AU684893B2 - Pharmaceutical compositions permitting the prolonged release of trimetazidine after oral administraiton - Google Patents

Pharmaceutical compositions permitting the prolonged release of trimetazidine after oral administraiton Download PDF

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AU684893B2
AU684893B2 AU15029/95A AU1502995A AU684893B2 AU 684893 B2 AU684893 B2 AU 684893B2 AU 15029/95 A AU15029/95 A AU 15029/95A AU 1502995 A AU1502995 A AU 1502995A AU 684893 B2 AU684893 B2 AU 684893B2
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pharmaceutical composition
trimetazidine
release
plasticizer
prolonged release
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AU1502995A (en
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Alain Cuine
Bruno Huet De Barochez
Patrick Genty
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Laboratoires Servier SAS
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ADIR SARL
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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
    • A61K9/48—Preparations in capsules, e.g. of gelatin, of chocolate
    • A61K9/50—Microcapsules having a gas, liquid or semi-solid filling; Solid microparticles or pellets surrounded by a distinct coating layer, e.g. coated microspheres, coated drug crystals
    • A61K9/5073—Microcapsules having a gas, liquid or semi-solid filling; Solid microparticles or pellets surrounded by a distinct coating layer, e.g. coated microspheres, coated drug crystals having two or more different coatings optionally including drug-containing subcoatings
    • A61K9/5078—Microcapsules having a gas, liquid or semi-solid filling; Solid microparticles or pellets surrounded by a distinct coating layer, e.g. coated microspheres, coated drug crystals having two or more different coatings optionally including drug-containing subcoatings with drug-free core
    • 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
    • A61K9/28—Dragees; Coated pills or tablets, e.g. with film or compression coating
    • A61K9/2806—Coating materials
    • A61K9/2833—Organic macromolecular compounds
    • A61K9/286—Polysaccharides, e.g. gums; Cyclodextrin
    • A61K9/2866—Cellulose; Cellulose derivatives, e.g. hydroxypropyl methylcellulose
    • 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
    • A61K9/48—Preparations in capsules, e.g. of gelatin, of chocolate
    • A61K9/50—Microcapsules having a gas, liquid or semi-solid filling; Solid microparticles or pellets surrounded by a distinct coating layer, e.g. coated microspheres, coated drug crystals
    • A61K9/5005—Wall or coating material
    • A61K9/5021—Organic macromolecular compounds
    • A61K9/5026—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
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/48—Preparations in capsules, e.g. of gelatin, of chocolate
    • A61K9/50—Microcapsules having a gas, liquid or semi-solid filling; Solid microparticles or pellets surrounded by a distinct coating layer, e.g. coated microspheres, coated drug crystals
    • A61K9/5005—Wall or coating material
    • A61K9/5021—Organic macromolecular compounds
    • A61K9/5036—Polysaccharides, e.g. gums, alginate; Cyclodextrin
    • A61K9/5042—Cellulose; Cellulose derivatives, e.g. phthalate or acetate succinate esters of hydroxypropyl methylcellulose
    • A61K9/5047—Cellulose ethers containing no ester groups, e.g. hydroxypropyl methylcellulose
    • 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
    • A61P9/08—Vasodilators for multiple indications
    • 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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  • Health & Medical Sciences (AREA)
  • Engineering & Computer Science (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Chemical & Material Sciences (AREA)
  • Medicinal Chemistry (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Animal Behavior & Ethology (AREA)
  • General Health & Medical Sciences (AREA)
  • Public Health (AREA)
  • Veterinary Medicine (AREA)
  • Epidemiology (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • General Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Cardiology (AREA)
  • Heart & Thoracic Surgery (AREA)
  • Vascular Medicine (AREA)
  • Urology & Nephrology (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Medicinal Preparation (AREA)
  • Plural Heterocyclic Compounds (AREA)
  • Macromolecular Compounds Obtained By Forming Nitrogen-Containing Linkages In General (AREA)
  • Compositions Of Macromolecular Compounds (AREA)

Abstract

Compsn. for prolonged liberation of trimetazidine (II) or its salts, uses a polymer insoluble in water and a plasticiser to control liberation.

Description

UIIJ/u IU 28/0 Regulation 3.2(2)
AUSTRALIA
Patents Act 1990
ORIGINAL
COMPLETE SPECIFICATION STANDARD PATENT r Application Number: Lodged: 8 r Invention Title: PHARMACEUTICAL COMPOSITIONS PERMITTING THE PROLONGED RELEASE OF TRIMETAZIDINE AFTER ORAL ADMINISTRATION The following statement is a full description of this invention, including the best method of performing it known to us II, I, C~L-U i_ _I The subject of the present invention is a pharmaceutical composition permitting the prolonged release of trimetazidine or of one of its addition salts with a pharmaceutically acceptable acid.
Trimetazidine, or l-(2,3,4-trinlethoxybenzyl)piperazine, a compound of the formula:
HNH
N N is a molecule which, by preserving the energy metabolisms of the cell exposed to hypoxia or ischemia, avoids the collapse of the intracellular level of adenosine triphosphate (ATP). It thus S ensures the functioning of the ion pumps and the transmembrane flow of sodium-postassium and maintains cellular homeostasis.
Among the pharmaceutically acceptable salts of trimetazidine, there may be mentioned more S: 10 particularly the dihydrochloride which is used in therapy, as coronary vasodilator for the prophylactic treatment of angina pectoris crisis, during chorioretina impairments as well as for the treatment of vertigos of vascular origin (Meniere's vertigo, tinnitus).
Trimetazidine dihydrochloride was up until now administered orally at doses of 40 to 60 mg per day, in the form of tablets containing 20 mg doses or of oral solution containing a dose of 20 mg/ml. These two forms are immediate-release galenic forms.
Trimetazidine dihydrochloride is rapidly absorbed and eliminated by the body, its plasma half-life being less than 6 hours. This requires dividing the administration of the active ingredient to 2 or 3 doses per day in order to ensure relatively constant plasma levels. But, because of a rapid absorption, these immediate-release forms also lead to large plasma peaks shortly after administration and to very low blood levels at the time of the next dose.
A prolonged release form therefore has the advantage of reducing these blood peaks by offering uniform and constant blood levels. It also permits a single daily administration which is favorable to the patient's compliance with the treatment. It therefore permits better monitoring of the treatment.
d d I I -r at--p- -2- To do this, it is necessary to ensure a prolonged release over time, in a perfectly controlled manner. The rate of release should be reproducible and correlated with the blood concentrations observed after administration.
Among the mechanisms which can be invoked for controlling the diffusion of a soluble active ingredient, the prin-cipal one which can be retained is the diffusion of the active ingredient from a reservoir and across a polymer film when the galenic form is brought into contact with the dissolving fluid (in vitro) or with the gastro-intestinal fluid (in vivo).
Numerous polymers have been described as being capable of permitting such diffusion. The principal ones are ethyl cellulose and the methacrylic derivatives. The processes of manufacture commonly used for the manufacture of such reservoir systems require coatings: either coating of bare tablets, the dose of active ingredient being, in this case, distributed in a o single unit, or coating of minigranules; in this latter case, the dose of active ingredient to be administered is distributed in numerous small units which are then assembled either into a gelatin capsule, or into a tablet.
In order to form a barrier film permitting the prolonged release of the active ingredient, the polymers used are polymers which are insoluble in water and gastrointestinal fluids. They can be used either in the form of organic solution or in the form of aqueous dispersion (latex or pseudolatex). Processes using compression have also been described.
o The pharmaceutical composition described in the present invention is characterized by the fact that the prolonged release is ensured by the reservoir system which combines with the active ingredient presented either in the form of tablets, or in the form of minigranules, a polymer film of perfectly controlled thickness coating each tablet or minigranule individually, in order to obtain release of the active ingredient resulting in perfectly defined plasma levels.
Numerous studies have been carried out on the control of the release of highly water-soluble active ingredients. Many of them encountered the following problem: when the active ingredient is of a relatively small size (MW 300) and, in addition, highly soluble in water, the control of the release of the active ingredient is relatively complex, and in particular, it is not possible to ensure release of the active ingredient over more than 12 hours.
Previous studies showed us that the same applied to trimetazidine dihydrochloride.
The molecular weight of trimetazidine in base form is 266.33 and the solubility of the dihydrochloride in water is greater than 1000 mg/ml. Because of this, it was very difficult to 1 obtain matrix tablets controlling the release of the active ingredient over more than 16 hours.
This problem was solved by the use of the reservoir system described in the present invention.
It seemed to us that the combination of a water-insoluble polymer, such as ethyl cellulose or a polymethacrylate, with a plasticizer permitting the preparation of a film relatively permeable to the active ingredient made it possible to obtain a uniform release of the latter.
The influence of a plasticizer on the permeability of polymethacylate films (Eudragit RS®) measured with phenylpropanolamine hydrochloride has been described by K. Lehman (in "Aqueous polymeric coatings for pharmaceutical dosage forms", Ed. J.W. McGinity, Marcel Dekker, Inc., NY, 1989, p. 205). The results obtained by K. Lehman are assembled in the table below.
S.
0
OS..
Plasticizer Permeability Solubility in water (added at 20 (mg.cm-2.h- 1 at room temperature Acetyltrietyl citrate 3.8 0.72 Dibutyl phthalate 5.4 0.04 Triethyl citrate 6.2 6.9 Triacetin 6.2 7.1 Tributyl citrate 9.0 <0.002 Acetyltributyl citrate 11.8 <0.002 Dietyl phthalate 14.8 0.15 Given the very high solubility of the trimetazidine dihydrochloride and the results presented in the preceding table, it appeared judicious to use plasticizers having the lowest permeability.
5 Now, surprisingly, it was shown that the best results were obtained with acetyltributyl citrate.
Indeed, the use of plasticizers such as acetyltriethyl citrate, triethyl citrate or triacetin, causes a very long lag time which can be as high as four hours at the end of which the release is much more rapid than with acetyltributyl citrate. These results are presented in Figure 1 (annex).
For the treatment of coronary disorders for which trimetazidine is intended, it was very important that the release of the active ingredient can start upon the administration of the galenic form to the patient, so as to offer him rapid and effective treatment. A lag time greater than one hour is therefore a handicap which the present invention was able to overcome.
Furthermore, gradual release of the active ingredient is essential if it is desired to obtain relatively constant plasma levels.
The pharmaceutical compositions described in the present invention are provided more particularly in the form of reservoir tablets or minigranules.
4pl __I
Y~
Principle of the manufacture of the galenic forms Principle of the manufacture of the reservoir tablets The tablets are prepared in several stages.
First, a preliminary mixture of the constituents makes it possible to obtain regularity of the final trimetazidine dihydrochloride dosage. A granulation phase then makes it possible to densify the initial powder mixture. This agglomeration can be achieved with the aid of a binder which is soluble in an aqueous or aqueous-alcoholic solvent. A lubrication phase then makes it possible to allow correct operation of the machines for producing the tablets.
After preparation of the tablets, the latter are coated by means of a solution or suspension of the "0 polymer chosen to ensure the diffusion of the active ingredient and thus to control the kinetics of release. A plasticizer is used at this stage in order to achieve good coating of the tablet with the polymeric film.
S Principle of the manufacture of the reservoir minigranules The minigranules can be prepared according to two processes, either a process using extrusion and spheronization techniques, or a process using techniques for mounting the active ingredient on a neutral nucleus.
a Manufacture of minigranules by extrusion and spheronization In this process, a wet mass containing trimetazidine dihydrochloride and auxiliary excipients is extruded through a perforated grid. The product obtained in the form of oblong cylinders is then spheronized by means of a toothed plate spheronizer. The minigranules thus obtained are subsequently dried, either in a ventilated oven, or in a fluidized bed.
b Manufac.ure of minigranules by mounting the active ingredient on a neutral nucleus In this process, the neutral nuclei are coated with successive layers of active ingredient by means of a coating turbine, perforated or otherwise, or of fluidized bed apparatus. The active ingredient, prepared in the form of an aqueous or organic solution or suspension, is sprayed over the neutral nuclei and then dried by hot air for example.
II c Coating of the minigranules The minigranules, prepared by either of the processes, are subsequently coated, either in a coating turbine, perforated or otherwise, or in a fluidized bed-type apparatus. The minigranules are coated by means of a :solution or a suspension of the polymer chosen to ensure the diffusion of the active ingredient and thus to control the kinetics of release. A plasticizer is used at this stage in order to achieve good coating of the minigranules by the polymeric film.
The following examples illustrate the invention but do not limit it in any manner.
Tablets
S
*s.
4
S
5.15 *r S 4..1 The preparation of the prolonged-release tablets is carried out in the following manner: Stage A Mixing of trimetazidine dihydrochloride, a diluent and polyvidone acting as binder aud then wetting by means of an aqueous or aqueous-alcoholic solution. The wet mass is then granulated, dried and then sized so as to obtain a granule whose physical characteristics permit good filling of the matrices of a rapid tableting machine.
Stage B Lubrication of the granule obtained in Stage A with colloidal silica and/or magnesium stearate.
Stage C Tableting of the lubricated mixture obtained in Stage B on an alternating or rotary tableting machine.
Stage D Coating of the tablets obtained in Stage C by means of an aqueous or organic solution or suspension of a polymer ensuring the diffusion of the active ingredient. This solution or suspension may also contain a plasticizer. The coating is carried out in a coating turbine or a fluidized-bed apparatus.
d~ I Example 1: A i iged release tablet (PR1) is prepared using the formula given in Table 2, according to the operating procedure described in Stages A to C.
Table 2 Unit formula for the PR1 tablet Constituents Quantities (mg) Trimetazidine dihydrochloride Calcium hydrogen phosphate Polyvidone 8 Colloidal silica 0.4 Magnesium stearate 1.6 This tablet is then coated in a perforated turbine by means of an alcoholic solution of ethyl S cellulose containing acetyltributyl citrate used as plasticizer. The dissolution profile in vitro for 0: 10 this form (PR1) is represented in Figure 2 (annex).
The lag time for this prolonged release form is equal to one hour. Beyond, the solution kinetics in vitro is linear over more than 10 hours.
Example 2: A prolonged release tablet (PR2) is obtained following the procedure described above and with 15 the formula described in Table 2. This tablet is then coated in a Manesty type Accela Cota S perforated turbine by means of an aqueous suspension of ethyl cellulose (Aquacoat®) containing dibuty! sebacate used as plasticizer. The dissolution profile in vitro for this form (PR2) is presented in Figure 3 (annex).
With this PR2 form, the lag time of the dissolution kinetics in vitro of the active ingredient is less than one hour. The rate of release is higher in this example. The use of an aqueous suspension of ethyl cellulose in place of an organic solution makes it possible to obtain a release profile which is a little different.
Minigranules: The preparation of the prolonged-release minigranules is carried out according to two processes: Extrusion and spheronization process Stage A Mixing of trimetazidine dihydrochloride with micro-crystalline cellulose and then wetting by means of purified water. The wet mass is then granulated and then extruded by means of an extruder. The extrudates are then spheronized and dried.
Stage B 44 4.
44 4 4.
4 4* 4 *4 Coating of the minigranules obtained in Stage A by means of an organic solution or of an aqueous suspension of polymer which may also contain a plasticizer, in a coating turbine or a fluidized bed apparatus.
Stage C Placing of the coated minigranules in gelatin capsules.
Process based on mounting: Stage A Coating of neutral minigranules composed for example of sucrose, or of sucrose and starch or of microcrystalline cellulose by means of an aqueous solution of active ingredient which may contain a binder such as polyvidone or methylhydroxypropyl cellulose. This coating can be carried out in a coating turbine or in a fluidized-bed apparatus.
Stage B Stage B is identical to Stage B of the process based on extrusion and spheronization.
Stage C Placing the coated minigranules in gelatin capsules.
Example 3: sees 0 6 'a10 00.0
S
.4 0.0.
*5 A gelatin capsule containing prolonged-release minigranules (PR3) is prepared using the formula given in Table 3, according to the operating process based on extrusion and spheronization.
Table 3 Formula for the PR3 gelatin capsule Constituents Quantities (mg) Trimetazidine dihydrochloride Microcrystalline cellulose Ethyl cellulose Acetyltributyl citrate 4 The minigranules obtained in Stage A are coated with an alcoholic solution of ethyl cellulose (polymer controlling the release of the active ingredient) supplemented with acetyltributyl citrate used as plasticizer.
The dissolution profile in vitro for this form (PR3) is presented in Figure 4 (annex).
The plasma concentrations of trimetazidine were measured in twelve subjects after administration either of one PR3 gelatin capsule per day, or of one immediate-release tablet (IR) three times per day. The curve of the mean plasma concentrations is given in Figure (annex).
Example 4: A gelatin capsule containing prolonged-release minigranules (PR4) is prepared using the formula given in Table 4, according to the operating procedure based on mounting.
Table 4 Formula for the PR4 gelatin capsule Constituents Quantities(mg) Trimetazidine dihydrochloride Neutral granule sucrose-starch 74 Methylhydroxypropyl cellulose 6 Ethyl cellulose 16 Ac6tyltributyl citrate 1.6 The minigranules obtained in Stage A are coated with an alcoholic solution of ethyl cellulose supplemented with acetyltributyl citrate.
S a a* S* a *r S I I The dissolution profile of the PR4 form is presented in Figure 6 (annex).
Example A PR5 gelatin capsule is prepared using the process described for the PR3 type gelatin capsule (Example 3) in which the coating by means of an alcoholic solution of ethyl cellulose is replaced with a coating by means of an aqueous suspension of ethyl cellulose (Aquacoat®). Its dissolutio profile in vitro is presented in Figure 7 (annex).
The lag time does not exist. The dissolution kinetic in vitro is linear after 4 hours.
Example 6: S* A PKo type gelatin capsule is prepared using the process described for the PR4 gelatin capsule 0 in which the coat'ag by means of an alcoholic solution of ethyl cellulose is replaced with a S coating by means of an aqueous dispersion of polymethacrylates (Eudragit®). Its dissolution profile in vitro is presented in Figure 8 (annex).
Thus, with the coating by means of an aqueous suspension of Eudragit® there is no lag time.
The kinetics of release in vitro of the active ingredient is virtually linear over 12 hours.
9 o 0 i III11 1 i

Claims (8)

1.A pharmaceutical composition for the prolonged release of trimetazidine or one of its pharmaceutically acceptable salts, wherein the prolonged release of the trimetazidine is controlled by the use of a water-insoluble polymer and of a plasticizer.
2.The pharmaceutical composition as claimed in claim 1, wherein the controlled release of 1the trimetazidine is ensured by a reservoir system in which the mixture of the polymer and the plasticizer is in the form of a film which coats tablets or ,ninigranules containing trimetazidine or one of its addition salts with a pharmaceutically acceptable acid.
3.The pharmaceutical composition as claimed in claim 1, in which the trimetazidine is in the form of a dihydrochloride. *9S* a 4.The pharmaceutical composition as claimed in claim 2, such that the reservoir system is a S" reservoir tablet. 0 0 0* *g 0 5.The pharmaceutical composition as claimed in claim 2, such that the reservoir system is a 0 reservoir gelatin capsule containing coated minigranules. ee0.
6.The pharmaceutical composition as claimed in claim 1, such that the polymer used is ethyl cellulose in the form of an organic solution or an aqueous dispersion.
7.The pharmaceutical composition as claimed in claim 1, such that the polymer used is an acrylic derivative. 0 9 0o
8.The pharmaceutical composition as claimed in claim 1, such that the plasticizer is acetyltributyl citrate.
9.The pharmaceutical composition as claimed in claim 1, such that the plasticizer is dibutyl sebacate. pharmaceutical composition as claimed in claim 1, which makes it possible to obtain a controlled and uniform release of trimetazidine from the beginning of the administration and over a period of at least 16 hours.
11.The pharmaceutical composition as claimed in claim 1, which is useful in the prophylactic treatment of argina pectoris crisis during chorioretinal impairments as well as during the treatment of vertigos of vascular origins. DATED this 21st day of March 1995. ADIR ET COMPAGNIE WATERMARK PATENT TRADEMARK ATTORNEYS 290 BURWOOD ROAD HAWTHORN. VIC. 3122. I_ 44 I ABSTRACT PHARMACEUTICAL COMPOSITIONS PERMITI[NG THE PROLONGED RELEASE OF TR]METAZIDINE AFT'ER ORAL ADMINISTRATION 6* 5 e ADIR ET COMPAGNIE 1 rue Carle H6bert 92415 COUR13EVO'E Cedex The invention relates to pharmaceutical co~apositions permitting the prolonged release of trimetazidine after oral administration. to
AU15029/95A 1994-03-24 1995-03-22 Pharmaceutical compositions permitting the prolonged release of trimetazidine after oral administraiton Expired AU684893B2 (en)

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
FR9403434 1994-03-24
FR9403434A FR2717687B1 (en) 1994-03-24 1994-03-24 Pharmaceutical compositions for the sustained release of trimetazidine after oral administration.

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AU684893B2 true AU684893B2 (en) 1998-01-08

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JP (1) JP3017040B2 (en)
CN (1) CN1056057C (en)
AT (1) ATE216583T1 (en)
AU (1) AU684893B2 (en)
CA (1) CA2145248C (en)
DE (1) DE69526467T2 (en)
DK (1) DK0673649T3 (en)
ES (1) ES2176296T3 (en)
FI (1) FI116881B (en)
FR (1) FR2717687B1 (en)
NO (1) NO306450B1 (en)
NZ (1) NZ270791A (en)
PT (1) PT673649E (en)
ZA (1) ZA952418B (en)

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WO2009034541A3 (en) * 2007-09-11 2009-07-30 Ranbaxy Lab Ltd Controlled release pharmaceutical dosage forms of trimetazidine

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FR2802424B1 (en) * 1999-12-17 2002-02-15 Adir MATRIX TABLET FOR THE EXTENDED RELEASE OF TRIMETAZIDINE AFTER ORAL ADMINISTRATION
PT1195160E (en) * 2000-10-05 2009-12-07 Usv Ltd Sustained release trimetazidine pharmaceutical compositions and a method of their preparation
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CN102319225B (en) * 2011-09-23 2013-04-03 广州白云山光华制药股份有限公司 Trimetazidine hydrochloride sustained release tablet and preparation method thereof
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
CN102764261A (en) * 2012-07-30 2012-11-07 沈阳药科大学 Oral composition controlling release of trimetazidine dihydrochloride and preparation method of oral composition
CN103565751A (en) * 2013-10-17 2014-02-12 广州帝奇医药技术有限公司 Long-acting sustained-release pellet and preparation method thereof
US20190381034A1 (en) * 2018-06-14 2019-12-19 Ming Fang Pharmaceutical composition and method for acute on chronic liver failure and related liver diseases
CN110237053A (en) * 2019-07-26 2019-09-17 湖北欣泽霏药业有限公司 A kind of trimetazidine hydrochloride sustained-release pellet and preparation method thereof

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AU1502995A (en) 1995-10-05
CN1056057C (en) 2000-09-06
CA2145248A1 (en) 1995-09-25
FI116881B (en) 2006-03-31
NO306450B1 (en) 1999-11-08
CN1124140A (en) 1996-06-12
DK0673649T3 (en) 2002-08-05
NO951110D0 (en) 1995-03-23
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FI951357A0 (en) 1995-03-22
DE69526467T2 (en) 2002-12-05
PT673649E (en) 2002-08-30
CA2145248C (en) 2004-01-06
JPH07258086A (en) 1995-10-09
ZA952418B (en) 1995-12-18
ATE216583T1 (en) 2002-05-15
FI951357A (en) 1995-09-25
FR2717687B1 (en) 1996-06-14
EP0673649B1 (en) 2002-04-24
NO951110L (en) 1995-09-25

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