Classifications

• • 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
  • A61K9/2022—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

Definitions

• the present invention relates to sustained release pharmaceutical tablet formulations suitable for oral use comprising l-(2 3 4-trimethoxybenzyl)piperazine dihydrochloride as the active agent and production method thereof Trimetazidine, with the chemical name l-(2 3 4-trimethoxybenzyl) piperazine dihydrochloride ⁇ Formula I) is disclosed in the molecule patent numbered US 3262852 in detail. It is known that the molecule trimetazidine is used in treatment of ischemic vascular diseases in neurosensorial tissues such as angina pectoris and Meniere's disease.
• Trimetazidine is a cardioprotective and anti-ischemic 3-ketoacyl Co A thiolase inhibitor acting generally in its hydrochloride and dihydrochloride salts form.
• the active agent is available in 20 mg film coated tablet and 35 mg modified release tablet forms on the market.
• Trimetazidine is a well water soluble powder in white or whitish colour. Trimetazidine is easily absorbed by the organism and its half-life is approximately six hours. Therefore, it is recommended to use 3 times in a day in order to provide an effective treatment. However, due to dysmnesia, the patients cannot take the required dose of the drug and therefore using a drug 3 times in a day reduces efficiency of the treatment and increases side and toxic effects.
• the prior art recommends the sustained release formulations comprising trimetazidine.
• EP 1 108424 relates to the sustained release pharmaceutical formulations wherein the release is provided by cellulose or a cellulose derivative matrix.
• the cellulose derivative matrix used in order to provide release is hydroxypropyl cellulose and its percentage is in the range of 25 to 50% in the formulations.
• the sustained release trimetazidine formulations of the European patent application numbered EP 2200591 comprise a water insoluble polymer as the rate-controlling agent.
• the water insoluble polymers recommended to be used in the formulations of the invention are selected from ethyl cellulose, cellulose acetate, cellulose acetate phthalate, cellulose acetate, trimellitate, acrylic or metacrylic compounds, polyvinyl acetate or a combination thereof.
• release rate of the formulations are not only affected from the type of the rate- controlling agent but also its amount in the formulations. As given in the application numbered EP1108424, use of a rate controlling agent less than 50% in the formulations is not sufficient for obtaining the required sustained release characteristics of trimetazidine.
• the most suitable release rate and the highest therapeutic efficiency have been provided by using at least one rate-controlling agent minimum in an amount of 50% by weight in the formulations.
• the present invention discloses the sustained release trimetazidine formulations suitable for oral use.
• the present invention discloses the sustained release formulations comprising trimetazidine or a salt thereof as the active agent, at least one rate-controlling agent minimum in an amount of 50% and one other excipient.
• the present invention discloses the sustained release formulations comprising trimetazidine or a salt thereof as the active agent, at least one rate-controlling agent minimum in an amount of 50% by weight and one other excipient wherein the ratio of the active agent/at least one rate-controlling agent is in the range of 0.1 to 1 by weight.
• the present invention discloses the sustained release formulations comprising trimetazidine or a salt thereof as the active agent, at least one rate-controlling agent minimum in an amount of 50% by weight and one other excipient wherein the ratio of the active agent/at least one rate-controlling agent is in the range of 0.1 to 0.8 by weight.
• the present invention discloses the sustained release formulations comprising trimetazidine or a salt thereof as the active agent, at least one rate-controlling agent minimum in an amount of 50% by weight and one other excipient wherein the ratio of the active agent/at least one rate-controlling agent is in the range of 0.1 to 0.6 by weight.
• the rate controlling agents that can be comprised in the formulations of the present invention can be soluble or insoluble in water.
• the rate-controlling agent preferred in the scope of the present invention is the combination of a water soluble agent and water insoluble agent and the ratio of these agents to each other is respectively in the range of 1 to 10 by weight, preferably in the range of 1 to 8 by weight, more preferably in the range of 1 to 7 by weight.
• the water-soluble rate controlling agents that can be comprised in the formulations can be selected from a group comprising hydroxypropyl cellulose, hydroxymethyl cellulose, methylcellulose, vinyl acetate copolymers, polysaccharides, polyethylene oxide, methacrylic acid copolymers, alginic acid or alginic acid salts (for instance sodium alginate) or combinations thereof.
• the water insoluble rate controlling agents that can be comprised in the formulations can be selected from a group comprising cellulose derivatives such as acrylates, ethyl cellulose, cellulose acetate, methacrylates, acrylic acid copolymers or combinations thereof.
• the water soluble rate-controlling agent is polyvinylpyrrolidone
• the water insoluble rate-controlling agent is polyvinyl acetate
• the rate-controlling agent comprised in the formulations is the combination of polyvinylpyrrolidone and polyvinyl acetate.
• a characteristic feature of the sustained release trimetazidine formulations of the present invention is that the rate-controlling agent is the combination of polyvinylpyrrolidone and polyvinyl acetate wherein the ratio of polyvinylpyrrolidone to polyvinyl acetate is in the range of 1 to 10 by weight, preferably in the range of 1 to 8 by weight, more preferably in the range of 1 to 7 by weight.
• a characteristic feature of the pharmaceutical compositions of the present invention is that total amount of the active agent comprised in the formulation is in the range of 0.1 - 95% by weight, preferably in the range of 1 - 90% by weight.
• Trimetazidine comprised in the pharmaceutical formulations of the present invention can be in the form of trimetazidine' s pharmaceutically acceptable salts, hydrates, solvates, esters, enantiomers, diastereomers or combinations thereof.
• the active agent preferred in the scope of the present invention is trimetazidine dihydrochloride salt.
• sustained release trimetazidine formulations of the present invention comprises at least one pharmaceutically acceptable excipient in addition to the active agent.
• the other excipients that can be comprised in the sustained release formulations of the present invention comprising trimetazidine and the combination of polyvinylpyrrolidone to polyvinyl as the at least one rate-controlling agent can be selected from a group comprising binders, disintegrants, viscosity enhancing agents, filling agents, drying agents, surface active agents, stabilizing agents, oiling agents, lubricants, diluents, glidants, wetting agents, oiling agents, pH regulators, gelling agents, flavouring agent, sweeteners, taste regulating agents, emulgators, anti foaming agents, anti-oxidants, preservatives, solvent or solvent mixtures, colouring agents and complexing agents, film coating agents or combinations thereof.
• the disintegrant that can be used in the sustained release formulations of the present invention comprising trimetazidine can be selected from a group comprising carboxymethyl cellulose, carboxymethyl cellulose calcium, carboxymethyl cellulose sodium, croscarmellose sodium, crospovidone, hydroxypropyl cellulose, microcrystalline cellulose, methylcellulose, chitosan, starch, sodium starch glycolate.
• the diluent that can be used in the sustained release formulations of the present invention comprising trimetazidine can be selected from a group comprising calcium carbonate, dibasic calcium phosphate, tribasic calcium phosphate, calcium sulphate, microcrystalline cellulose, dextrose, fructose, lactitol, lactose, magnesium carbonate, magnesium oxide, maltitol, maltodextrin, maltose, mannitol, simethicone, sorbitol, starch, sodium chloride, sucrose, talc, xylitol.
• the glidant that can be used in the sustained release formulations of the present invention comprising trimetazidine can be selected from a group comprising tribasic calcium phosphate, colloidal silicone dioxide, magnesium silicate, magnesium trisilicate, talc.
• the binder that can be used in the sustained release formulations of the present invention comprising trimetazidine can be selected from a group comprising carboxymethyl cellulose sodium, ethyl cellulose, gelatine, hydroxyethyl cellulose, hydroxymethyl cellulose, hydroxypropyl cellulose, hypromellose, magnesium aluminium silicate, maltodextrin, methylcellulose, povidone, starch.
• the pH-regulating agent that can be used in the sustained release formulations of the present invention comprising trimetazidine can be selected from citrate, phosphate, carbonate tartarate, fumarate, acetate and amino acid salts.
• the surfactant that can be used in the sustained release formulations of the present invention comprising trimetazidine can be selected from a group comprising sodium lauryl sulphate, polysorbate, polyoxyethylene, polyoxypropylene glycol and similar agents.
• the stabilizing agents that can be used in the sustained release formulations of the present invention comprising trimetazidine can be selected from a group comprising tocopherol, tetrasodium edetate, nicotinamide, cyclodextrin.
• the sweetener and/or taste-regulating agent that can be used in the sustained release formulations of the present invention comprising trimetazidine can be selected from a group comprising acesulphame, aspartame, dextrose, fructose, maltitol, maltose, mannitol, saccharin, saccharin sodium, sodium cyclamate, sorbitol, sucralose, sucrose, xylitol, sodium chloride.
• flavouring agent that can be used in the sustained release formulations of the present invention comprising trimetazidine can be selected from menthol, lemon, orange, vanilla, strawberry, raspberry, caramel and similar flavours.
• the lubricants that can be used in the sustained release formulations of the present invention comprising trimetazidine can be selected from a group comprising calcium stearate, magnesium stearate, polyethylene glycol, sodium benzoate, potassium benzoate, sodium lauryl sulphate, talc, stearic acid, zinc stearate or combinations thereof.
• the formulations of the present invention can be formulated in solid oral dosage forms such as tablet; layered tablet (for instance, bilayer tablet); capsule; enterically coated or modified release tablets; controlled release tablet; prolonged release tablet; delayed release tablet; slow or fast release tablet; pellet; mini tablet; micro tablet; granule in capsule; pellet in capsule; mini tablet in capsule; micro tablet in capsule.
• tablet dosage form is a preferred embodiment of the present invention.
• sustained release formulations of the present invention comprising trimetazidine are prepared in tablet form
• said tablet formulations can optionally be film coated.
• the film coating agents that can be used in coating of the formulations can be selected from a group comprising lactose, hydroxypropyl methylcellulose, triacetine, ferric oxide, titanium dioxide, polyvinyl alcohol, talc, lecithin, sodium alginate, stearic acid, glyceride, oils and gelatines, sugar derivatives, polyethylene glycol.
• Any production method can be used in the prior art in formulating the formulations of the present invention; wet granulation, dry granulation and dry blending methods can be listed among these production methods.
• the formulations of the present invention are preferably produced by dry blending method.
• the preferred method for production of the sustained release formulations of the present invention comprising trimetazidine is composed of the following steps: 1. Trimetazidine, at least one rate-controlling agent, the binder and the diluent are mixed.
• the lubricant is added into the mixture obtained and the mixture is mixed.
• sustained release trimetazidine formulations of the present invention are preferably compressed in tablet form in the final step of the production method and the tablets obtained are film coated.
• Trimetazidine, polyvinylpyrrolidone, polyvinyl acetate, the diluent and the binder are mixed.
• the mixture obtained by adding the lubricant is mixed again, sent to tablet compression machine, and compressed in tablet dosage form.
• the compressed tablets are coated with the film coating agent.

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• Health & Medical Sciences (AREA)
• Chemical & Material Sciences (AREA)
• Medicinal Chemistry (AREA)
• Pharmacology & Pharmacy (AREA)
• Epidemiology (AREA)
• Life Sciences & Earth Sciences (AREA)
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• General Health & Medical Sciences (AREA)
• Public Health (AREA)
• Veterinary Medicine (AREA)
• Medicinal Preparation (AREA)
• Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)

Applications Claiming Priority (2)

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Citations (3)

• 2013
  • 2013-05-27 WO PCT/TR2013/000156 patent/WO2013180676A1/fr not_active Ceased

Patent Citations (3)

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