as claimed in claim 1, wherein Trimetazidine is present in unit dose of about 20mg to about 60mg.
16. The composition as claimed in claim 15, wherein Trimetazidine is present in unit dose of 35mg or 60mg.
17. The composition as claimed in claim 1, wherein the composition is in the form of tablets or capsules.
18. The composition as claimed in claim 1, wherein the composition comprises about 8.0% to about 50.0% by weight of Trimetazidine dihydrochloride, 10.0% to 80.0% by weight of rate modifying agent, 10.0% to 70.0% by weight of diluent, 1.0% to 15.0% by weight of binder, 0.1% to 5.0% by weight of lubricant, 0.1% to 5.0% by weight of anti- adherant.
19. The composition as claimed in claim 18, wherein the composition comprises 10.0% to 30.0% by weight of Trimetazidine dihydrochloride, 15.0% to 70.0% by weight of polyethylene oxide, 20.0% to 60.0% by weight of lactose monohydrate, 2.0% to 10.0% by weight of povidone, 0.1% to 3.0% by weight of magnesium stearate, 0.1% to 3.0% by weight of colloidal silicon dioxide.
20. The composition as claimed in claim 18, wherein the composition comprises 10.0% to 30.0% by weight of Trimetazidine dihydrochloride, 15.0% to 70.0% by weight of xanthan gum, 20.0% to 60.0% by weight of lactose monohydrate, 2.0% to 10.0% by weight of povidone, 0.1% to 3.0% by weight of magnesium stearate, 0.1% to 3.0% by weight of colloidal silicon dioxide.
21. A process for preparation of sustained release compositions of Trimetazidine comprising the steps of:
(i) preparing intra-granular composition of Trimetazidine dihydrochloride, release modifying agent/(s) and suitable pharmaceutically acceptable excipients;
(ii) mixing the intra-granular composition with extra granular composition comprising suitable pharmaceutically acceptable excipients and optionally one or more release modifying agents to form a granule blend;
(iii) lubricating the granule blend with lubricants;
(iv) compressing the lubricated blend to form tablets or optionally filling the lubricated blend into hard gelatin capsules;
(v) coating the compressed tablets with polymer based coating.
22. A process for preparation of sustained release compositions of Trimetazidine comprising the steps of:
(i)preparing an intra-granular composition of Trimetazidine dihydrochloride, release modifying agent/(s) and suitable pharmaceutically acceptable excipients;
(ii) mixing the intra-granular composition with extra granular composition comprising suitable pharmaceutically acceptable excipients;
(iii) lubricating the granule blend with lubricants;
(iv) compressing the lubricated blend into minitablet;
(v) coating the mini-tablets with/without release modifying agent and suitable pharmaceutically acceptable excipients;
(vi)mixing the coated mini-tablets with suitable pharmaceutical acceptable excipients and finally compressing into tablets;
(vii)coating the compressed tablets.
23. The process as claimed in claim 21 or claim 22, wherein the intra-granular composition is prepared by the process comprising the steps of:
(a) mixing Trimetazidine dihydrochloride 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 with the binder solution to form desired wet mass;
(d) screening the wet mass to form granules;
(e) drying and sizing the granules to form the intra-granular composition.
24. The process as claimed in claim 21 to claim 23, wherein the release modifying agents are water soluble materials, water insoluble materials or water swellable materials.
25. The process as claimed in claim 24, wherein the water soluble materials are selected from the group consisting of polyethylene oxide, sodium alginate, calcium alginate, propylene glycol alginate, polyvinyl alcohol, povidone, carbomer, xanthan gum, triethyl citrate or mixtures thereof.
26. The process as claimed in claim 24, wherein the water insoluble materials are selected from the group consisting of stearic acid, glyceryl monostearate, glyceryl behenate, glyceryl palmitostearate, microcrystalline wax, polymethacrylate, stearyl alcohol, cetyl alcohol, cetostearyl alcohol, hydrogenated castor oil, polyvinyl acetate, polyvinyl acetate pthalate, waxes, shellac, magnesium aluminium silicates or mixtures thereof.
27. The process as claimed in claim 24, wherein the water swellable materials are selected from the group consisting of alginic acid, guar gum or mixtures thereof.
28. The composition as claimed in claims 1 to 20 , wherein the composition is useful for the treatment of angina pectoris.
29. A sustained release pharmaceutical composition and process of preparation thereof substantially as herein described and illustrated by the examples.
EP08852448A 2007-08-08 2008-08-07 Sustained release compositions of trimetazidine and process for preparation thereof Withdrawn EP2187874A2 (en)

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