WO2013180676A1 - A new sustained release formulation - Google Patents
A new sustained release formulation Download PDFInfo
- Publication number
- WO2013180676A1 WO2013180676A1 PCT/TR2013/000156 TR2013000156W WO2013180676A1 WO 2013180676 A1 WO2013180676 A1 WO 2013180676A1 TR 2013000156 W TR2013000156 W TR 2013000156W WO 2013180676 A1 WO2013180676 A1 WO 2013180676A1
- Authority
- WO
- WIPO (PCT)
- Prior art keywords
- sustained release
- agent
- agents
- trimetazidine
- release formulation
- Prior art date
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- GVJHHUAWPYXKBD-UHFFFAOYSA-N d-alpha-tocopherol Natural products OC1=C(C)C(C)=C2OC(CCCC(C)CCCC(C)CCCC(C)C)(C)CCC2=C1C GVJHHUAWPYXKBD-UHFFFAOYSA-N 0.000 description 1
- 239000007950 delayed release tablet Substances 0.000 description 1
- 235000019700 dicalcium phosphate Nutrition 0.000 description 1
- 229940095079 dicalcium phosphate anhydrous Drugs 0.000 description 1
- AMTWCFIAVKBGOD-UHFFFAOYSA-N dioxosilane;methoxy-dimethyl-trimethylsilyloxysilane Chemical compound O=[Si]=O.CO[Si](C)(C)O[Si](C)(C)C AMTWCFIAVKBGOD-UHFFFAOYSA-N 0.000 description 1
- 239000007948 fast release tablet Substances 0.000 description 1
- 235000019634 flavors Nutrition 0.000 description 1
- 229960002737 fructose Drugs 0.000 description 1
- 229960001031 glucose Drugs 0.000 description 1
- 125000005456 glyceride group Chemical group 0.000 description 1
- 239000008187 granular material Substances 0.000 description 1
- 235000019447 hydroxyethyl cellulose Nutrition 0.000 description 1
- 229940071826 hydroxyethyl cellulose Drugs 0.000 description 1
- UFVKGYZPFZQRLF-UHFFFAOYSA-N hydroxypropyl methyl cellulose Chemical compound OC1C(O)C(OC)OC(CO)C1OC1C(O)C(O)C(OC2C(C(O)C(OC3C(C(O)C(O)C(CO)O3)O)C(CO)O2)O)C(CO)O1 UFVKGYZPFZQRLF-UHFFFAOYSA-N 0.000 description 1
- 229960003943 hypromellose Drugs 0.000 description 1
- 239000003112 inhibitor Substances 0.000 description 1
- UQSXHKLRYXJYBZ-UHFFFAOYSA-N iron oxide Inorganic materials [Fe]=O UQSXHKLRYXJYBZ-UHFFFAOYSA-N 0.000 description 1
- 230000000302 ischemic effect Effects 0.000 description 1
- 239000000832 lactitol Substances 0.000 description 1
- 235000010448 lactitol Nutrition 0.000 description 1
- VQHSOMBJVWLPSR-JVCRWLNRSA-N lactitol Chemical compound OC[C@H](O)[C@@H](O)[C@@H]([C@H](O)CO)O[C@@H]1O[C@H](CO)[C@H](O)[C@H](O)[C@H]1O VQHSOMBJVWLPSR-JVCRWLNRSA-N 0.000 description 1
- 229960003451 lactitol Drugs 0.000 description 1
- 239000007942 layered tablet Substances 0.000 description 1
- 239000000787 lecithin Substances 0.000 description 1
- 235000010445 lecithin Nutrition 0.000 description 1
- 229940067606 lecithin Drugs 0.000 description 1
- 239000011777 magnesium Substances 0.000 description 1
- 229910052749 magnesium Inorganic materials 0.000 description 1
- 235000001055 magnesium Nutrition 0.000 description 1
- ZLNQQNXFFQJAID-UHFFFAOYSA-L magnesium carbonate Chemical compound [Mg+2].[O-]C([O-])=O ZLNQQNXFFQJAID-UHFFFAOYSA-L 0.000 description 1
- 239000001095 magnesium carbonate Substances 0.000 description 1
- 229910000021 magnesium carbonate Inorganic materials 0.000 description 1
- 239000000395 magnesium oxide Substances 0.000 description 1
- CPLXHLVBOLITMK-UHFFFAOYSA-N magnesium oxide Inorganic materials [Mg]=O CPLXHLVBOLITMK-UHFFFAOYSA-N 0.000 description 1
- 229910052919 magnesium silicate Inorganic materials 0.000 description 1
- 235000019792 magnesium silicate Nutrition 0.000 description 1
- 235000019359 magnesium stearate Nutrition 0.000 description 1
- 229940091250 magnesium supplement Drugs 0.000 description 1
- 229910000386 magnesium trisilicate Inorganic materials 0.000 description 1
- 235000019793 magnesium trisilicate Nutrition 0.000 description 1
- 229940099273 magnesium trisilicate Drugs 0.000 description 1
- AXZKOIWUVFPNLO-UHFFFAOYSA-N magnesium;oxygen(2-) Chemical compound [O-2].[Mg+2] AXZKOIWUVFPNLO-UHFFFAOYSA-N 0.000 description 1
- 229960002160 maltose Drugs 0.000 description 1
- 229960001855 mannitol Drugs 0.000 description 1
- 229940041616 menthol Drugs 0.000 description 1
- 125000000007 metacrylic acid group Chemical group 0.000 description 1
- 208000010125 myocardial infarction Diseases 0.000 description 1
- 239000003921 oil Substances 0.000 description 1
- 239000006186 oral dosage form Substances 0.000 description 1
- NDLPOXTZKUMGOV-UHFFFAOYSA-N oxo(oxoferriooxy)iron hydrate Chemical compound O.O=[Fe]O[Fe]=O NDLPOXTZKUMGOV-UHFFFAOYSA-N 0.000 description 1
- NBIIXXVUZAFLBC-UHFFFAOYSA-K phosphate Chemical compound [O-]P([O-])([O-])=O NBIIXXVUZAFLBC-UHFFFAOYSA-K 0.000 description 1
- 239000010452 phosphate Substances 0.000 description 1
- 229920001451 polypropylene glycol Polymers 0.000 description 1
- 229920000136 polysorbate Polymers 0.000 description 1
- 229950008882 polysorbate Drugs 0.000 description 1
- 229920002451 polyvinyl alcohol Polymers 0.000 description 1
- 235000019422 polyvinyl alcohol Nutrition 0.000 description 1
- 229920000523 polyvinylpolypyrrolidone Polymers 0.000 description 1
- 235000013809 polyvinylpolypyrrolidone Nutrition 0.000 description 1
- XAEFZNCEHLXOMS-UHFFFAOYSA-M potassium benzoate Chemical compound [K+].[O-]C(=O)C1=CC=CC=C1 XAEFZNCEHLXOMS-UHFFFAOYSA-M 0.000 description 1
- 239000004300 potassium benzoate Substances 0.000 description 1
- 229940103091 potassium benzoate Drugs 0.000 description 1
- 235000010235 potassium benzoate Nutrition 0.000 description 1
- 229940069328 povidone Drugs 0.000 description 1
- 239000000843 powder Substances 0.000 description 1
- 230000002035 prolonged effect Effects 0.000 description 1
- 238000011321 prophylaxis Methods 0.000 description 1
- CVHZOJJKTDOEJC-UHFFFAOYSA-N saccharin Chemical compound C1=CC=C2C(=O)NS(=O)(=O)C2=C1 CVHZOJJKTDOEJC-UHFFFAOYSA-N 0.000 description 1
- 235000019204 saccharin Nutrition 0.000 description 1
- 229940081974 saccharin Drugs 0.000 description 1
- 239000000901 saccharin and its Na,K and Ca salt Substances 0.000 description 1
- 229940085605 saccharin sodium Drugs 0.000 description 1
- HFHDHCJBZVLPGP-UHFFFAOYSA-N schardinger α-dextrin Chemical compound O1C(C(C2O)O)C(CO)OC2OC(C(C2O)O)C(CO)OC2OC(C(C2O)O)C(CO)OC2OC(C(O)C2O)C(CO)OC2OC(C(C2O)O)C(CO)OC2OC2C(O)C(O)C1OC2CO HFHDHCJBZVLPGP-UHFFFAOYSA-N 0.000 description 1
- 229940083037 simethicone Drugs 0.000 description 1
- WXMKPNITSTVMEF-UHFFFAOYSA-M sodium benzoate Chemical compound [Na+].[O-]C(=O)C1=CC=CC=C1 WXMKPNITSTVMEF-UHFFFAOYSA-M 0.000 description 1
- 239000004299 sodium benzoate Substances 0.000 description 1
- 235000010234 sodium benzoate Nutrition 0.000 description 1
- 229960001462 sodium cyclamate Drugs 0.000 description 1
- 229920003109 sodium starch glycolate Polymers 0.000 description 1
- 239000008109 sodium starch glycolate Substances 0.000 description 1
- 229940079832 sodium starch glycolate Drugs 0.000 description 1
- 239000007787 solid Substances 0.000 description 1
- 229960002920 sorbitol Drugs 0.000 description 1
- 239000000126 substance Substances 0.000 description 1
- 235000019408 sucralose Nutrition 0.000 description 1
- BAQAVOSOZGMPRM-QBMZZYIRSA-N sucralose Chemical compound O[C@@H]1[C@@H](O)[C@@H](Cl)[C@@H](CO)O[C@@H]1O[C@@]1(CCl)[C@@H](O)[C@H](O)[C@@H](CCl)O1 BAQAVOSOZGMPRM-QBMZZYIRSA-N 0.000 description 1
- UEUXEKPTXMALOB-UHFFFAOYSA-J tetrasodium;2-[2-[bis(carboxylatomethyl)amino]ethyl-(carboxylatomethyl)amino]acetate Chemical compound [Na+].[Na+].[Na+].[Na+].[O-]C(=O)CN(CC([O-])=O)CCN(CC([O-])=O)CC([O-])=O UEUXEKPTXMALOB-UHFFFAOYSA-J 0.000 description 1
- 239000004408 titanium dioxide Substances 0.000 description 1
- 235000010215 titanium dioxide Nutrition 0.000 description 1
- 229960001295 tocopherol Drugs 0.000 description 1
- 229930003799 tocopherol Natural products 0.000 description 1
- 235000010384 tocopherol Nutrition 0.000 description 1
- 239000011732 tocopherol Substances 0.000 description 1
- 231100000331 toxic Toxicity 0.000 description 1
- 230000002588 toxic effect Effects 0.000 description 1
- VZCYOOQTPOCHFL-UHFFFAOYSA-N trans-butenedioic acid Natural products OC(=O)C=CC(O)=O VZCYOOQTPOCHFL-UHFFFAOYSA-N 0.000 description 1
- URAYPUMNDPQOKB-UHFFFAOYSA-N triacetin Chemical compound CC(=O)OCC(OC(C)=O)COC(C)=O URAYPUMNDPQOKB-UHFFFAOYSA-N 0.000 description 1
- 229960002622 triacetin Drugs 0.000 description 1
- 125000005591 trimellitate group Chemical group 0.000 description 1
- 208000019553 vascular disease Diseases 0.000 description 1
- 229920002554 vinyl polymer Polymers 0.000 description 1
- 235000020681 well water Nutrition 0.000 description 1
- 239000002349 well water Substances 0.000 description 1
- XOOUIPVCVHRTMJ-UHFFFAOYSA-L zinc stearate Chemical compound [Zn+2].CCCCCCCCCCCCCCCCCC([O-])=O.CCCCCCCCCCCCCCCCCC([O-])=O XOOUIPVCVHRTMJ-UHFFFAOYSA-L 0.000 description 1
- GVJHHUAWPYXKBD-IEOSBIPESA-N α-tocopherol Chemical compound OC1=C(C)C(C)=C2O[C@@](CCC[C@H](C)CCC[C@H](C)CCCC(C)C)(C)CCC2=C1C GVJHHUAWPYXKBD-IEOSBIPESA-N 0.000 description 1
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)
- Animal Behavior & Ethology (AREA)
- General Health & Medical Sciences (AREA)
- Public Health (AREA)
- Veterinary Medicine (AREA)
- Medicinal Preparation (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Abstract
The present invention relates to sustained release pharmaceutical tablet formulations suitable for oral use comprising 1-(2 3 4-trimethoxybenzyl)piperazine dihydrochloride as the active agent and production method thereof.
Description
A NEW SUSTAINED RELEASE FORMULATION
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.
Formula I. Trimetazidine
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.
In other aspect, the risks of ischemia and fatal myocardial infarction caused by ischemia are mostly seen in patients at nights and usually in the small hours. Therefore, 24 hour-sustained release active agent is quite important in ischemia prophylaxis for treatment.
The prior art recommends the sustained release formulations comprising trimetazidine. For instance, the European patent application numbered EP 1 108424 relates to the sustained release pharmaceutical formulations wherein the release is provided by cellulose or a
cellulose derivative matrix. In the application, it is disclosed that 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.
In other aspect, 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. As a result of the studies they conducted in the scope of the present invention, the inventors have found that use of at least one water insoluble rate-controlling agent in the sustained release trimetazidine formulations as stated in the prior art does not provide suitable release rate and therapeutic efficiency.
In other aspect, 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.
According to this, 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.
In one aspect, the present invention discloses the sustained release trimetazidine formulations suitable for oral use.
In another aspect, 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 development studies conducted in the scope of the present invention have shown that the most suitable release rate is provided when the ratio of the active agent / at least one rate- controlling agent is in the range of 0.1 to 1 by weight, preferably in the range of 0.1 to 0.8 by weight, more preferably in the range of 0.1 to 0.6 by weight.
In another aspect, 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. In another aspect, 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.
In another aspect, 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.
Another characteristic feature of the sustained release trimetazidine formulations of the present invention is that the water soluble rate-controlling agent is polyvinylpyrrolidone, the water insoluble rate-controlling agent is polyvinyl acetate.
In other words, a characteristic feature of the sustained release trimetazidine formulations of the present invention is that the rate-controlling agent comprised in the formulations is the combination of polyvinylpyrrolidone and polyvinyl acetate.
In other aspect, 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.
In the sustained release trimetazidine formulations of the present invention, minimum 40% of trimetazidine releases in the 60th minute, minimum 60% of trimetazidine releases in the 120th minute, minimum 80% of trimetazidine releases in the 240 minute.
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.
Another characteristic feature of the sustained release trimetazidine formulations of the present invention is that said formulations comprise 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.
The 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. However, tablet dosage form is a preferred embodiment of the present invention.
In the case that the 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.
2. The lubricant is added into the mixture obtained and the mixture is mixed.
3. The mixture obtained in the final step is formed into the required dosage form.
The 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.
The pharmaceutical formulations of the present invention are given below. The formulations of the present invention should not be limited to these examples.
EXAMPLES
Sustained Release Film Coated Tablet Formulation comprising Trimetazidine
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.
Claims
1. Sustained release formulations suitable for oral use, characterized in that said formulations comprise trimetazidine or at least one pharmaceutically acceptable salt thereof as the active agent, at least one rate-controlling agent minimum in an amount of 50% by weight and at least one other excipient.
2. The sustained release formulations according to claim 1, characterized in that the ratio of the active agent/at least one rate controlling agent is in the range of 0.1 to 1.
3. The sustained release formulations according to claim 2, characterized in that the ratio of the active agent/at least one rate-controlling agent is in the range of 0.1 to 0.8.
4. The sustained release formulations according to claims 2-3, characterized in that the ratio of the active agent/at least one rate-controlling agent is in the range of 0.1 to 0.6.
5. The sustained release formulation according to claim 1, characterized in that at least one rate-controlling agent is the combination of a water soluble agent and a water insoluble agent.
6. The sustained release formulation according to claim 5, characterized in that the ratio of the water soluble agent to the water insoluble agent is in the range of 1 to 10 by weight.
7. The sustained release formulation according to claims 5-6, characterized in that the ratio of the water soluble agent to the water insoluble agent is in the range of 1 to 8 by weight.
8. The sustained release formulation according to claims 5-7, characterized in that the ratio of the water soluble agent to the water insoluble agent is in the range of 1 to 7 by weight.
9. The sustained release formulations according to claims 5-8, characterized in that the water soluble agent is 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.
10. The sustained release formulations according to claims 5-8, characterized in that the water insoluble agent is selected from a group comprising cellulose derivatives such as acrylates, ethyl cellulose, cellulose acetate, methacrylates, acrylic acid copolymers or combinations thereof.
11. The sustained release formulation according to claims 9-10, characterized in that the rate-controlling agent is the combination of polyvinylpyrrolidone and polyvinyl acetate.
12. The pharmaceutical sustained release formulation comprising trimetazidine according to any preceding claims, wherein said pharmaceutical formulation comprises trimetazidine in the range of 0.1 to 95% by weight.
13. The pharmaceutical sustained release formulation comprising trimetazidine according to claim 12, wherein said formulation comprises trimetazidine in the range of 1 to 90% by weight.
14. The pharmaceutical sustained release formulation comprising trimetazidine according to any preceding claims, characterized in that said formulation comprises trimetazidine, its pharmaceutically acceptable salts, hydrates, solvates, esters, enantiomers, diastereomers or combinations thereof as the active agent.
15. The sustained release formulation according to claim 14, characterized in that said formulation comprises trimetazidine dihydrochloride as the active agent.
16. The sustained release formulation according to claim 1, characterized in that said formulations comprise at least one pharmaceutically acceptable excipient 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.
17. The sustained release formulation according to claim 1, characterized in that said formulation is film coated.
18. The method for production of the sustained release formulation according to any preceding claims, characterized in that said method is wet granulation, dry granulation, dry blending or a method composed of the combinations thereof.
19. The method for the sustained release formulation according to claim 18, characterized in that said method is dry blending.
20. The method according to claims 18-19, characterized in that said method is composed of the following steps:
Mixing trimetazidine, at least one rate-controlling agent, the binder and the diluent,
Adding the lubricant into the mixture obtained and mixing the mixture, Forming the mixture obtained in the final step into the required dosage form.
Applications Claiming Priority (2)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| TR201206205 | 2012-05-28 | ||
| TR2012/06205 | 2012-05-28 |
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|---|---|
| WO2013180676A1 true WO2013180676A1 (en) | 2013-12-05 |
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|---|---|---|---|
| PCT/TR2013/000156 WO2013180676A1 (en) | 2012-05-28 | 2013-05-27 | A new sustained release formulation |
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| Country | Link |
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| WO (1) | WO2013180676A1 (en) |
Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2009066315A2 (en) * | 2007-08-08 | 2009-05-28 | Usv Limited | Sustained release compositions of trimetazidine and process for preparation thereof |
| WO2010086868A1 (en) * | 2009-01-30 | 2010-08-05 | Lupin Limited | Pharmaceutical compositions of trimetazidine |
| EP2394644A2 (en) * | 2010-05-04 | 2011-12-14 | Sanovel Ilac Sanayi ve Ticaret A.S. | Trimetazidine Formulation With Different Release Profiles |
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2013
- 2013-05-27 WO PCT/TR2013/000156 patent/WO2013180676A1/en active Application Filing
Patent Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2009066315A2 (en) * | 2007-08-08 | 2009-05-28 | Usv Limited | Sustained release compositions of trimetazidine and process for preparation thereof |
| WO2010086868A1 (en) * | 2009-01-30 | 2010-08-05 | Lupin Limited | Pharmaceutical compositions of trimetazidine |
| EP2394644A2 (en) * | 2010-05-04 | 2011-12-14 | Sanovel Ilac Sanayi ve Ticaret A.S. | Trimetazidine Formulation With Different Release Profiles |
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