SK286752B6 - Matrix tablet for sustained release of trimetazidine and process for preparing thereof - Google Patents

Matrix tablet for sustained release of trimetazidine and process for preparing thereof Download PDF

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SK286752B6
SK286752B6 SK863-2002A SK8632002A SK286752B6 SK 286752 B6 SK286752 B6 SK 286752B6 SK 8632002 A SK8632002 A SK 8632002A SK 286752 B6 SK286752 B6 SK 286752B6
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matrix tablet
tablet according
matrix
trimethazidine
total weight
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SK8632002A3 (en
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De Barochez Bruno Huet
Claude Dauphant
Patrick Wuthrich
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Les Laboratoires Servier
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    • 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
    • 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
    • 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
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
    • A61P1/08—Drugs for disorders of the alimentary tract or the digestive system for nausea, cinetosis or vertigo; Antiemetics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P27/00—Drugs for disorders of the senses
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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
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    • A61P27/16—Otologicals
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
    • 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
    • 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

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Abstract

Matrix tablet for the prolonged release of trimetazidine or a pharmaceutically acceptable salt thereof wherein the prolonged release is controlled by the use of a cellulose derivative polymer present in the matrix, said polymer being hydroxypropylcellulose, hydroxyethylcellulose, hydroxymethylcellulose, methylcellulose or hydroxypropyl methylcellulose. Process for the preparation of the tablet comprises wet granulation of a mixture of trimetazidine, polyvidone and a diluent, mixing the granulate thus obtained with the cellulose derivative, adding a lubricant and a flow agent and compressing the mixture so obtained. The tablet is suitable for use in the prevention or the treatment of angina pectoris, chorioretinal attacks and in the treatment of vertigo of vascular origin.

Description

Tento vynález sa týka matricovej tablety umožňujúcej predĺžené uvoľňovanie trimetazidínu alebo jeho adičnej soli s farmaceutický prijateľnou kyselinou po orálnom podaní.The present invention relates to a matrix tablet allowing sustained release of trimethazidine or a pharmaceutically acceptable acid addition salt thereof after oral administration.

Trimetazidín (l-(2,3,4-trimetoxybenzyl)piperazín je zlúčenina, ktorá udržovaním energetického metabolizmu buniek vystavených hypotoxii alebo ischémii bráni kolapsu intracelulámej hladiny adenozíntrifosfátu (ATP). Tým zaisťuje fungovanie iónových púmp a transmembránový prienik sodíka a draslíka a zachovanie bunkovej homeostázy.Trimetazidine (1- (2,3,4-trimethoxybenzyl) piperazine) is a compound that, by maintaining the energy metabolism of cells exposed to hypotoxicity or ischemia, prevents the collapse of intracellular adenosine triphosphate (ATP) levels, ensuring the functioning of ion pumps and transmembrane penetration of sodium and potassium homease and .

Doterajší stav technikyBACKGROUND OF THE INVENTION

Trimetazidíndihydrochlorid sa dnes terapeuticky užíva na profylaktickú liečbu kritických stavov angíny pectoris, v prípade chorioretinálnych atakov a na liečbu závratov cievneho pôvodu (Meniérova choroba, ušné šelesty).Trimethazidine dihydrochloride is currently used therapeutically for the prophylactic treatment of critical angina pectoris, in the case of chorioretinal attacks and for the treatment of dizziness of vascular origin (Meniere's disease, ear murmurs).

Trimetazidíndihydrochlorid sa až dosiaľ podáva orálne v dávkach od 40 do 60 mg/deň v tabletách obsahujúcich 20 mg aktívnej zložky alebo ako roztok na orálnu aplikáciu obsahujúcu 20 mg aktívnej prísady/ml. Obe formy sú liekové formy s bezprostredným uvoľňovaním. Patent FR 2 490 963 opisuje tabletovú formu s bezprostredným uvoľňovaním. Trimetazidíndihydrochlorid sa rýchlo absorbuje a rýchlo je eliminovaný z tela, jeho biologický polčas v plazme je nižší než 6 hodín, čo má za následok, že sa podávanie účinnej látky musí rozdeliť na 2 až 3 podania denne, ak sa má zaistiť udržanie dostatočných hladín v plazme. Najčastejšie vyžadovaný dávkovací režim pri liečbe je tri tablety denne. Častejšie denné podanie prináša riziko, že na bratie lieku zabudne buď pacient s aktívnym životným štýlom, alebo starší pacienti, ktorí už berú viac liekov.Up to now, the trimetazidine dihydrochloride has been administered orally in doses of 40 to 60 mg / day in tablets containing 20 mg of active ingredient or as an oral solution containing 20 mg of active ingredient / ml. Both forms are immediate release dosage forms. Patent FR 2,490,963 discloses an immediate release tablet form. Trimetazidine dihydrochloride is rapidly absorbed and rapidly eliminated from the body, with a plasma half-life of less than 6 hours, with the consequence that the administration of the active ingredient must be divided into 2 to 3 administrations per day to ensure sufficient plasma levels are maintained. . The most frequently required dosage regimen for treatment is three tablets per day. More frequent daily administration risks losing the medicine to either an active lifestyle patient or elderly patients who are already taking multiple medicines.

Podstata vynálezuSUMMARY OF THE INVENTION

V dôsledku rýchleho vstrebávania a šesťhodinového polčasu sú dôsledkom bratia liekových foriem s bezprostredným uvoľňovaním nízke hladiny v krvi pred ďalším podaním. Je známe, že je dôležité udržovať účinnú ochranu myokardu počas celej 24-hodinovej periódy a zvlášť v skorých ranných hodinách, keď má ischémia najzávažnejšie príznaky. Pretože sa liekovými formami s bezprostredným uvoľňovaním nedocieľuje úplné pokrytie dennej potreby, vyvinul prihlasovateľ liekovú formu s riadeným uvoľňovaním umožňujúcu dokonalé 24-hodinové pokrytie a zaisťujúcu dostatočnú hladinu v krvi medzi dvoma podaniami pri zachovaní účinnosti trimetazidínu, pričom po každom podaní zostáva veľký plazmový pík, udržujúci energetický metabolizmus bunky vystavenej hypoxii a ischémii a brániaci zníženiu intracelulámej hladiny ATP.Due to the rapid absorption and the half-hour half-life, brothers of immediate release dosage forms result in low blood levels prior to further administration. It is known that it is important to maintain effective myocardial protection throughout the 24-hour period and especially in the early morning hours when ischemia has the most severe symptoms. Since immediate release dosage forms do not achieve complete coverage of the daily requirement, the Applicant has developed a controlled release dosage form allowing perfect 24-hour coverage and ensuring sufficient blood levels between the two administrations while maintaining the efficacy of trimethazidine, maintaining a large plasma peak after each administration. energetic metabolism of a cell exposed to hypoxia and ischemia and preventing a decrease in intracellular ATP levels.

Taktiež umožňuje prevenciu periférnych vazodilatačných efektov, pričom stabilizuje prietok krvi a tonus.It also allows the prevention of peripheral vasodilatory effects while stabilizing blood flow and tone.

Nová formulácia podľa vynálezu tiež zachováva pozitívne charakteristiky formulácie opísané v patente FR 2 490 963, pričom umožňuje lepšie pokrytie dennej potreby, čo má za následok lepšiu komplianciu a trvalú ochranu.The new formulation according to the invention also maintains the positive characteristics of the formulation described in patent FR 2,490,963, while allowing better coverage of daily needs, resulting in better compliance and durability.

Tento vynález sa predovšetkým týka matricovej tablety umožňujúcej riadené uvoľňovanie trimetazidínu alebo jeho farmaceutický prijateľnej soli po orálnom podaní, ktorá je zložená z hydrofilnej matrice, vyznačujúcej sa tým, že riadené uvoľňovanie reguluje polymér na báze celulózového derivátu.In particular, the present invention relates to a matrix tablet for the controlled release of trimethazidine or a pharmaceutically acceptable salt thereof after oral administration, which consists of a hydrophilic matrix, characterized in that the controlled release polymer is controlled by a cellulose derivative polymer.

Táto matricová tableta výhodne podávaná dvakrát denne umožňuje riadené uvoľňovanie účinnej látky, pričom po každom podaní zachováva veľký plazmový pík. Umožňuje dosiahnutie hladiny vyššej než 70 pg/l v plazme pacienta po každom podaní a udržanie hladiny vyššej než 40 pg/l v plazme do budúceho podania, čo sa podstatne líši od pôsobenia tablety podľa patentu FR 2 490 963 podávanej trikrát denne.This matrix tablet preferably administered twice daily allows for controlled release of the active ingredient, maintaining a large plasma peak after each administration. It allows to achieve levels above 70 pg / l in the patient's plasma after each administration and to maintain levels above 40 pg / l in the plasma until future administration, which is significantly different from that of the tablet of FR 2,490,963 administered three times a day.

Spomedzi derivátov celulózy použitých v matrici podľa vynálezu je možné spomenúť najmä étery celulózy, ako je hydroxypropylcelulóza, hydroxyetylcelulóza, hydroxymetylcelulóza, metylcelulóza a hydroxypropylmetylcelulóza.Among the cellulose derivatives used in the matrix according to the invention, mention may be made in particular of cellulose ethers such as hydroxypropylcellulose, hydroxyethylcellulose, hydroxymethylcellulose, methylcellulose and hydroxypropylmethylcellulose.

Je výhodné, keď týmto derivátom celulózy je hydroxypropylmetylcelulóza. Polymér na báze derivátu celulózy predstavuje 25 až 50 % celkovej hmotnosti tablety.Preferably, the cellulose derivative is hydroxypropylmethylcellulose. The cellulose derivative polymer represents 25 to 50% of the total weight of the tablet.

Môžu byť použité hydroxypropylmetylcelulózy s viskozitou od 100 cP do 100 000 cP. Výhodná viskozita je 4000 cP.Hydroxypropylmethylcelluloses with a viscosity of from 100 cP to 100,000 cP can be used. The preferred viscosity is 4000 cP.

Do hydrofilnej matrice sa pridávajú rôzne prísady, napríklad spojivá, riedidlá, mazivá a reologické prísady. Ako spojivo sa výhodne používa polyvidón. Obsah polyvidónu dosahuje 3 až 12 % celkovej hmotnosti tablety. Ako riedidlo sa výhodne používa dihydrát hydrogenfosforečnanu vápenatého, vykazujúci lepšiu tekutosť a stlačiteľnosť než iné riedidlá, napríklad monohydrát laktózy. Obsah hydrogenfosforečnanu vápenatého je od 25 do 75 % z celkovej hmotnosti tablety.Various additives such as binders, diluents, lubricants and rheological additives are added to the hydrophilic matrix. Polyvidone is preferably used as a binder. The polyvidone content is 3-12% of the total tablet weight. The diluent used is preferably calcium hydrogen phosphate dihydrate, which exhibits better flowability and compressibility than other diluents, for example lactose monohydrate. The calcium hydrogen phosphate content is from 25 to 75% of the total weight of the tablet.

Spomedzi mazív môžu byť spomenuté - bez toho, aby bolo vymenovanie obmedzujúce - stearát horečnatý, stearová kyselina, glycerylbehenát a benzoát sodný. Výhodným mazivom je stearát horečnatý. Nakoniec, ako reologická prísada sa výhodne používa koloidný oxid kremičitý.Among the lubricants may be mentioned - without limitation - magnesium stearate, stearic acid, glyceryl behenate and sodium benzoate. A preferred lubricant is magnesium stearate. Finally, colloidal silicon dioxide is preferably used as the rheological additive.

Trimetazidín použitý v matricovej tablete podľa vynálezu je výhodne vo forme dihydrochloridu. Obsah trimetazidíndihydrochloridu predstavuje 15 až 30 % celkovej hmotnosti tablety, výhodne 15 až 18 %.The trimetazidine used in the matrix tablet of the invention is preferably in the form of the dihydrochloride. The content of trimethazidine dihydrochloride represents 15 to 30% of the total weight of the tablet, preferably 15 to 18%.

Odborník by isto predpokladal, že kinetika uvoľňovania z matricových tabliet bude závisieť od povahy a množstva základnej zložky matrice - ktorou je v tomto prípade derivát celulózy.The skilled person would surely assume that the release kinetics of the matrix tablets will depend on the nature and amount of the matrix constituent - which in this case is a cellulose derivative.

Teraz sa však prekvapivo zdá, že kinetika uvoľňovania účinnej látky z matricovej tablety podľa vynálezu nie je ovplyvňovaná ani množstvom ani druhom derivátu celulózy.Surprisingly, however, it now appears that the release kinetics of the active ingredient from the matrix tablet of the invention are not affected by either the amount or the second cellulose derivative.

Rôzne pripravené formulácie používajúce na jednej strane hydroxypropylmetylcelulózy s rôznymi viskozitami a na druhej strane rôzne množstvá toho istého typu hydroxypropylmetylcelulózy vykazovali rovnaké kinetiky uvoľňovania, čo vedie k záveru, že existuje špecifický synergizmus medzi derivátom celulózy a trimetazidínom.The various formulations prepared using, on the one hand, hydroxypropylmethylcellulose with different viscosities and, on the other hand, different amounts of the same type of hydroxypropylmethylcellulose showed the same release kinetics, leading to the conclusion that there is a specific synergism between the cellulose derivative and trimethazidine.

Tento vynález sa tiež týka spôsobu prípravy matricovej tablety. Matricová tableta sa môže pripraviť granuláciou za vlhka, po ktorej nasleduje lisovanie, granuláciou za sucha, po ktorej nasleduje lisovanie, alebo priamym lisovaním. Je výhodné, keď spôsob prípravy predstavuje granuláciu za vlhka, po ktorej nasleduje lisovanie.The present invention also relates to a process for preparing a matrix tablet. The matrix tablet may be prepared by wet granulation followed by compression, dry granulation followed by compression, or direct compression. Preferably, the method of preparation is a wet granulation followed by compression.

Granulácia za vlhka sa uskutočňuje zmiešaním trimetazidínu, polyvidónu a riedidla a následným zvlhčením tejto zmesi. Prvý stupeň umožňuje vznik hydrofilného prostredia v okolí aktívnej prísady, ktorá je užitočná na rozpustenie a tiež umožňuje maximálne uniformnú jednotkovú dávku.The wet granulation is performed by mixing trimethazidine, polyvidone and diluent and then wetting the mixture. The first step allows the formation of a hydrophilic environment around the active ingredient, which is useful for dissolution and also allows a maximum uniform unit dose.

V druhom stupni sa takto získaný granulát zmieša s derivátom celulózy. Potom sa ku zmesi pridajú mazivo a reologické činidlo. Tretí stupeň je lisovanie získanej lubrikovanej zmesi.In a second step, the granulate thus obtained is mixed with a cellulose derivative. Lubricant and rheological agent are then added to the mixture. The third step is the compression of the lubricated mixture obtained.

Podľa potreby sú potom takto vytvorené tablety poťahované bežnými technikami poťahovania.If desired, the tablets thus formed are then coated with conventional coating techniques.

Nasledujúce príklady vynález ilustrujú, ale nijako ho neobmedzujú. Matricové tablety opisované v príkladoch sa pripravili nasledujúcim spôsobom:The following examples illustrate the invention but do not limit it in any way. The matrix tablets described in the examples were prepared as follows:

- Stupeň A: Pripraví sa zmes trimetazidínu, polyvidónu a dihydrátu hydrogenfosforečnanu vápenatého, nasleduje zvlhčenie zmesi dostatočným množstvom prečistenej vody, granulácia a sušenie granulátu.- Step A: A mixture of trimethazidine, polyvidone and dibasic calcium phosphate dihydrate is prepared, followed by wetting the mixture with plenty of purified water, granulating and drying the granulate.

- Stupeň B: Granulát získaný v stupni A sa zmieša s hydroxypropyl- metylcelulózou.Step B: The granulate obtained in Step A is mixed with hydroxypropyl methylcellulose.

- Stupeň C : Lubrikácia zmesi získanej v stupni B stearátom horečnatým a koloidným oxidom kremičitým ako mazivami.- Step C: Lubricate the mixture obtained in Step B with magnesium stearate and colloidal silicon dioxide as lubricants.

- Stupeň D: Lisovanie lubrikovanej zmesi získanej v stupni C na rotorovom tabletovacom lise s cieľom získať tablety s tvrdosťou v rozmedzí od asi 40 N do asi 160 N pri meraní lomu v priemere tablety.Step D: Compress the lubricated mixture obtained in Step C on a rotary tablet press to obtain tablets with a hardness ranging from about 40 N to about 160 N when measuring refraction in the tablet diameter.

Prehľad obrázkov na výkresochBRIEF DESCRIPTION OF THE DRAWINGS

Obrázok 1 znázorňuje priemernú koncentrácia trimetazidmu (v pg/l) v plazme po jeho ústnom podaní vo forme jednak F3, jednak IR (s bezprostredným uvoľňovaním) dvanástim zdravým dobrovoľníkom.Figure 1 shows the mean plasma concentrations of trimethazide (in pg / L) after oral administration in the form of both F 3 and IR (immediate release) to twelve healthy volunteers.

Táto krivka jasne ukazuje, že lieková forma F3 umožňuje dosiahnuť riadené uvoľňovanie pri zachovaní veľkého plazmového piku po každom podaní.This curve clearly shows that the dosage form of F 3 allows for controlled release while maintaining a large plasma peak after each administration.

Hladina v plazme zistená po každom podaní je asi 90 pg/l a prakticky sa nelíši od hladiny získanej s liekovou formou s bezprostredným uvoľňovaním. Na konci 24 hodín je hladina v plazme väčšia než 40 pg/l, zatiaľ čo v prípade formulácie s bezprostredným uvoľňovaním je len asi 25 pg/l.The plasma level observed after each administration is about 90 pg / L and is practically not different from that obtained with the immediate release dosage form. At the end of 24 hours, the plasma level is greater than 40 pg / l, whereas in the immediate release formulation it is only about 25 pg / l.

Príklady uskutočnenia vynálezuDETAILED DESCRIPTION OF THE INVENTION

Príklad 1Example 1

Formulácie rôznych matricových tabliet obsahujúcich rôzne množstvá trimetazidínu Tabuľka 1: Jednotkové kompozície 3 typov tablietFormulations of different matrix tablets containing varying amounts of trimethazidine Table 1: Unit compositions of 3 types of tablets

Zlúčenina compound Množstvo (mg) Quantity (mg) Fr fr f2 f 2 f3 f 3 Trimetazidíndihydrochlorid trimetazidine dihydrochloride 60 60 30 30 35 35 Hydroxypropylmetylcelulóza hydroxypropyl methylcellulose 112 112 74 74 74 74 Polyvidón povidone 13,3 13.3 8,7 8.7 8,7 8.7 Dihydrát hydrogenfosforečnanu vápenatého Calcium hydrogen phosphate dihydrate 92 92 85,9 85.9 80,9 80.9 Stearát horečnatý Magnesium stearate 2,2 2.2 1 1 1 1 Bezvodý koloidný oxid kremičitý Anhydrous colloidal silica 0,5 0.5 0,4 0.4 0,4 0.4 Celková hmotnosť tabliet Total weight of tablets 280 280 200 200 200 200

Príklad 2Example 2

Príklad 2 ukazuje, že rôzne množstvá hydroxypropylmetylcelulózy nemajú vplyv na kinetiku rozpúšťania tabliet.Example 2 shows that different amounts of hydroxypropylmethylcellulose do not affect the dissolution kinetics of the tablets.

Tabuľka 2: Jednotkové kompozície pri premenlivom množstve HPMCTable 2: Unit compositions at varying amounts of HPMC

Zlúčenina compound Množstvo (mg) Quantity (mg) f4 f 4 Fs F p T rimetazidíndihydrochlorid Trimetazidine dihydrochloride 35 35 35 35 Hydroxypropylmetylcelulóza hydroxypropyl methylcellulose 54 54 94 94 Polyvidón povidone 10,1 10.1 7,3 7.3 Dihydrát hydrogenfosforečnanu vápenatého Calcium hydrogen phosphate dihydrate 99,5 99.5 62,3 62.3 Stearát horečnatý Magnesium stearate 1 1 1 1 Bezvodý koloidný oxid kremičitý Anhydrous colloidal silica 0,4 0.4 0,4 0.4 Celková hmotnosť tabliet Total weight of tablets 200 200 200 200

Tabuľka 3 ukazuje percentuálne množstvo uvoľnenej zlúčeniny ako funkciu času pre formulácie F4 a F5.Table 3 shows the percentage of compound released as a function of time for formulations F 4 and F 5 .

Tabuľka 3: Kinetika uvoľňovaniaTable 3: Release kinetics

Čas (hodiny) Time (hours) Množstvo uvoľnenej zlúčeniny (%) Quantity of compound released (%) |  | 1 2 3 4 1 2 3 4 41 38 59 59 80 77 97 96 41 38 59 59 80 77 97 96

Príklad 3Example 3

Príklad 3 ukazuje, že rôzne typy hydroxypropylmetylcelulózy nemajú vplyv na kinetiku rozpúšťania tabliet.Example 3 shows that different types of hydroxypropylmethylcellulose do not affect the dissolution kinetics of the tablets.

Tabuľka 4: Formulácie/rôzne druhy HPMCTable 4: Formulations / Different Types of HPMC

Zlúčenina compound Množstvo (mg) Quantity (mg) f3 f 3 f6 f 6 f7 f 7 Trimetazidíndihydrochlorid trimetazidine dihydrochloride 35 35 35 35 35 35 Hydroxypropylmetylcelulóza 4000 cP Hydroxypropylmethylcellulose 4000 cP 74 74 - - - - Hydroxypropylmetylcelulóza 100 cP Hydroxypropylmethylcellulose 100 cP - - - - 74 74 Hydroxypropylmetylcelulóza 100.000 cP Hydroxypropylmethylcellulose 100.000 cP - - 74 74 - - Polyvidón povidone 8,7 8.7 8,7 8.7 8,7 8.7 Dihydrát hydrogenfosforečnanu vápenatého Calcium hydrogen phosphate dihydrate 80,9 80.9 80,9 80.9 80,9 80.9 Stearát horečnatý Magnesium stearate 1 1 1 1 1 1 Bezvodý koloidný oxid kremičitý Anhydrous colloidal silica 0,4 0.4 0,4 0.4 0,4 0.4

Tabuľka 5 ukazuje množstvá v percentách uvoľnenej zlúčeniny ako funkciu času pre formulácie F3, F6 a F7.Table 5 shows the percentages of compound released as a function of time for formulations F 3 , F 6 and F 7 .

Tabuľka 5: Kinetika uvoľňovaniaTable 5: Release kinetics

Čas (hodiny) Time (hours) Množstvo uvoľnenej zlúčeniny (%) Quantity of compound released (%) F3 F 3 f6 f 6 f7 f 7 1 1 43 43 41 41 40 40 2 2 62 62 59 59 60 60 3 3 86 86 83 83 83 83 4 4 105 105 102 102 100 100

Príklad 4Example 4

Štúdia plazmovej kinetikyPlasma kinetics study

Plazmová kinetika sa študovala po podaní matricovej tablety formulácie F3 opisovanej v príklade 1 dvanástim zdravým dobrovoľníkom. Podávanie sa uskutočňovalo 4 dni pri dávkovaní dve tablety denne. Plaz4 mová kinetika tablety typu F3 sa porovnávala s kinetikou tablety s bezprostredným uvoľňovaním (IR) podávanej 4 dni pri dávkovaní tri tablety denne.Plasma kinetics were studied after administration of the matrix tablet of Formulation F 3 described in Example 1 to twelve healthy volunteers. Administration was performed for 4 days at a dosage of two tablets daily. The plasma kinetics of type F 3 tablets were compared to those of an immediate release (IR) tablet administered 4 days at a dose of three tablets daily.

Jednotková formulácia tablety s bezprostredným uvoľňovaním (IR) je táto:The unit formulation of an immediate release (IR) tablet is as follows:

Trimetazidíndihydrochlorid Kukuričný škrob Mannit Polyvidón Stearát horečnatý Mastenec Trimetazidine dihydrochloride Corn starch mannitol povidone Magnesium stearate Talc 20 mg 26 mg 34 mg 4 mg 1 mg 5 mg 20 mg 26 mg 34 mg 4 mg 1 mg 5 mg

Priemernú koncentráciu v plazme ukazuje obrázok 1.The mean plasma concentration is shown in Figure 1.

PATENTOVÉ NÁROKYPATENT CLAIMS

Claims (16)

t ý m , že percentuálny obsah derivátu t ý m , že tiež obsahuje spojivo, riedidt ý m , že spojivo je polyvidón.characterized in that the percentage of derivative also contains a binder, the binder being polyvidone. t ý m , že percentuálny obsah polyvidó-characterized in that the percentage content of polyvidone- 1. Matricová tableta na predĺžené uvoľňovanie trimetazidínu alebo jeho farmaceutický prijateľnej soli, vyznačujúca sa tým, že predĺžené uvoľňovanie sa reguluje použitím polyméru na báze derivátu celulózy prítomného v matrici, ktorý je vybraný z hydroxypropylcelulózy, hydroxyetylcelulózy, hydroxymetylcelulózy, metylcelulózy a hydroxypropylmetylcelulózy.A matrix tablet for the sustained release of trimethazidine or a pharmaceutically acceptable salt thereof, wherein the sustained release is controlled by the use of a cellulose derivative polymer present in a matrix selected from hydroxypropylcellulose, hydroxyethylcellulose, hydroxymethylcellulose, methylcellulose and hydroxypropylmethylcellulose. 2. Matricová tableta podľa nároku 1,vyznačujúca celulózy predstavuje 25 až 50 % celkovej hmotnosti tabliet.Matrix tablet according to claim 1, characterized in that the celluloses represent 25 to 50% of the total weight of the tablets. 3. Matricová tableta podľa nároku 1,vyznačujúca lo, mazivo a reologické činidlo.Matrix tablet according to claim 1, characterized by a lo, a lubricant and a rheological agent. 4. Matricová tableta podľa nároku 3,vyznačuj úcaMatrix tablet according to claim 3, characterized in 5. Matricová tableta podľa nároku 4, vyznačujúca nu je od 3 do 12 % celkovej hmotnosti tabliet.The matrix tablet according to claim 4, characterized in that it is from 3 to 12% of the total weight of the tablets. 6. Matricová tableta podľa ktoréhokoľvek z nárokov 3, 4 alebo 5,vyznačujúca sa tým, že riedidlo je dihydrát hydrogenfosforečnanu vápenatého.Matrix tablet according to any one of claims 3, 4 or 5, characterized in that the diluent is dicalcium phosphate dihydrate. 7. Matricová tableta podľa nároku 6, vyznačujúca sa tým, že percentuálny obsah dihydrátu hydrogenfosforečnanu vápenatého je od 25 do 75 % celkovej hmotnosti tablety.Matrix tablet according to claim 6, characterized in that the percentage of dicalcium phosphate dihydrate is from 25 to 75% of the total weight of the tablet. 8. Matricová tableta podľa ktoréhokoľvek z nárokov 3, 4, 5, 6 alebo 7, vyznačujúca sa tým, že mazivo je stearát horečnatý a reologické činidlo je bezvodý koloidný oxid kremičitý.Matrix tablet according to any one of claims 3, 4, 5, 6 or 7, characterized in that the lubricant is magnesium stearate and the rheological agent is anhydrous colloidal silica. 9. Matricová tableta podľa nároku 1, vyznačujúca sa tým, že trimetazidín je vo forme dihydrochloridu.The matrix tablet according to claim 1, wherein the trimethazidine is in the form of the dihydrochloride. 10. Matricová tableta podľa nároku 9, vyznačujúca sa tým, že obsah trimetazidíndihydrochloridu je od 15 do 30 % celkovej hmotnosti tablety.A matrix tablet according to claim 9, characterized in that the content of trimethazidine dihydrochloride is from 15 to 30% of the total weight of the tablet. 11. Matricová tableta podľa ktoréhokoľvek z nárokov 9 alebo 10, vyznačujúca sa tým, že obsah trimetazidíndihydrochloridu je 17,5 % celkovej hmotnosti tablety.Matrix tablet according to either of claims 9 or 10, characterized in that the content of trimethazidine dihydrochloride is 17.5% of the total weight of the tablet. 12. Matricová tableta podľa ktoréhokoľvek z nárokov 1 až 11,vyznačujúca sa tým, že obsahuje 35 mg trimetazidíndihydrochloridu, 74 mg hydroxypropylmetylcelulózy, 8,7 mg polyvidónu, 80,9 mg dihydrátu hydrogenfosforečnanu vápenatého, 1 mg stearátu horečnatého a 0,4 mg koloidného oxidu kremičitého.Matrix tablet according to any one of claims 1 to 11, characterized in that it contains 35 mg of trimetazidine dihydrochloride, 74 mg of hydroxypropylmethylcellulose, 8.7 mg of polyvidone, 80.9 mg of calcium hydrogen phosphate dihydrate, 1 mg of magnesium stearate and 0.4 mg of colloidal silica. 13. Matricová tableta podľa nároku 12, vyznačujúca sa tým, že sa podáva dvakrát denne.Matrix tablet according to claim 12, characterized in that it is administered twice a day. 14. Matricová tableta podľa nároku 1,vyznačujúca sa tým, že umožňuje u ľudí dosiahnuť plazmovú hladinu vyššiu než 70 pg/l po každom podaní a udržať plazmovú hladinu vyššiu alebo rovnú 40 pg/l do nasledujúceho podania.A matrix tablet according to claim 1, characterized in that it allows to achieve a plasma level of greater than 70 pg / L in humans after each administration and to maintain a plasma level of greater than or equal to 40 pg / L until the next administration. 15. Spôsob prípravy matricovej tablety podľa ktoréhokoľvek z nárokov 1 až 12, vyznačujúca sa t ý m , žeA process for preparing a matrix tablet according to any one of claims 1 to 12, characterized in that - sa uskutočňuje granulácia za vlhka zmiešaním trimetazidínu, polyvidónu a riedidla a zvlhčením zmesi,- wet granulation is performed by mixing trimethazidine, polyvidone and diluent and moistening the mixture, - takto získaný granulát sa zmieša s derivátom celulózy,- the granulate thus obtained is mixed with a cellulose derivative, - potom sa pridá mazivo a reologické činidlo,- then the lubricant and rheological agent are added, - získaná zmes sa lisuje.- the mixture obtained is pressed. 16. Matricová tableta podľa ktoréhokoľvek z nárokov 1 až 14 na použitie na profylaktickú liečbu angíny pectoris, chorioretinálnych atakov a na liečbu závratov cievneho pôvodu.A matrix tablet according to any one of claims 1 to 14 for use in the prophylactic treatment of angina, chorioretinal attacks and for the treatment of dizziness of vascular origin.
SK863-2002A 1999-12-17 2000-12-15 Matrix tablet for sustained release of trimetazidine and process for preparing thereof SK286752B6 (en)

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FR9915960A FR2802424B1 (en) 1999-12-17 1999-12-17 MATRIX TABLET FOR THE EXTENDED RELEASE OF TRIMETAZIDINE AFTER ORAL ADMINISTRATION
PCT/FR2000/003546 WO2001043747A1 (en) 1999-12-17 2000-12-15 Matrix tablet for prolonged release of trimetazidine after oral administration

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Families Citing this family (21)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
PT1195160E (en) * 2000-10-05 2009-12-07 Usv Ltd Sustained release trimetazidine pharmaceutical compositions and a method of their preparation
US20070092566A1 (en) 2003-08-04 2007-04-26 Ryouichi Hoshino Oral sustained-release tablet
SG126792A1 (en) * 2005-04-27 2006-11-29 Servier Lab Matrix tablet enabling the prolonged release of trimetazidine after administration by the oral route
FR2885807B1 (en) * 2005-05-18 2008-05-16 Mg Pharma SOLID PHARMACEUTICAL COMPOSITION WITH PROLONGED RELEASE OF 1- (2,3,4-TRIMETHOXYBENZYL) PIPERAZINE, AND PREPARATION METHOD
CZ300307B6 (en) * 2006-01-04 2009-04-15 Zentiva, A. S. Modified release tablet containing trimetazidine or pharmacologically acceptable salts thereof
EA009776B1 (en) * 2006-07-18 2008-04-28 Мераб Ревазович Кокеладзе Method for preparing tablets of dihydrochloride trimethazine and composition thereof
EA009810B1 (en) * 2006-12-26 2008-04-28 Закрытое Акционерное Общество "Канонфарма Продакшн" Matrix for manufacturing tableted dosage form and method of treatment
EP2200591A2 (en) * 2007-09-11 2010-06-30 Ranbaxy Laboratories Limited Controlled release pharmaceutical dosage forms of trimetazidine
EP2389167A2 (en) 2009-01-20 2011-11-30 Micro Labs Limited Modified release solid pharmaceutical compositions of trimetazidine and process thereof
ES2567722T3 (en) * 2009-01-30 2016-04-26 Lupin Limited Trimetazidine pharmaceutical compositions
TR201001902A2 (en) 2010-03-12 2011-04-21 Ali̇ Rai̇f İlaç Sanayi̇ Ve Ti̇caret A.Ş. Trimetazidine tablets with extended release
RU2445958C2 (en) * 2010-04-20 2012-03-27 Общество с ограниченной ответственностью "Озон" (ООО "Озон") Matrix tablet with trimetazidine prolonged-release base and method for preparing it
ES2508490T3 (en) 2010-05-04 2014-10-16 Sanovel Ilaç Sanayi Ve Ticaret Anonim Sirketi Formulation of trimetazidine with different release profiles
EP2386302A1 (en) 2010-05-11 2011-11-16 Ranbaxy Laboratories Limited A controlled release pharmaceutical dosage form of trimetazidine and processes for the preparation thereof
EP2491930A1 (en) 2011-02-25 2012-08-29 Deva Holding Anonim Sirketi Pharmaceutical combination of betahistine and trimetazidine
FR2978916B1 (en) * 2011-08-10 2013-07-26 Servier Lab SOLID PHARMACEUTICAL COMPOSITION FOR BUCCAL ADMINISTRATION OF AGOMELATIN
FR2986431B1 (en) * 2012-02-03 2017-03-17 Servier Lab PROLONGED RELEASE OF TRIMETAZIDINE PHARMACEUTICAL COMPOSITION, PROCESS FOR THE PRODUCTION THEREOF AND USE IN THERAPEUTIC TREATMENTS
CN102824644B (en) * 2012-09-13 2013-12-25 浙江诚意药业有限公司 High-stability sustained-release tablet prepared by using hydroxy propyl cellulose
KR20160118733A (en) 2015-04-03 2016-10-12 이인현 Hose guide apparatus for hose winder and hose winder
CN109316455B (en) * 2017-07-31 2021-05-25 北京福元医药股份有限公司 Trimetazidine hydrochloride sustained release tablet
CN109908096A (en) * 2017-12-12 2019-06-21 武汉武药科技有限公司 A kind of trimetazidine hydrochloride sustained-release tablets and preparation method thereof

Family Cites Families (13)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US4226849A (en) * 1979-06-14 1980-10-07 Forest Laboratories Inc. Sustained release therapeutic compositions
FR2490963B1 (en) * 1980-09-30 1986-04-18 Science Union & Cie NOVEL THERAPEUTIC COMPOSITION WITH ANTI-ISCHEMIC ACTION CONTAINING TRIMETHOXY 2, 3, 4-BENZYL 1-PIPERAZINE
KR850006132A (en) * 1984-02-29 1985-10-02 진 크라메르, 한스 루돌프 하우스 Bromocriptine Composition
JPS61293931A (en) * 1985-06-24 1986-12-24 Teijin Ltd Slow-releasing pharmaceutical composition
JPH0625055B2 (en) * 1985-03-18 1994-04-06 日本ケミフア株式会社 Persistent tablets
EP0207638B1 (en) * 1985-06-04 1990-12-19 Teijin Limited Sustained-release pharmaceutical preparation
SE455836B (en) * 1985-10-11 1988-08-15 Haessle Ab PREPARATION WITH CONTROLLED RELEASE CONTAINING A SALT OF METOPROLOL AND METHOD FOR PREPARING THIS PREPARATION
SE8601624D0 (en) * 1986-04-11 1986-04-11 Haessle Ab NEW PHARMACEUTICAL PREPARATIONS
FR2677886B1 (en) * 1991-06-18 1995-03-31 Adir MATRIX TABLET FOR THE EXTENDED RELEASE OF INDAPAMIDE AFTER ORAL ADMINISTRATION.
FR2681324B1 (en) * 1991-09-18 1993-10-29 Adir Cie NOVEL TRIMETAZIDINE DERIVATIVES, PROCESS FOR THEIR PREPARATION AND PHARMACEUTICAL COMPOSITIONS CONTAINING THEM.
KR940021051A (en) * 1993-03-03 1994-10-17 손정삼 3-step drug release sustained tablet
RU2082400C1 (en) * 1993-12-16 1997-06-27 Акционерное общество - Фармацевтическая фирма "Ник-Фарм" Method of nitroglycerol prolonged action preparing
FR2717687B1 (en) * 1994-03-24 1996-06-14 Adir Pharmaceutical compositions for the sustained release of trimetazidine after oral administration.

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