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WO2011008183A1 - Médicament contenant un dihydrochlorure de trimétazidine sous la forme d'un comprimé à matrice à libération prolongée (variantes) et procédés de préparation de ce médicament (variantes) - Google Patents

Médicament contenant un dihydrochlorure de trimétazidine sous la forme d'un comprimé à matrice à libération prolongée (variantes) et procédés de préparation de ce médicament (variantes) Download PDF

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Publication number
WO2011008183A1
WO2011008183A1 PCT/UA2010/000026 UA2010000026W WO2011008183A1 WO 2011008183 A1 WO2011008183 A1 WO 2011008183A1 UA 2010000026 W UA2010000026 W UA 2010000026W WO 2011008183 A1 WO2011008183 A1 WO 2011008183A1
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WIPO (PCT)
Prior art keywords
drug according
trimetazidine dihydrochloride
amount
hydrophilic
drug
Prior art date
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Ceased
Application number
PCT/UA2010/000026
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English (en)
Russian (ru)
Inventor
Роман Николаевич ПРИХОДЬКО
Марк Вольфович ШТЕЙНГАРТ
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Individual
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Publication of WO2011008183A1 publication Critical patent/WO2011008183A1/fr
Anticipated expiration legal-status Critical
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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
    • 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

Definitions

  • the invention relates to medicine and the pharmaceutical industry, in particular to the creation, production and use of a cardiovascular drug, trimetazidine dihydrochloride in the form of tablets with controlled release of a drug substance for a long time, which, taking into account the kinetics of biotransformation, provides a stable concentration level active substance.
  • Trimetazidine dihydrochloride has the formula:
  • Trimetazidine dihydrochloride is used to prevent angina pectoris, to treat ischemia, dizziness of vascular origin.
  • Patent FR 2 490 963, A61K9 / 20, 1982 shows that a daily dose of 60 mg trimetazidine dihydrochloride should be divided into three times. However, this does not achieve uniform release of trimetazidine dihydrochloride during the day, especially before morning use, and at this time critical moments of cardiac activity most often occur.
  • wet granulation is performed by mixing trimetazidine dihydrochloride, polyvinylpyrrolidone and a diluent, followed by wetting the resulting mixture; the granulate obtained in this way is mixed with a cellulose derivative; then a lubricant and a flow agent are added; then the resulting mixture is pressed.
  • the rate of release depends on the nature of the pores of the matrix and the conditions of its formation.
  • One of the conditions for achieving the necessary release is to reduce the solubility of the active substance.
  • Patent EP 1 195 160 A A61K9 / 20, 2005 proposes the use of a hydrocolloid material, for example, cellulose derivatives, alginates, carbomers, guar or xanthan gums, a hydrophobic polymer, for example, fatty acids, alcohols, esters, some waxes, or a combination of hydrophobic polymer with a hydrophilic material, granulation of trimetazidine dihydrochloride with a mixture of, for example, stearic acid with glyceryl palmitates, shellac, polyvinyl chloride, polyethylene powders, varnishes and others to create a prolonged release of t rimetazidine dihydrochloride.
  • a hydrocolloid material for example, cellulose derivatives, alginates, carbomers, guar or xanthan gums
  • a hydrophobic polymer for example, fatty acids, alcohols, esters, some waxes, or a combination of hydrophobic polymer with a
  • This patent provides several methods for producing tablets:
  • trimetazidine dihydrochloride is dispersed in a molten insoluble polymer, wax, fatty acids, cooled, granulated, mixed with swelling polymers and other excipients and pressed, monolithic matrix. This matrix provides the dissolution of trimetazidine within 24 hours, while at least 75% of the active substance is dissolved in 16 hours.
  • mannitol as a filler was a finding of Segvieg company for tablets with a three-time use of 20 mg of trimetazidine dihydrochloride.
  • a significant drawback of matrix tablets is that they use an insoluble filler - calcium dihydrogen phosphate instead of mannitol as a filler. It is known that mannitol improves the performance of redox processes in Suzuki et al. JP2008266203 A61K31 / 03, A61P ⁇ / 10, A61P21 / 04 and contributes to the speed of other processes in cellular structures, while calcium ions impede these processes.
  • the used gel-forming polymers create a gel matrix in which the prolongation of release depends on the viscosity of the gel formed and its strength. In the practical use of such a pill, these indicators will depend on the time of use, food, and its composition. Solid matrices that withstand mechanical loads without deforming are more independent of food and intestinal tract motility, and the active substance and some soluble components gradually dissolve and are released from the dosage form due to diffusion through the pores of the tablets or by gradual erosion.
  • trimetazidine dihydrochloride including a polymer of methacrylic acid, montan glycol wax and excipients in the following ratio, May. %: trimetazidine dihydrochloride 15-30
  • the disadvantage of the claimed composition is that at 30% content of the active substance relative to the average weight of the tablet cores, the content of other components, in particular the filler, is insufficient to ensure dissolution within 8 hours.
  • the disadvantage of this invention is that it is impossible to create tablets with a single composition of excipients that would ensure one-time and two-time use of this drug — dissolution of at least 80% within 8 hours for single use and more than 90% within 18 hours for single use.
  • the method of obtaining these matrix tablets is carried out by wet granulation.
  • a methacrylic acid polymer for example, RS PO eudragit
  • RS PO eudragit a methacrylic acid polymer
  • an organic solvent moistened with this solution is a mixture of trimetazidine dihydrochloride, filler (mannitol, lactose, calcium dihydrogen phosphate), montan glycol wax, disintegrant (microcrystalline cellulose).
  • the wet mixture is granulated, dried, dusted with magnesium stearate, pressed and coated with a solution of Oradra in water.
  • the disadvantage of this method is that the claimed materials experimentally do not show the possibility of increasing the dissolution time to 16-24 hours, as is necessary for a dose of 60-70 mg of trimetazidine dihydrochloride.
  • the claimed 12 hours in the patent materials are also not confirmed by experimental materials, and the verification does not confirm this result.
  • the basis of the invention the task of creating a medicinal product trimetazidine dihydrochloride in the form of a matrix tablet with a prolonged action by selecting the composition of the components, their amount to ensure the action of trimetazidine dihydrochloride for 12 hours for a dose of 35 mg of trimetazidine dihydrochloride and 24 hours for a dose of 60 mg of trimetazidine dihydrochloride with the possibility of using the drug twice or once a day .
  • the second task which is the basis of the invention, is the creation of a method for producing a medicinal product of trimetazidine dihydrochloride in the form of a matrix tablet with a prolonged action, providing different times of release of trimetazidine dihydrochloride.
  • the drug trimetazidine dihydrochloride in the form of a matrix tablet with a prolonged action containing trimetazidine dihydrochloride, hydrophilic substances including a hydrophilic filler, hydrophilic structurant, insoluble substances, including the polymer of methacrylic acid, hydrophobic substance, according to the invention, and auxiliary substances to ensure release within 12 hours with a fixed therapeutic content of trimetazidine dig it contains hydrochloride, wt.%
  • trimetazidine dihydrochloride 9-25 including trimetazidine dihydrochloride 9-25,
  • methacrylic acid polymer 26.0 -27.0 including methacrylic acid polymer 26.0 -27.0,
  • mannitol As a hydrophilic filler, mannitol is used.
  • the amount of mannitol is 7.5 - 14.5%, mainly 7.9 - 14.17%.
  • microcrystalline cellulose is used as a hydrophilic structurant.
  • the amount of microcrystalline cellulose is 12-22%.
  • Eudragit RS PO is used as the methacrylic acid polymer.
  • the amount of eudragit RS PO is 26 - 27%
  • Montan wax is used as an insoluble hydrophobic substance.
  • the amount of montan wax is 26 - 27%.
  • lubricants As auxiliary substances, lubricants and lubricants are used.
  • magnesium stearate As an auxiliary substance, magnesium stearate can be used.
  • the amount of magnesium stearate is 0.5-1.5%.
  • the problem is also solved by the fact that the drug trimetazidine dihydrochloride in the form of a matrix tablet with a prolonged action, containing trimetazidine dihydrochloride, hydrophilic substances, including a hydrophilic filler, hydrophilic structure-forming agent, insoluble substances, including a polymer of methacrylic acid, hydrophobic substance according to the invention and auxiliary substances to ensure release within 24 hours with a fixed therapeutic content of trimetazide it comprises at dihydrochloride, wt.%
  • mannitol As a hydrophilic filler, mannitol is used.
  • the amount of mannitol is 6–7%, mainly 6–6.6%.
  • microcrystalline cellulose is used as a hydrophilic structurant.
  • microcrystalline cellulose 12.4 - 12.6%
  • Eudragit RS PO is used as the methacrylic acid polymer.
  • the amount of eudragit RS PO is 45.2 - 45.6%.
  • Montan glycol wax is used as an insoluble hydrophobic substance.
  • the amount of montan glycol wax is 19-21%
  • lubricants As auxiliary substances, lubricants and lubricants are used.
  • magnesium stearate As an auxiliary substance, magnesium stearate can be used.
  • the amount of magnesium stearate is 0.5-1.5%.
  • trimetazidine dihydrochloride in the form of a matrix tablet with a prolonged action, including loading the components, mixing, moistening, drying, calibrating, dusting and pressing the tablets according to the invention, trimetazidine dihydrochloride is loaded into a fluidized bed installation for granulation and coating of tablets, together with microcrystalline cellulose, mannitol and montan wax, the components are mixed at an air speed of 25 00-3100 m 3 / h and a temperature of 65-75 0 C, moisten with an alcoholic solution of eudragit RS PO, dried at an air temperature of 40-50 0 C, and the resulting dry granulate is dusted with magnesium stearate.
  • Tablets - cores are coated with OPADRY P.
  • the second task is also solved by the fact that in a method for producing a medicinal product trimetazidine dihydrochloride in the form of a matrix tablet with a prolonged action, including loading the components, mixing, moistening, drying, calibrating, dusting and pressing the tablet cores according to the invention, alcohol is preliminarily prepared 22 , 5% solution of RS PO eudragit, for which 65% of the prescribed RS PO eudragit is dissolved in alcohol, trimetazidine dihydrochloride, mannitol and 50% montan wax are mixed and moistened half of a 22.5% solution of RS PO eudragite, the wet mixture is granulated, dried at a temperature of 40-50 ° C, calibrated through a mesh with a hole diameter of 0.7 -1 mm, mixed with the remaining half of montan wax, RS PO powder and microcrystalline cellulose , the whole powder mixture is moistened with the remainder of a 22.5% RS PO alcohol solution, the wet
  • the core tablets are film coated with OPADRY II.
  • the technical result obtained thanks to the proposed solution is that it creates the possibility of obtaining a medicinal product of the same quality composition with different programs for the release of the active substance.
  • the found regularities of the quantitative ratio of the components and methods of preparation make it possible to predict the rate of release of trimetazidine dihydrochloride and the procedure for using the drug.
  • the positive result is that, regardless of the time of release, the tablet is intact in the gastrointestinal tract for more than a day and the applied excipients do not affect the intestinal wall or its microflora.
  • the kinetics of the release of trimetazidine dihydrochloride at a two-time intake and a dose of 35 mg has the following characteristics: one hour after taking 25-45%, after 3 hours - 43-63%, after 8 hours - not less than 80%, with a single dose and a dose of 60 mg : after an hour - 8-26%, after 3 hours - 16-36%, after 6 hours - 34-59%, after 16 hours - not less than 85%, after 18 hours - not less than 90% ..
  • the matrix is formed from a mixture of two water-soluble crystalline substances - trimetazidine dihydrochloride and mannitol with a hydrophilic limited swelling substance having a porous structure formed by small crystals - microcrystalline cellulose.
  • This mixture is treated with a hydrophobic substance - micronized wax, and the particles of the powder mass are coated with a film of a polymer of methacrylic acid with a low diffusion rate of aqueous solutions independent of PH.
  • a polymer is RS PO eudragit.
  • the total percentage of hydrophilic substances is 45.4 - 45.8%.
  • the total content of hydrophilic components is 33 - 34.7% of the matrix weight.
  • microcrystalline cellulose and a hydrophobic plastic substance - montan wax has led to the creation of closed porous structures containing mixtures of hydrophilic substances - trimetazidine dihydrochloride and mannitol.
  • a matrix which, unlike gel matrices having an open porous structure with polymers such as hydroxypropyl methylcellulose and monolithic polymer matrices, has a porous structure with programmed release of hydrophilic substances.
  • the results obtained suggest that the proposed composition of the tablet with technical solutions for its production creates a new type of solid matrix, which occupies an intermediate place between the solid matrix, which releases the active substance by erosion from the surface of the tablet, and the gel matrix, which releases substance by diffusion through a viscous layer of swollen polymer.
  • the created matrix forms a solid porous matrix, the pores of which formed hydroxypropyl methylcellulose particles, which absorb the solution of the substance and then gradually release it.
  • composition of the tablet core is determined in May. % of the weight of the tablet core and are shown in Table 1.
  • Purified water and ethyl or isopropyl alcohol are used and evaporated in the process, therefore, they are not included in the composition of the final product and the total weight of the tablet.
  • Step 1 The amount of RS PO prescribed in Examples 1 to 3 is weighed, ethyl alcohol or isopropyl alcohol, and a 22.5% polymer solution in alcohol is prepared.
  • Step 2 Trimetazidine dihydrochloride, mannitol, cellulose, montan wax are weighed and placed in a fluidized bed installation.
  • Step 3 Mix the powders for 30 minutes, supplying purified air at a speed of 2500 - 3100 m 3 / h.
  • Step 4 Raise the temperature in the chamber to a temperature of up to 65 ° and supply the solution from step l.
  • Step 5 Dry the granulate to a residual moisture content of 2-3%, unload, calibrate through a mesh with a hole diameter lmm,
  • Step 6 Magnesium stearate is weighed, added to the granulate and mixed for no more than 3 minutes.
  • Step 7 Press with a press tool tablets with an average weight corresponding to examples 1-3, crushing strength no lower than 8OH, abrasion no more than 0.2% Step 8.
  • the OPADRY II coating is dissolved in water to a concentration of 18%.
  • Step 9 The tablets are placed in a coating apparatus and the tablets are coated with the solution from Step 7 until a dry coating is obtained on the surface of the tablet with the mass indicated in Examples 1-3.
  • Step 1 Weigh 65% of the amount of RSPO prescribed by Examples 4-6 and ethyl alcohol or isopropyl alcohol and prepare a 22.5% polymer solution in alcohol
  • Step 2 Weigh trimetazidine dihydrochloride, mannitol, 50% montan wax and place in a mixer.
  • Step 3 Mix the powders for 30 minutes.
  • Step 4 Serve 50% solution from step l.
  • Step 5 Dry the granulate at a temperature of 40-50 ° to a residual moisture content of 2-3%, unload, calibrate through a mesh with a hole diameter of 0.7-1 mm.
  • Step 6 The remaining 50% montan wax, 35% RS PO eudragit powder, microcrystalline cellulose are weighed and placed in a mixer.
  • Step 7 Add the granulate from Step 5 to the mixer and mix the powder mixture for 30 minutes.
  • Step 8 Serve the remaining 50% solution from step
  • Step 9 Dry the granulate at a temperature of 40-50 ° to a residual moisture content of 2-3%, unload it, calibrate it through a mesh with a hole diameter of 0.7- lmm ..
  • Step 10 Weigh magnesium stearate, add to the granulate and mix for no more than Zmin.
  • Step 11 Press the pressing tool tablets with an average weight corresponding to examples 4-6, crushing strength not lower than 8OH, abrasion not more than 0.2%
  • Step 12 The OPADRY II coating is dissolved in water to a concentration of 18%.
  • Step 13 The tablets are placed in a coating apparatus and the tablets are coated with the solution from Step 12 until a dry coating is obtained on the surface of the tablet with the mass indicated in Examples 4-6.
  • Purified water and ethyl or isopropyl alcohol are used and evaporated in the process, therefore, they are not part of the final product and the total weight of the tablet
  • the proposed matrix composition allows the use of a soluble filler, mannitol, to withstand the release program used in the pharmaceutical industry for a two-time or one-time use of trimetazidine dihydrochloride in a wide range of tablet sizes and weights.

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Abstract

l'invention porte sur le domaine de la médecine et concerne un médicament contenant un dihydrochlorure de trimétazidine sous la forme d'un comprimé à matrice à libération prolongée pendant 12 heures, ce comprimé contenant : 45,4 à 46,4 % en poids de substance hydrophiles, à savoir 9 à 25 % en poids de dihydrochlorure de trimétazidine; 52,2 à 54,0 % en poids de substances non solubles, à savoir 26,0 à 27,0 % en poids d'un polymère d'acide méthacrylique; et des adjuvants. L'invention concerne également un médicament contenant un dihydrochlorure de trimétazidine sous la forme d'un comprimé à matrice à libération prolongée pendant 24 heures, ce comprimé contenant : 33,0 à 34,7 % en poids de substances hydrophiles, à savoir 13,6 à 16,7 % en poids de dihydrochlorure de trimétazidine; 52,2 à 54,0 % en poids de substances non solubles, à savoir 26,0 à 27,0 % en poids d'un polymère d'acide méthacrylique; et des adjuvants. L'invention concerne également des procédés de production de ces médicaments. L'invention concerne également des procédés de production de ce médicament contenant un dihydrochlorure de trimétazidine sous la forme d'un comprimé à matrice à libération prolongée pendant 12 heures ou 24 heures.
PCT/UA2010/000026 2009-07-15 2010-05-14 Médicament contenant un dihydrochlorure de trimétazidine sous la forme d'un comprimé à matrice à libération prolongée (variantes) et procédés de préparation de ce médicament (variantes) Ceased WO2011008183A1 (fr)

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
UAA200907425A UA94980C2 (ru) 2009-07-15 2009-07-15 лекарственное средство триметазидина дигидрохлорида в форме матриксной таблетки с прологированным действием (варианты) и способы его получения (варианты)
UAA200907425 2009-07-15

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WO2011008183A1 true WO2011008183A1 (fr) 2011-01-20

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Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP1195160A1 (fr) * 2000-10-05 2002-04-10 USV Ltd. Composition pharmaceutique à effet de retard contenant de la trimétazidine et procédé pour sa préparation
RU2006122367A (ru) * 2005-11-24 2008-01-10 Товарыство з обмэжэною видповидальнистью "Фарма Старт" (UA) Матриксная таблетка с регулируемым высвобождением триметазидина
RU2007142557A (ru) * 2007-11-20 2009-05-27 Закрытое акционерное общество "Канонфарма продакшн" (RU) Матричная таблетка с основой для пролонгированного высвобождения триметазидина дигидрохлорида, способ ее получения и способ лечения

Patent Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP1195160A1 (fr) * 2000-10-05 2002-04-10 USV Ltd. Composition pharmaceutique à effet de retard contenant de la trimétazidine et procédé pour sa préparation
RU2006122367A (ru) * 2005-11-24 2008-01-10 Товарыство з обмэжэною видповидальнистью "Фарма Старт" (UA) Матриксная таблетка с регулируемым высвобождением триметазидина
RU2007142557A (ru) * 2007-11-20 2009-05-27 Закрытое акционерное общество "Канонфарма продакшн" (RU) Матричная таблетка с основой для пролонгированного высвобождения триметазидина дигидрохлорида, способ ее получения и способ лечения

Non-Patent Citations (1)

* Cited by examiner, † Cited by third party
Title
POD PED. L.A. ET AL.: "Tekhnologya lekarstvennykh form", MEDITSINA, vol. 2, 1991, pages 153 *

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