WO2003043610A2 - Procede de fabrication d'une composition pharmaceutique a liberation prolongee contenant des microbilles de trimetazidine dihydrochloride - Google Patents

Procede de fabrication d'une composition pharmaceutique a liberation prolongee contenant des microbilles de trimetazidine dihydrochloride Download PDF

Info

Publication number
WO2003043610A2
WO2003043610A2 PCT/IN2002/000223 IN0200223W WO03043610A2 WO 2003043610 A2 WO2003043610 A2 WO 2003043610A2 IN 0200223 W IN0200223 W IN 0200223W WO 03043610 A2 WO03043610 A2 WO 03043610A2
Authority
WO
WIPO (PCT)
Prior art keywords
range
hci
tmz
polymer
drug core
Prior art date
Application number
PCT/IN2002/000223
Other languages
English (en)
Other versions
WO2003043610A3 (fr
Inventor
Amit Krishna Antarkar
Rajendra Ghanshamlal Lala
Gaurang Hasmukhlal Thanawala
Maya Janak Shah
Janak Ramanlal Shah
Original Assignee
Themis Laboratories Private Limited
Priority date (The priority date 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 date listed.)
Filing date
Publication date
Application filed by Themis Laboratories Private Limited filed Critical Themis Laboratories Private Limited
Priority to EP02803493A priority Critical patent/EP1448173A2/fr
Priority to HU0500382A priority patent/HUP0500382A3/hu
Priority to AU2002356425A priority patent/AU2002356425A1/en
Publication of WO2003043610A2 publication Critical patent/WO2003043610A2/fr
Publication of WO2003043610A3 publication Critical patent/WO2003043610A3/fr

Links

Classifications

    • 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
    • A61K9/48—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
    • 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
    • A61K9/5084—Mixtures of one or more drugs in different galenical forms, at least one of which being granules, microcapsules or (coated) microparticles according to A61K9/16 or A61K9/50, e.g. for obtaining a specific release pattern or for combining different drugs

Definitions

  • Trimetazidine Dihydrochloride is an anti ischemic agent that has been used in the management and prophylaxis of angina pectoris and in ischemia of neuro-sensorial tissues as in menieres disease.
  • TMZ HCI regulates ionic and extracellular exchanges correcting the abnormal flow of ions across the cell membrane caused by ischemia & preventing cellular edema caused by anoxia.
  • TMZ HCI has been in market for above 20 years, as 20-mg tablets.
  • the plasma half-life of trimetazidine Dihydrochloride is 6 ⁇ 1.4 hours, and T max is around 1.8 ⁇ 0.7 hours and is therefore recommended for dosing regimen of 2-3 times a day.
  • TMZ HCI is highly water-soluble and has a potential problem of burst release. In the case of TMZ HCI it is desirable to develop dosage form that ensure consistent d elivery a nd p rolonged p lasma levels with insignificant contribution to the initial release in case of a failure of the system avoiding a situation of dose dumping, exhibiting less variation in gastro- intestinal transit time thereby providing dosage forms with minimized inter subject and intra subject variation.
  • US Patent 4814176 describes sustained release preparation comprising chitin, chitosan, or a mixture thereof, anionic polymer having carboxyl group, sulfonic acid group or a group capable of providing the same and a pharmaceutical active agent including TMZ HCI.
  • the process involves pulverization of each of these components to a particle size of about 5-500 mu.m followed by mixing of all the polymers with pharmaceutical active agent in a single step and then preparing dosage forms in the form of tablets, granules, grains, dental cones, films, or tablets in hard gelatin capsules.
  • This patent does not disclose any relevant information on the release characteristic for TMZ HCI.
  • EP 0673649 describes pharmaceutical compositions for the prolonged release of trimetazidine or its salts, a polymer insoluble in water and a plasticizer to control its liberation.
  • the manufacturing process involves preparation of tablets or minigranules with 80mg dose for once a day dosing followed by coating with ethyl cellulose or acrylic derivatives and specific plasticizers such as acetyl tributyl citrate or dibutyl sebacate for prolonged release.
  • This patent specifically discourages the use of plasticizers like triacetin, triethylcitrate and acetyltriethylcitrate and demonstrate that their use cause an undesirable latency period of upto 4 hours, at the end of which the release is very fast.
  • trimetazidine dihydrochloride In such a case the loading dose of trimetazidine dihydrochloride is not available for immediate absorption and pharmacological action.
  • the formulation described releases only upto 75% of the drug in-vitro in a period of 16 hours. This incomplete drug release can lead to non- utilization of the total amount of drug administered to the patient.
  • Bioavailability studies conducted on 12 volunteers shows steady state plasma concentration at around 110ng/ml with 80mg oral dose.
  • the total daily recommended dose in case of trimetazidine dihydrochloride is 40 - 60 mg in single or divided doses.
  • the dose of TMZ HCI in this patent is 80mg, which far exceeds the recommended dose.
  • the publication EP 1195160 A1 relates to sustained release matrix pharmaceutical tablet compositions containing 60 mg of TMZ HCI and hydrocolloid forming materials and or hydrophobic polymers and or other hydrophobic materials as a retardant, which release TMZ HCI in a sustained and reproducible manner over a prolonged period of time to achieve the sustained effect of trimetazidine over a 24 hour period after oral administration.
  • This invention makes use of multi-step process involving multiple equipments that is laborious, time consuming with potential of cross - contamination.
  • EP1108424 describes matrix tablets for sustained release of TMZ HCI for oral administration characterized in that the prolonged release is controlled by the use of a polymer derived from cellulose.
  • the invention describes sustained release tablet composition containing 35 mg of TMZ HCI for twice a day dosing. This invention also makes use of multi-step process involving multiple equipments that is laborious, time consuming with potential of cross - contamination.
  • microbeads are desirable forms of drug delivery systems as they can be packed into capsules for patient convenience. It may also be noted that though prior art describes several process of manufacturing of sustained release microbeads and tablets, there is no teaching related to processes involving TMZ HCI formulations in microbeads.
  • the main object of the present invention is to provide novel compositions and process for manufacturing of novel pharmaceutical compositions in the form of microbeads comprising of TMZ HCI and further coating of the beads with polymeric membrane to tailor the drug release characteristics enabling "once a day” dosing for 60 mg dose of TMZ HCI per unit dose.
  • Another object of the invention is to provide continuous process for efficient manufacturing of novel pharmaceutical compositions in the form of agglomeration free, uniform shaped and sized microbeads comprising of TMZ HCI in a single equipment viz. fluid bed processor.
  • Another object of the invention is to provide a continuous process for manufacturing of novel pharmaceutical compositions in the form of microbeads comprising of TMZ HCI which can be encapsulated in size '3' capsules for d ose 60 m g thus p roviding a patient easy to consume dosage form.
  • Another object of the invention is to provide a continuous process for manufacturing of novel pharmaceutical compositions in the form of microbeads comprising of TMZ HCI, which will provide therapeutic blood levels of the drug for once a day dosing for a dose of 60mg.
  • Another object of the invention is to provide a continuous process for manufacturing of novel pharmaceutical compositions in the form of microbeads comprising of TMZ HCI without the problem of dose dumping and burst effect from the formulation.
  • Another object of the invention is to provide a continuous process for manufacturing of novel pharmaceutical compositions in the form of microbeads comprising of T MZ H CI which when tested in vitro provides pH independent release of TMZ HCI atleast for a period of 8 - 10 hours without any latent period.
  • Another object of the invention is to provide a continuous process for manufacturing of novel pharmaceutical compositions in the form of microbeads comprising of TMZ HCI in a single equipment fluid bed processor which essentially consists of spraying aqueous TMZ HCI solution with binder, antitack agent, glidants on inert seeds such as sugar spheres to produce drug core.
  • the drug cores are further coated with water insoluble polymer/s with or without plasticizers in fluid bed processor to produce sustained release microbeads comprising of TMZ HCI.
  • the objective of the invention is to provide novel compositions and process for optional but "novel use” of plasticizers such as triacetin and triethylcitrate.
  • This invention relates to novel compositions and continuous process using a single equipment for manufacturing novel pharmaceutical compositions in the form of microbeads comprising of TMZ HCI wherein TMZ HCI solution with inert excipients in aqueous or hydroalcoholic media is sprayed on inert seeds such as sugar sphere which are further sequentially coated with a polymer/s with or without plasticizers for controlling the release of TMZ HCI to obtain a stable, patient convenient dosage form.
  • the manufacturing process is carried out essentially in two stages with a n o ptional third stage continuously in single equipment to give a product capable of being filled in hard gelatin capsules as follows: Stage I: Production of drug core
  • Stage II Production of sustained release microbeads (SR I)
  • Stage III Optionally a second polymer coat on SR I (SR II)
  • the first stage in manufacturing TMZ HCI sustained release microbeads is to manufacture drug core. This is carried out by dissolving TMZ HCI in water. Water-soluble binder, antitack agent and glidants are added to above solution. The resulting suspension is then filtered through 100 mesh and is sprayed on sugar spheres in a bottom spray fluid bed coater with inlet air temperature between 50 - 80°C, outlet air temperature 40 - 55°C, atomization air pressure 1.5 - 3.5 bars, fluidization flap open between 15 - 90%. After spraying this drug suspension, the drug cores are dried in the same equipment maintaining the inlet temperature between 50-80°C and outlet temperature between 40 - 60°C to have moisture content of less than 5% and preferably less than 3%.
  • the content of TMZ HCI in drug core is about 20 to about 70% by weight and preferably from about 20 to about 50% by weight.
  • the particle size of sugar spheres may vary from about 1405 to about 420 m icrons a nd a re p referably b etween a bout 1 000 to a bout 500 microns.
  • the sugar spheres have hardness, which can withstand the rigors of the fluid bed processor.
  • the binder is selected but not limited to hydroxypropyl methylcellulose, hydroxypropyl cellulose, polyvinylpyrollidone, sodium carboxymethylcellulose, methylcellulose and their mixtures thereof. Hydroxypropyl methylcellulose is preferred as a binder, which has a nominal viscosity of 5 - 15 cps, measured on 2% w/w solution at 20°C.
  • the concentration of binder in drug core is optimized and is 5 - 30% w/w of TMZ HCI and preferably between 7.5 - 20% w/w.
  • Antitack agent and glidants wherever used such as talc, colloidal silicon dioxide, glycerin monostearate, glycerin behenate are optimized and used in the concentration level of 10 - 30% w/w of TMZ HCI and is preferably around 15 - 25 % w/w.
  • the total solid content in the spray solution is in the range of 20 - 60% w/w. This is illustrated with an example below.
  • the drug cores after drying are coated with water insoluble polymer/s with or without plasticizer and antitack agent.
  • the water insoluble polymer/s is selected f rom the g roup b ut n ot l imited to alkyl cellulose, (meth)acrylic acid derivatives.
  • Ethylcellulose, a queous dispersion of Eudragit NE and aqueous dispersion of Eudragit RS are preferred and used as water insoluble polymers alone or in combination.
  • the above-mentioned polymer/s are used in the concentration level of about 1 to about 20% w/w and preferably in the range of about 5 to about 15 % w/w of the drug core.
  • the polymer may be used alone or in combination where drug cores are coated with one polymer (SR I) which is followed by coating with another polymer (SR II) as illustrated in the example below.
  • SR I polymer
  • SR II polymer
  • the antitack agent wherever used is not limited to but preferably is talc and is used in the concentration level of 5 - 40% w/w of the polymer and preferably in the range of about 10 to about 30% w/w.
  • Plasticizers wherever used are selected but not limited to triethylcitrate, triacetin and are used in the concentration level of about 10 to about 25% w/w and preferably from about 10 to about 20% w/w of the polymer/s used.
  • Water or organic solvents like methanol and methylene chloride (about 2:8 to about 8:2 and preferably about 4:6) can be used for the dissolution of the polymer/s to which plasticizer and antitack agent are added.
  • the solid content of this solution is in the range of about 5 to about 25% w/w and preferably from about 7.5 to about 20% w/w.
  • the sustained release microbeads are dried in the same equipment till the moisture content of the final product is less than 5% w/w and preferably less than 3% w/w.
  • Use of (meth)acrylic acid derivatives involves curing of microbeads in hot air oven at 40°C for 12 hours.
  • the process parameters for polymer/s sustained release coating involves inlet air temperature of about 20 to about 50°C, outlet air temperature of about 20 to about 40°C, atomization air pressure of about 1.0 - 3.5 bars, fluidization flap open from about 15 to about 90% w/w. This is illustrated with an example below.
  • the test for acceptability of coating level is determined by analysis of the dissolution rate of the finished sustained release microbeads prior to encapsulation.
  • the dissolution procedure followed uses USP apparatus II (paddle) at 50 rpm in 500 ml distilled water at 37°C.
  • Conformance with the dissolution rate given in table I provides 24 hours therapeutic blood levels for the drug component of the sustained release capsule of this invention in capsule form where a given batch of sustained release coated microbeads releases drug too slowly to comply with the desired dissolution rate study, a portion of uncoated (drug coated) or with a lower coating level may be added to the batch to provide, after thorough mixing, a loading dose for rapid increase of the blood drug levels.
  • a batch of sustained release coated microbeads that releases the drug too rapidly may be treated to an additional coat to achieve the desired dissolution profile.
  • the polymer coated pellets were encapsulated in size '3' hard gelatin capsules for a dose of 60 mg and subjected to accelerated stability condition at 40°C / 75 %RH and 25°C / 60 % RH.
  • the stability results are as follows.
  • Single dose oral in-vivo bioavailability study shows well-sustained plasma levels of TMZ HCI over 24 hours with AUC 0 -26hrs 1602.60 ng.hrs/ml and a C ma ⁇ of 113.78 ng/ml.

Landscapes

  • Health & Medical Sciences (AREA)
  • Engineering & Computer Science (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Epidemiology (AREA)
  • Medicinal Chemistry (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Chemical & Material Sciences (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Animal Behavior & Ethology (AREA)
  • General Health & Medical Sciences (AREA)
  • Public Health (AREA)
  • Veterinary Medicine (AREA)
  • Medicinal Preparation (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)

Abstract

L'invention concerne de nouvelles compositions ainsi qu'un procédé de fabrication de nouvelles compositions pharmaceutiques. Ce procédé consiste à former des microbilles comprenant du trimétazidine dihydrochloride, puis à enrober ces billes d'une membrane polymère afin d'adapter les caractéristiques de libération du médicament, ce qui permet un dosage 'une fois par jour' pour une dose de 60 mg de trimétazidine dihydrochloride par dose unitaire.
PCT/IN2002/000223 2001-11-21 2002-11-20 Procede de fabrication d'une composition pharmaceutique a liberation prolongee contenant des microbilles de trimetazidine dihydrochloride WO2003043610A2 (fr)

Priority Applications (3)

Application Number Priority Date Filing Date Title
EP02803493A EP1448173A2 (fr) 2001-11-21 2002-11-20 Procede de fabrication d'une composition pharmaceutique a liberation prolongee contenant des microbilles de trimetazidine dihydrochloride
HU0500382A HUP0500382A3 (en) 2001-11-21 2002-11-20 Sustained release pharmaceutical compositions containing microbeads of trimetazidine dihydrochloride and process for producing them
AU2002356425A AU2002356425A1 (en) 2001-11-21 2002-11-20 A process for manufacture of a sustained release composition containing microbe

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
IN1106MU2001 2001-11-21
IN1106/MUM/2001 2001-11-21

Publications (2)

Publication Number Publication Date
WO2003043610A2 true WO2003043610A2 (fr) 2003-05-30
WO2003043610A3 WO2003043610A3 (fr) 2003-08-21

Family

ID=11097321

Family Applications (1)

Application Number Title Priority Date Filing Date
PCT/IN2002/000223 WO2003043610A2 (fr) 2001-11-21 2002-11-20 Procede de fabrication d'une composition pharmaceutique a liberation prolongee contenant des microbilles de trimetazidine dihydrochloride

Country Status (4)

Country Link
EP (1) EP1448173A2 (fr)
AU (1) AU2002356425A1 (fr)
HU (1) HUP0500382A3 (fr)
WO (1) WO2003043610A2 (fr)

Cited By (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2006123073A1 (fr) * 2005-05-18 2006-11-23 Les Laboratoires Servier Composition pharmaceutique solide a liberation prolongee de 1-(2,3,4-trimethoxybenzyl)piperazine, et procede de preparation.
WO2009034541A2 (fr) 2007-09-11 2009-03-19 Ranbaxy Laboratories Limited Formes galéniques à libération contrôlée à base de trimétazidine
CN102133195A (zh) * 2011-03-17 2011-07-27 王国栋 盐酸曲美他嗪的缓控释微丸及其制备方法
MD20130005A2 (ro) * 2012-02-03 2013-07-31 Les Laboratoires Servier Compoziţie farmaceutică cu eliberare prelungită a trimetazidinei

Families Citing this family (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
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

Citations (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP0673649A1 (fr) * 1994-03-24 1995-09-27 Adir Et Compagnie Compositions pharmaceutiques permettant la libération prolongée de trimétazidine après administration par voie orale

Patent Citations (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP0673649A1 (fr) * 1994-03-24 1995-09-27 Adir Et Compagnie Compositions pharmaceutiques permettant la libération prolongée de trimétazidine après administration par voie orale

Cited By (13)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2006123073A1 (fr) * 2005-05-18 2006-11-23 Les Laboratoires Servier Composition pharmaceutique solide a liberation prolongee de 1-(2,3,4-trimethoxybenzyl)piperazine, et procede de preparation.
FR2885807A1 (fr) * 2005-05-18 2006-11-24 Mg Pharma Composition pharmaceutique solide a liberation prolongee de 1-(2,3,4-trimethoxybenzyl) piperazine, et procede de preparation
EA013645B1 (ru) * 2005-05-18 2010-06-30 Ле Лаборатуар Сервье Твердая фармацевтическая композиция с пролонгированным высвобождением 1-(2,3,4-триметоксибензил)пиперазина и способ ее получения
WO2009034541A2 (fr) 2007-09-11 2009-03-19 Ranbaxy Laboratories Limited Formes galéniques à libération contrôlée à base de trimétazidine
CN102133195A (zh) * 2011-03-17 2011-07-27 王国栋 盐酸曲美他嗪的缓控释微丸及其制备方法
US20130202710A1 (en) * 2012-02-03 2013-08-08 Les Laboratoires Servier Pharmaceutical composition for the prolonged release of trimetazidine
MD20130005A2 (ro) * 2012-02-03 2013-07-31 Les Laboratoires Servier Compoziţie farmaceutică cu eliberare prelungită a trimetazidinei
JP2013159609A (ja) * 2012-02-03 2013-08-19 Lab Servier トリメタジジンの持続放出のための医薬組成物
TWI508755B (zh) * 2012-02-03 2015-11-21 Servier Lab 供三甲氧苄嗪（ｔｒｉｍｅｔａｚｉｄｉｎｅ）延長釋放之醫藥組合物
RU2621128C2 (ru) * 2012-02-03 2017-05-31 Ле Лаборатуар Сервье Фармацевтическая композиция для пролонгированного высвобождения триметазидина
EA030227B1 (ru) * 2012-02-03 2018-07-31 Ле Лаборатуар Сервье Мини-гранулы для пролонгированного высвобождения триметазидина, способ их получения и применение
US10117838B2 (en) * 2012-02-03 2018-11-06 Les Laboratoires Servier Pharmaceutical composition for the prolonged release of trimetazidine
KR101918211B1 (ko) * 2012-02-03 2018-11-14 르 라보레또레 쎄르비에르 트리메타지딘의 장기간 방출을 위한 약제학적 조성물

Also Published As

Publication number Publication date
HUP0500382A3 (en) 2008-03-28
HUP0500382A2 (hu) 2005-07-28
AU2002356425A8 (en) 2003-06-10
WO2003043610A3 (fr) 2003-08-21
EP1448173A2 (fr) 2004-08-25
AU2002356425A1 (en) 2003-06-10

Similar Documents

Publication Publication Date Title
CA2462637C (fr) Formes posologiques a particules multiples et a liberation echelonnee de propanolol
AU2007211091B8 (en) Drug delivery systems comprising weakly basic selective serotonin 5-HT3 blocking agent and organic acids
US20090148532A1 (en) Preparation of controlled release skeletal muscle relaxant dosage forms
JP2003524592A (ja) 持続放出薬物製剤
EP2073798A2 (fr) Compositions pharmaceutiques à base de nimodipine
PL164770B1 (pl) Sposób wytwarzania dwuimpulsowej postaci uzytkowej leku zawierajacego minocykline PL PL PL PL PL PL
JP2012107048A (ja) 時限拍動性薬物送達システム
JP2005508922A6 (ja) プロプラノロールの時限徐放性多粒子剤型
HU227490B1 (en) Sustained release pharmaceutical preparation containing carvedilol
EP2265261A1 (fr) Systèmes d administration de médicaments comprenant des médicaments faiblement basiques et des acides organiques
CA2383405A1 (fr) Procede relatif a la formation de granules a revetement aqueux
US20060121114A1 (en) Method of manufacturing sustained release microbeads containing venlafaxine HCL
CN102046155A (zh) 包含多颗粒的具有双重释放特性的固体口服剂型
US8642078B2 (en) Coated formulations for tolterodine
CA2634006C (fr) Compositions pharmaceutiques a liberation prolongee comprenant de la liothyronine ou du sel de sodium de liothronine
US20180369151A1 (en) Multiparticulate oral dosage form providing prolonged release of tapentadol
EP2386302A1 (fr) Forme pharmaceutique à libération prolongée de trimetazidine et ses procédés de préparation
WO2001087269A1 (fr) Une composition de pellicule pour faciliter la liberation regulee
WO2003043610A2 (fr) Procede de fabrication d'une composition pharmaceutique a liberation prolongee contenant des microbilles de trimetazidine dihydrochloride
JPWO2002034268A1 (ja) ５−アセチル−４，６−ジメチル−２−［２−［４−（２−メトキシフェニル）ピペラジニル］エチルアミノ］ピリミジン・三塩酸塩を有効成分として含有する徐放性製剤
US20100080846A1 (en) Dipyridamole and acetylsalicylic acid formulations and process for preparing same
JPH06345649A (ja) イプサピロン薬剤組成物
AU2013204408B2 (en) Drug delivery systems comprising weakly basic selective serotonin 5-HT3 blocking agent and organic acids
AU2013204400B2 (en) Drug delivery systems comprising weakly basic drugs and organic acids
CN111278434A (zh) 劳拉西泮的耐酒精口服药物组合物

Legal Events

Date Code Title Description
AK Designated states

Kind code of ref document: A2

Designated state(s): AE AG AL AM AT AU AZ BA BB BG BR BY BZ CA CH CN CO CR CU CZ DE DK DM DZ EC EE ES FI GB GD GE GH GM HR HU ID IL IN IS JP KE KG KP KR KZ LC LK LR LS LT LU LV MA MD MG MK MN MW MX MZ NO NZ OM PH PL PT RO RU SD SE SG SI SK SL TJ TM TN TR TT TZ UA UG US UZ VN YU ZA ZM ZW

AL Designated countries for regional patents

Kind code of ref document: A2

Designated state(s): GH GM KE LS MW MZ SD SL SZ TZ UG ZM ZW AM AZ BY KG KZ MD RU TJ TM AT BE BG CH CY CZ DE DK EE ES FI FR GB GR IE IT LU MC NL PT SE SK TR BF BJ CF CG CI CM GA GN GQ GW ML MR NE SN TD TG

121 Ep: the epo has been informed by wipo that ep was designated in this application
DFPE Request for preliminary examination filed prior to expiration of 19th month from priority date (pct application filed before 20040101)
WWE Wipo information: entry into national phase

Ref document number: 2002803493

Country of ref document: EP

WWP Wipo information: published in national office

Ref document number: 2002803493

Country of ref document: EP

NENP Non-entry into the national phase

Ref country code: JP

WWW Wipo information: withdrawn in national office

Country of ref document: JP