EP2200591A2 - Formes galéniques à libération contrôlée à base de trimétazidine - Google Patents
Formes galéniques à libération contrôlée à base de trimétazidineInfo
- Publication number
- EP2200591A2 EP2200591A2 EP08807614A EP08807614A EP2200591A2 EP 2200591 A2 EP2200591 A2 EP 2200591A2 EP 08807614 A EP08807614 A EP 08807614A EP 08807614 A EP08807614 A EP 08807614A EP 2200591 A2 EP2200591 A2 EP 2200591A2
- Authority
- EP
- European Patent Office
- Prior art keywords
- trimetazidine
- dosage form
- pharmaceutically acceptable
- controlled release
- release
- 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- Withdrawn
Links
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
- A61K9/2013—Organic compounds, e.g. phospholipids, fats
-
- 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
- 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
- A61K9/2054—Cellulose; Cellulose derivatives, e.g. hydroxypropyl methylcellulose
-
- 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 new solid pharmaceutical dosage forms for the controlled release of trimetazidine suitable for once-daily dosing.
- Trimetazidine [l-(2,3,4-trimethoxybenzyl piperazine] is a 3-ketoacyl-coenzyme A thiolase inhibitor with a cytoprotective effect, which by preserving the energy metabolisms of the cell exposed to the hypoxia or ischaemia, avoids the collapse of the intracellular rate of adenosine triphosphate (ATP). Thus it ensures the functioning of the ion pumps and the sodium-potassium transmembrane flux and maintains the cellular homeostasis.
- ATP adenosine triphosphate
- Trimetazidine dihydrochloride is used therapeutically in the long-term treatment of angina pectoris. It is freely soluble in water and has two pKa values 4.32 and 8.95. 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. Servier had developed a modified-release dosage form containing 35mg for twice- daily administration, marketed under the brand name "VASTAREL MR".
- This dosage form was bioequivalent to the 20 mg conventional thrice-a-day formulation of trimetazidine hydrochloride.
- the modified-release formulation is based on a hydrophilic matrix that utilizes polymers which swell in contact with gastrointestinal fluids to form gels.
- This formulation has been covered by Servier in a European patent published as EP 1 108 424, which discloses a matrix tablet enabling prolonged release of trimetazidine comprised of cellulose derivative polymers.
- the formulation described releases more than 90% of the drug in-vitro within a period of 4 hours.
- European patent EP 0 673 649 also assigned to Servier describes pharmaceutical compositions for the prolonged release of trimetazidine wherein prolonged release is ensured by the reservoir system.
- the composition is prepared by compression of the active ingredient mixture and excipient, which are then coated with an insoluble polymer.
- hydrophilic polymers for controlling the release of trimetazidine from the controlled release pharmaceutical compositions.
- water-soluble salts such as hydrochloride salt of trimetazidine, it may result in burst release or dose dumping.
- the PCT application WO 03/043610 filed by Themis Laboratories discloses a process for manufacturing microbeads, which enable "once a day” dosing for 60 mg dose of trimetazidine dihydrochloride per unit dose.
- the application further provides dissolution rates at different time periods which correspond to 24 hours therapeutic blood levels. Further, it discloses the dissolution rate to be not less than 65% w/w in 6 hours.
- the European patent application EP 1 195 160 filed by USV discloses a sustained release dosage form of trimetazidine that releases more than 90% of the drug in- vitro within a period of about 6 hours to about 8 hours.
- the dosage form employs hydrophobic substance and a hydrocolloid for sustaining the release.
- a controlled in vitro release of trimetazidine is of most importance in the context of in vivo drug profiles.
- Drug absorption from a solid dosage form following oral administration depends on the release of the drug substance from the drug product, the dissolution or solubilization of the drug under physiological conditions, and the permeability across the gastrointestinal tract. Because of the critical nature of the first two of these steps, in vitro dissolution may be relevant to the prediction of in vivo performance.
- trimetazidine taking into account the great therapeutic interest of trimetazidine, there exists a need in the state of the art for new pharmaceutical dosage forms for "once a day” dosing of trimetazidine, prepared by a simpler process that is cost-effective and yields a dosage form with pH independent release of trimetazidine for at least 16 hours without any lag period.
- the present invention provides new solid pharmaceutical dosage forms for the controlled release of trimetazidine suitable for once-daily dosing, in which the dosage form exhibits a controlled in vitro release of trimetazidine in phosphate buffer at pH 6.8 of not less than about 75% after 16 hours when measured using USP Apparatus I at 100 rpm, thereby decreasing the incidence and severity of burst release or dose dumping.
- the pharmaceutical dosage form of the present invention uses a cost effective and rapid operation process.
- water-insoluble polymers have been employed as a coating polymer in reservoir systems, these systems produced a release profile where trimetazidine hydrochloride is not available for immediate absorption and pharmacological action.
- Other factors such as complexity of process, need for specialized equipment, incomplete release, etc. may also limit its use.
- the present invention utilizes a simpler process of employing water-insoluble polymers as the matrix forming polymer.
- the water insoluble polymers due to their nature, may result in a slower release, particularly in the beginning, leading to a lag phase. This is mainly due to less intake of aqueous medium.
- a water swellable polymer may be incorporated in the matrix which results in increased early wetting.
- a controlled release monolithic matrix dosage form comprising:
- trimetazidine or its pharmaceutically acceptable salts
- one or more rate controlling polymers selected from the group consisting of a water- insoluble polymer , water- swellable polymer, and mixture thereof, and
- the dosage forms contain about 50 mg to about 80 mg of trimetazidine.
- controlled release dosage forms of trimetazidine suitable for once-daily dosing contain about 70 mg of trimetazidine.
- Controlled release dosage forms of the present invention comprise about 5 to 50% by weight of trimetazidine based upon the total weight of the dosage form.
- water-insoluble rate controlling polymers include but are not limited to, one or more of ethyl cellulose, cellulose acetate, cellulose acetate phthalate, cellulose acetate trimellitate, co-polymers of acrylate or methacrylate having a low quaternary ammonium content, poly vinyl acetate, or mixtures thereof.
- the water- insoluble polymers are ethyl cellulose, acrylic acid polymers or a combination of the two.
- the water-insoluble polymers comprise about 5 to about 90% by weight of the dosage form.
- the water-insoluble polymers may comprise about 20 to about 60% by weight of the dosage form.
- water swellable rate controlling polymers include but are not limited to, hydroxypropyl methylcellulose, hydroxypropyl cellulose, hydroxypropyl ethylcellulose, hydroxyethylcellulose, methylcellulose, starch, gums, alginates, acrylic acid derivatives, gelatin and polyethylene oxide. Particularly the water swellable rate controlling polymer is xanthan gum.
- the water swellable polymers may comprise about 5 to about 90% by weight of the dosage form. Particularly the water swellable polymers may comprise about 7% to about 60% by weight of the dosage form.
- the highly water soluble drug trimetazidine or one of its salts is dispersed in a hydrophobic material.
- a controlled release monolithic matrix dosage form of trimetazidine comprising:
- rate controlling polymers selected from the group consisting of a water- insoluble polymer , water- swellable polymer, and mixture thereof, wherein trimetazidine is dispersed uniformly in the hydrophobic material, and wherein the dosage form exhibits in vitro release of trimetazidine or its pharmaceutically acceptable salt in phosphate buffer at pH 6.8 of not less than about 75% after 16 hours.
- hydrophobic material examples include but are not limited to, one or more of fatty acids, long chain fatty alcohols, waxes, vegetable oil and glycerides of C ⁇ -Ci 8 fatty acids or mineral oil or mixtures thereof.
- the hydrophobic material comprises carnauba wax, stearic acid or mixtures thereof.
- the hydrophobic materials may comprise about 5 to about 90% by weight of the dosage form. Particularly the hydrophobic materials may comprise about 20 to about 60% by weight of the dosage form.
- step (b) compressing the blend of step (a) into tablets; wherein the dosage form exhibits in vitro release of trimetazidine or its pharmaceutically acceptable salt in phosphate buffer at pH 6.8 of not less than about 75% after 16 hours.
- step (b) blending/mixing the material of step (a) with one or more pharmaceutically acceptable excipients, and (c) compressing the blend of step (b) into tablets; wherein the dosage form exhibits in vitro release of trimetazidine or its pharmaceutically acceptable salt in phosphate buffer at pH 6.8 of not less than about 75% after 16 hours.
- the granulation is carried out by wet granulating the active and the pharmaceutically acceptable excipients with a solution or dispersion of rate controlling polymer.
- a part of the rate controlling polymer is added along with the active.
- the granulation is carried out by dry blending the active, the pharmaceutically acceptable excipients and the rate controlling polymers and compacting to form granules.
- a process for preparing a controlled release monolithic matrix dosage form of trimetazidine comprising the steps of: (a) dispersing trimetazidine in at least one hydrophobic material;
- step (b) milling the material of step (a);
- step (c) mixing/blending the material of step (b) with a rate controlling polymer and other excipients;
- step (d) compressing the blend of step (c) into tablets; wherein the dosage form exhibits in vitro release of trimetazidine or its pharmaceutically acceptable salt in phosphate buffer at pH 6.8 of not less than about 75% after 16 hours.
- step (a) dispersing trimetazidine in atleast one hydrophobic material; (b) milling the material of step (a);
- step (c) granulating the material of step (b) with a rate controlling polymer and other excipients;
- step (d) compressing the blend of step (c) into tablets; wherein the dosage form exhibits in vitro release of trimetazidine or its pharmaceutically acceptable salt in phosphate buffer at pH 6.8 of not less than about 75% after 16 hours.
- the active is dispersed in at least one hydrophobic material with the help of solvents or by melting the hydrophobic material slightly above its melting point and dispersing the active in it.
- the granulation is carried out by wet granulating the active and the pharmaceutically acceptable excipients with a solution or dispersion of rate controlling polymer.
- a part of the rate controlling polymer is added along with the active.
- the granulation is carried out by dry blending the active, the pharmaceutically acceptable excipients and the rate controlling polymers and compacting to form granules.
- Example of solvents used for granulation comprise methylene chloride, isopropyl alcohol, acetone, methanol, ethanol, water or mixtures thereof.
- the hydrophobic materials were melted at temperatures ranging from about 4O 0 C to about 120° C. Particularly, the hydrophobic materials were melted at a temperature range of about 60° C to about 80° C.
- the controlled release dosage forms comprise one or more pharmaceutically acceptable excipients selected from one or more of binders, fillers, lubricants, glidants, coloring agents and flavoring agents.
- the dosage form is optionally coated with one or more layers comprising film forming agents and/or pharmaceutically acceptable excipients.
- a method of prophylactic treatment of angina pectoris comprising administering a controlled release monolithic matrix dosage form of trimetazidine, wherein the dosage form exhibits in vitro release of trimetazidine or its pharmaceutically acceptable salt in phosphate buffer at pH 6.8 of not less than about 75% after 16 hours.
- the controlled release monolithic matrix dosage form of trimetazidine may be administered in combination with other cardio therapeutic agents.
- the details of one or more embodiments of the inventions are set forth in the description below. Other features, objects, and advantages of the invention will be apparent from the description and claims.
- the present invention relates to controlled release dosage forms of trimetazidine suitable for once-daily dosing, containing less than about lOOmg of trimetazidine.
- the dosage forms Preferably contain about 50 mg to about 80 mg of trimetazidine.
- controlled release dosage forms of trimetazidine suitable for once-daily dosing contain about 70mg of trimetazidine.
- Trimetazidine used herein should be understood as the base or any of its pharmaceutically acceptable salt thereof. Particularly, the salt is dihydrochloride. Controlled release dosage forms of the present invention comprise about 5 to 50% by weight of trimetazidine.
- controlled-release includes any type of controlled- release including prolonged release, sustained release, modified release and extended release.
- the pharmaceutical dosage forms of the present invention can be administered orally in the form of tablets or capsules filled with pellets, beads, granules, multiparticulates, tablets or powder.
- the present invention employs water insoluble polymeric matrix to control the release of highly water soluble trimetazidine.
- a water swellable polymer is also added to the matrix to allow the aqueous medium to penetrate the dosage form and provide a tortuous path for uniform drug release.
- the active is released uniformly over a period of 12 to 24 hours in a substantially linear or zero order release.
- water-insoluble rate controlling polymers include but are not limited to, one or more of ethyl cellulose, cellulose acetate, cellulose acetate phthalate, cellulose acetate trimellitate, co-polymers of acrylate or methacrylate having a low quaternary ammonium content, poly vinyl acetate, or mixtures thereof.
- the water- insoluble polymers are ethyl cellulose, acrylic acid polymers or a combination of the two.
- the water-insoluble polymers comprise about 5 to about 90% by weight of the dosage form.
- the water-insoluble polymers may comprise about 20 to about 60% by weight of the dosage form.
- water swellable rate controlling polymers include but are not limited to, hydroxypropyl methylcellulose, hydroxypropyl cellulose, hydroxypropyl ethylcellulose, hydroxyethylcellulose, methylcellulose, starch, gums, alginates, acrylic acid derivatives, gelatin and polyethylene oxide.
- the water swellable polymers may comprise about 5 to about 90% by weight of the dosage form. Particularly the water swellable polymers may comprise about 7% to about 60% by weight of the dosage form.
- trimetazidine from the dosage form is further controlled in the early phase and a near zero-order release profile is obtained when the drug is dispersed in a hydrophobic material.
- hydrophobic material examples include but are not limited to, one or more of fatty acids, long chain fatty alcohols, waxes, vegetable oil and glycerides of C ⁇ -Ci 8 fatty acids or mineral oil or mixtures thereof.
- the hydrophobic materials may comprise about 5 to about 90% by weight of the dosage form. Particularly the hydrophobic materials may comprise about 20 to about 60% by weight of the dosage form.
- the controlled release dosage forms may further comprise one or more pharmaceutically acceptable excipients.
- the pharmaceutically acceptable excipients are those known to the skilled in the art and may be selected from binders, fillers, lubricants, glidants, coloring agents and flavoring agents.
- binders include, but are not limited to, methyl cellulose, hydroxypropyl cellulose, hydroxypropyl methylcellulose, polyvinylpyrrolidone, gelatin, gum Arabic, ethyl cellulose, polyvinyl alcohol, pregelatinized starch, agar, tragacanth, sodium alginate and propylene glycol.
- fillers or diluents include, but are not limited to, corn starch, lactose, white sugar, sucrose, sugar compressible, sugar confectioners, glucose, sorbitol, calcium carbonate, calcium dihydrogen phosphate dihydrates, calcium phosphate-dibasic, calcium phosphate-tribasic, calcium sulfate, microcrystalline cellulose, silicified microcrystalline cellulose, cellulose powdered, dextrates, dextrins, dextrose, fructose, kaolin, lactitol, mannitol, starch and starch pregelatinized.
- the fillers comprise microcrystalline cellulose, calcium dihydrogen phosphate dihydrate or a mixture of both.
- lubricants and glidants include, but are not limited to, colloidal anhydrous silica, stearic acid, magnesium stearate, calcium stearate, talc, hydrogenated castor oil, sucrose esters of fatty acids, microcrystalline wax, yellow beeswax and white beeswax.
- the coloring agents and flavoring agents of the present invention may be selected from any FDA approved colors and flavors for oral use.
- the ingredients discussed above may be formed into dosage forms by conventional techniques, for example either by direct compression, or first compacting some of the ingredients, milling the compacts, blending with the remaining ingredients and then compressing as appropriate.
- the controlled release monolithic matrix dosage forms may also be prepared using wet granulation techniques.
- the process may include granulation of trimetazidine and the rate controlling polymers with a solvent or granulation of trimetazidine with a solution of the polymer.
- the process may further include drying the granules prior to compressing into tablets.
- controlled release dosage forms of the present invention can optionally be coated with one or more layers comprising film forming agents and/or pharmaceutically acceptable excipients.
- Coating may be performed by applying one or more film forming polymers with or without other pharmaceutically inert excipients. This may be done as a solution or suspensions using any conventional coating technique known in the prior art, such as spray coating in a conventional coating pan or fluidized bed processor, or dip coating.
- Suitable film forming polymers include one or more of ethylcellulose, hydroxypropyl methylcellulose, hydroxypropyl cellulose, methylcellulose, carboxymethylcellulose, hydroxymethylcellulose, hydroxyethylcellulose, cellulose acetate, hydroxypropyl methylcellulose phthalate, cellulose acetate phthalate, cellulose acetate trimellitate, waxes, methacrylic acid polymers such as Eudragit® RL and RS, and mixtures thereof.
- the coating can also be performed using any commercially available ready to coat preparations such as Opadry-AMB, Opadry- White, Opadry-Clear, etc.
- Suitable solvents used for making a solution/suspension of film forming polymer include one or more of methylene chloride, isopropyl alcohol, acetone, methanol, ethanol, water and mixtures thereof.
- a controlled release monolithic matrix dosage form of trimetazidine in the prophylactic treatment of angina pectoris wherein the dosage form exhibits in vitro release of trimetazidine or its pharmaceutically acceptable salt in phosphate buffer at pH 6.8 of not less than about 75% after 16 hours.
- the controlled release monolithic matrix dosage form of trimetazidine may be administered in combination with other cardio therapeutic agents.
- Trimetazidine dihydrochloride, microcrystalline cellulose (High viscosity), xanthan gum & ethylcellulose (High viscosity) were mixed and granulated with ethylcellulose (Low viscosity).
- step-1 Granules of step-1 were blended with microcrystalline cellulose (Low viscosity), carbopol, colloidal silicon dioxide and magnesium stearate.
- the controlled release (CR) dosage forms prepared according to Examples 1, 2 and 3 were subjected to in vitro drug release test which utilizes the United States Pharmacopea (USP) Apparatus 1 (rotating basket) at 100 rpm with 500 ml of phosphate buffer at pH 6.8 and 37° C.
- USP United States Pharmacopea
- the results of the in vitro drug release test are given in Table 1.
- Table 1 Drug Release of Trimetazidine CR dosage forms prepared as per Examples 1, 2 and 3 in Phosphate buffer pH 6.8, 500 ml, USP 1 at 100 rpm.
- Example 4 Controlled release monolithic matrix dosage form of trimetazdine dihydrochloride
- Trimetazidine hydrochloride was dispersed in a molten mass of carnauba wax and stearic acid.
- step 1 Dispersion of step 1 was stirred till it cooled.
- step 2 Material of step 2 was milled and blended with ethyl cellulose; xanthan gum; microcrystalline cellulose; colloidal silicon dioxide and magnesium stearate.
- Trimetazidine hydrochloride was dispersed in a molten mass of carnauba wax and stearic acid.
- step 1 Dispersion of step 1 was stirred till it cooled. 3.
- Material of step 2 was milled and blended with ethyl cellulose; xanthan gum; microcrystalline cellulose; calcium dihydrogen phosphate dihydrate; colloidal silicon dioxide and magnesium stearate.
- step 3 Material of step 3 was compressed into tablets.
- step 4 Tablets of step 4 were coated with the coating composition.
- the controlled release (CR) dosage form prepared according to Example 5 were subjected to in vitro drug release test which utilizes the United States Pharmacopea (USP) Apparatus 1 (rotating basket) at 100 rpm with 500 ml of phosphate buffer at pH 6.8 and 37° C.
- USP United States Pharmacopea
- the results of the in vitro drug release test are given in Table 2.
- Table 2 Drug Release of Trimetazidine CR dosage form prepared as per Example 5 in Phosphate buffer pH 6.8, 500 ml, USP 1 at 100 rpm.
- Table 3 Pharmacokinetic data for controlled release (CR) monolithic matrix dosage forms prepared as per present invention. Once daily vs. three doses of VASTAREL 20 mg tablets (containing trimetazidine 20 mg) administered thrice daily
- Table 4 Pharmacokinetic data for controlled release controlled release monolithic matrix dosage forms prepared as per present invention. Once daily vs. two doses of VASTAREL MR 35 mg tablets (containing trimetazidine 35 mg) administered twice daily
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Abstract
La présente invention a trait à des formes galéniques solides inédites permettant la libération contrôlée de trimétazidine et ne nécessitant qu'une unique prise quotidienne, ladite forme galénique étant caractérisée par une libération contrôlée in vitro de trimétazidine dans du tampon phosphate à un pH de 6,8 à hauteur de pas moins d'environ 75 % au bout de 16 heures, comme mesuré au moyen d'un dispositif USP Apparatus I à 100 tr/mn, ce qui permet de limiter la fréquence et la gravité des problèmes associés à une libération trop importante ou trop rapide.
Applications Claiming Priority (3)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
IN1925DE2007 | 2007-09-11 | ||
IN1226DE2008 | 2008-05-16 | ||
PCT/IB2008/053679 WO2009034541A2 (fr) | 2007-09-11 | 2008-09-11 | Formes galéniques à libération contrôlée à base de trimétazidine |
Publications (1)
Publication Number | Publication Date |
---|---|
EP2200591A2 true EP2200591A2 (fr) | 2010-06-30 |
Family
ID=40120263
Family Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
EP08807614A Withdrawn EP2200591A2 (fr) | 2007-09-11 | 2008-09-11 | Formes galéniques à libération contrôlée à base de trimétazidine |
Country Status (2)
Country | Link |
---|---|
EP (1) | EP2200591A2 (fr) |
WO (1) | WO2009034541A2 (fr) |
Families Citing this family (34)
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US7776314B2 (en) | 2002-06-17 | 2010-08-17 | Grunenthal Gmbh | Abuse-proofed dosage system |
DE10336400A1 (de) | 2003-08-06 | 2005-03-24 | Grünenthal GmbH | Gegen Missbrauch gesicherte Darreichungsform |
DE102005005446A1 (de) | 2005-02-04 | 2006-08-10 | Grünenthal GmbH | Bruchfeste Darreichungsformen mit retardierter Freisetzung |
US20070048228A1 (en) | 2003-08-06 | 2007-03-01 | Elisabeth Arkenau-Maric | Abuse-proofed dosage form |
DE10361596A1 (de) | 2003-12-24 | 2005-09-29 | Grünenthal GmbH | Verfahren zur Herstellung einer gegen Missbrauch gesicherten Darreichungsform |
DE102004032049A1 (de) | 2004-07-01 | 2006-01-19 | Grünenthal GmbH | Gegen Missbrauch gesicherte, orale Darreichungsform |
DE102005005449A1 (de) | 2005-02-04 | 2006-08-10 | Grünenthal GmbH | Verfahren zur Herstellung einer gegen Missbrauch gesicherten Darreichungsform |
RU2493830C2 (ru) | 2008-01-25 | 2013-09-27 | Грюненталь Гмбх | Лекарственная форма |
BRPI0912014A2 (pt) | 2008-05-09 | 2019-03-06 | Grünenthal GmbH | processo para a preparação de uma formulação em pó intermediária e uma forma de dosagem sólida final sob uso de uma etapa de congelamento por atomização |
TW201105316A (en) | 2009-07-22 | 2011-02-16 | Gruenenthal Gmbh | Hot-melt extruded pharmaceutical dosage form |
KR101747156B1 (ko) | 2009-07-22 | 2017-06-27 | 그뤼넨탈 게엠베하 | 산화-안정화된 탬퍼-내성 용량형 |
TR201001902A2 (tr) | 2010-03-12 | 2011-04-21 | Ali̇ Rai̇f İlaç Sanayi̇ Ve Ti̇caret A.Ş. | Uzatılmış salınımlı trimetazidin tablet |
EP2394644B1 (fr) * | 2010-05-04 | 2014-07-09 | Sanovel Ilaç Sanayi Ve Ticaret Anonim Sirketi | Formulation de trimetazidine avec différents profils de distribution |
CN103179954A (zh) | 2010-09-02 | 2013-06-26 | 格吕伦塔尔有限公司 | 包含阴离子聚合物的抗破碎剂型 |
PE20131102A1 (es) | 2010-09-02 | 2013-10-12 | Gruenenthal Chemie | Forma de dosificacion resistente a manipulacion que comprende una sal inorganica |
MX348491B (es) | 2011-07-29 | 2017-06-15 | Gruenenthal Gmbh | Tableta a prueba de manipulacion que proporciona liberacion inmediata de fármaco. |
PT2736497T (pt) | 2011-07-29 | 2017-11-30 | Gruenenthal Gmbh | Comprimido resistente a adulteração proporcionando libertação imediata de fármaco |
WO2013127831A1 (fr) | 2012-02-28 | 2013-09-06 | Grünenthal GmbH | Forme pharmaceutique inviolable comprenant un composé pharmacologiquement actif et un polymère anionique |
AU2013248351B2 (en) | 2012-04-18 | 2018-04-26 | Grunenthal Gmbh | Tamper resistant and dose-dumping resistant pharmaceutical dosage form |
US10064945B2 (en) | 2012-05-11 | 2018-09-04 | Gruenenthal Gmbh | Thermoformed, tamper-resistant pharmaceutical dosage form containing zinc |
CN102824644B (zh) * | 2012-09-13 | 2013-12-25 | 浙江诚意药业有限公司 | 使用羟丙基纤维素制备的高稳定性的缓释片 |
AR096439A1 (es) | 2013-05-29 | 2015-12-30 | Gruenenthal Gmbh | Forma de dosificación resistente al uso indebido que contiene una o más partículas |
US10154966B2 (en) | 2013-05-29 | 2018-12-18 | Grünenthal GmbH | Tamper-resistant dosage form containing one or more particles |
EA032465B1 (ru) | 2013-07-12 | 2019-05-31 | Грюненталь Гмбх | Защищенная от применения не по назначению пероральная фармацевтическая лекарственная форма, содержащая этиленвинилацетатный полимер, и способ ее изготовления |
JP6480936B2 (ja) | 2013-11-26 | 2019-03-13 | グリュネンタール・ゲゼルシャフト・ミト・ベシュレンクテル・ハフツング | クライオミリングによる粉末状医薬組成物の調製 |
EP3142646A1 (fr) | 2014-05-12 | 2017-03-22 | Grünenthal GmbH | Formulation pour capsule à libération immédiate résistant aux manipulations illicites comprenant du tapentadol |
CN106456550A (zh) * | 2014-05-26 | 2017-02-22 | 格吕伦塔尔有限公司 | 避免乙醇剂量倾泻的多颗粒 |
AU2016251854A1 (en) | 2015-04-24 | 2017-10-19 | Grunenthal Gmbh | Tamper-resistant dosage form with immediate release and resistance against solvent extraction |
EP3346991A1 (fr) | 2015-09-10 | 2018-07-18 | Grünenthal GmbH | Protection contre un surdosage par voie orale à l'aide de formulations à libération immédiate dissuasives d'abus |
MX2019005782A (es) | 2016-11-21 | 2019-08-29 | Saghmos Therapeutics Inc | Prevencion y/o tratamiento de lesion aguda de riñon inducida por contraste. |
US20180190374A1 (en) * | 2017-01-03 | 2018-07-05 | Saghmos Therapeutics, Inc. | Methods of improving patient compliance to treat contrast-induced injury |
CN109908096A (zh) * | 2017-12-12 | 2019-06-21 | 武汉武药科技有限公司 | 一种盐酸曲美他嗪缓释片及其制备方法 |
CN110623934B (zh) * | 2019-09-26 | 2022-05-13 | 杭州百诚医药科技股份有限公司 | 一种盐酸曲美他嗪缓释片及其制备方法 |
CN111888476A (zh) * | 2020-08-17 | 2020-11-06 | 深圳市道科思医药有限公司 | 盐酸曲美他嗪的改良释放药物组合物 |
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JPH0625055B2 (ja) * | 1985-03-18 | 1994-04-06 | 日本ケミフア株式会社 | 持続性錠剤 |
FR2717687B1 (fr) * | 1994-03-24 | 1996-06-14 | Adir | Compositions pharmaceutiques permettant la libération prolongée de trimétazidine après administration par voie orale. |
FR2802424B1 (fr) * | 1999-12-17 | 2002-02-15 | Adir | Comprime matriciel permettant la liberation prolongee de trimetazidine apres administration par voie orale |
PT1195160E (pt) | 2000-10-05 | 2009-12-07 | Usv Ltd | Composições farmacêuticas de trimetazidina de libertação sustentada e método para a sua preparação |
FR2818549B1 (fr) * | 2000-12-26 | 2003-02-07 | Servier Lab | Composition pharmaceutique solide thermoformable pour la liberation controlee de trimetazidine |
WO2003043610A2 (fr) | 2001-11-21 | 2003-05-30 | Themis Laboratories Private Limited | Procede de fabrication d'une composition pharmaceutique a liberation prolongee contenant des microbilles de trimetazidine dihydrochloride |
FR2885807B1 (fr) * | 2005-05-18 | 2008-05-16 | Mg Pharma | Composition pharmaceutique solide a liberation prolongee de 1-(2,3,4-trimethoxybenzyl) piperazine, et procede de preparation |
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2008
- 2008-09-11 WO PCT/IB2008/053679 patent/WO2009034541A2/fr active Application Filing
- 2008-09-11 EP EP08807614A patent/EP2200591A2/fr not_active Withdrawn
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WO2009034541A2 (fr) | 2009-03-19 |
WO2009034541A3 (fr) | 2009-07-30 |
WO2009034541A9 (fr) | 2009-12-30 |
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