EP0973520A1 - Granules comprenant du clavulanate et un ou plusieurs excipients - Google Patents

Granules comprenant du clavulanate et un ou plusieurs excipients

Info

Publication number
EP0973520A1
EP0973520A1 EP98956907A EP98956907A EP0973520A1 EP 0973520 A1 EP0973520 A1 EP 0973520A1 EP 98956907 A EP98956907 A EP 98956907A EP 98956907 A EP98956907 A EP 98956907A EP 0973520 A1 EP0973520 A1 EP 0973520A1
Authority
EP
European Patent Office
Prior art keywords
granules
clavulanate
anyone
excipients
potassium clavulanate
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Withdrawn
Application number
EP98956907A
Other languages
German (de)
English (en)
Inventor
Jan Willem Groenendaal
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
DSM Delft BV
Original Assignee
Gist Brocades BV
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 Gist Brocades BV filed Critical Gist Brocades BV
Priority to EP98956907A priority Critical patent/EP0973520A1/fr
Publication of EP0973520A1 publication Critical patent/EP0973520A1/fr
Withdrawn legal-status Critical Current

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
    • A61K9/14—Particulate form, e.g. powders, Processes for size reducing of pure drugs or the resulting products, Pure drug nanoparticles
    • A61K9/16—Agglomerates; Granulates; Microbeadlets ; Microspheres; Pellets; Solid products obtained by spray drying, spray freeze drying, spray congealing,(multiple) emulsion solvent evaporation or extraction
    • A61K9/1605—Excipients; Inactive ingredients
    • A61K9/1629—Organic macromolecular compounds
    • A61K9/1652—Polysaccharides, e.g. alginate, cellulose derivatives; Cyclodextrin
    • 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
    • A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
    • A61K31/42—Oxazoles
    • A61K31/424—Oxazoles condensed with heterocyclic ring systems, e.g. clavulanic acid
    • 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
    • A61K9/14—Particulate form, e.g. powders, Processes for size reducing of pure drugs or the resulting products, Pure drug nanoparticles
    • A61K9/16—Agglomerates; Granulates; Microbeadlets ; Microspheres; Pellets; Solid products obtained by spray drying, spray freeze drying, spray congealing,(multiple) emulsion solvent evaporation or extraction
    • A61K9/1682—Processes
    • A61K9/1694—Processes resulting in granules or microspheres of the matrix type containing more than 5% of excipient
    • 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
    • A61K9/2072—Pills, tablets, discs, rods characterised by shape, structure or size; Tablets with holes, special break lines or identification marks; Partially coated tablets; Disintegrating flat shaped forms
    • A61K9/2077—Tablets comprising drug-containing microparticles in a substantial amount of supporting matrix; Multiparticulate tablets
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics

Definitions

  • the present invention relates to granules of clavulanate containing excipients and a process to prepare the same.
  • crystalline Mactam antibiotic powder itself is not suitable for the manufacturing of tablets and capsules containing oral grade /? ⁇ lactam antibiotics because the crystalline material has no satisfactory flowability and density so that controlled dosage per tablet or capsule is not guaranteed. Therefore, normally a granulate is produced by mixing the crystalline product ( 1 -1 50 ⁇ m) with other components as binders and fillers in a wet or dry granulation process. For preparing granules of potassium clavulanate, the situation is even more complex due to its hygroscopic nature and instability at already relative low humidities during the granulation process.
  • German patent application DE 2251 250 a process for relatively small tablets containing a high amount of antibiotic using a granulate prepared with a small amount (5-1 5%) of excipients (e.g. crystalline cellulose, binder, talc) has been described.
  • European patent EP 281 200 describes a pharmaceutical granulate comprising 35-45 wt% microcrystalline cellulose prepared by wet granulation, which granulate disintegrates quickly when immersed in water.
  • the antibiotic has been described to be mixed with excipients (e.g.
  • International patent application WO 971 7960 also describes an oral 5 composition containing clavulanate and amoxicillin in which a metal salt desiccant, for example sodium, calcium or magnesium chloride has been added in order to increase the stability of potassium clavulanate.
  • European patent EP 0002574 describes the preparation of particles comprising an anhydrous salt of clavulanic acid dispersed in a semi-synthetic polymer binder o of low water vapour permeability.
  • WO 9427557 a process has been claimed for the preparation of thermal infusion granules of clavulanate. These thermal infusion granules have been prepared by compacting blends of clavulanate, a hydrophobic waxy material, optionally excipients, milling, screening and, subsequently, subjecting the same to 5 thermal infusion.
  • wet granulation Difficulties one may encounter by using wet granulation are in the first place decomposition of potassium clavulanate because of use of water and/or organic solvents combined with elevated temperature during granulation. Besides that the use of organic solvents is restricted by governmental rules o concerning environmental protection. Furthermore, the wet granulation process is labour intensive, expensive and time consuming because of the large number of processing steps like mixing, granulating, wet sieving, drying etc. and a lot of energy is needed to dry the wet granules. Besides this, the granules produced by wet granulation are rather porous and high bulk volumes 5 are not or difficult to reach, whereby it is often not possible to achieve high dosages in gelatin capsules.
  • binder dissolved in a binder solution or dry mixed with the compound to be granulated usually gives problems with a homogeneous distribution because of its sticking nature. This results in an inhomogeneous composition which can cause differences in dissolution and/or o tablet hardness between dosage forms of various batches and therefore differences in bioavailability. Difficulties one may encounter by using dry granulation together with amoxicillin trihydrate are decomposition of potassium clavulanate because of a too high water activity during roller compaction or slugging developed by amoxicillin trihydrate.
  • the present invention provides granules of clavulanate containing inert excipients which are preferably substantially free of solvents with the provisio that the clavulanate has not been dispersed in a polymeric binder of low water vapour permeability.
  • the clavulanate granules are preferably potassium clavulanate and the inert excipient is a cellulose, preferably microcrystalline cellulose, more preferably with a water activity of less than 0.2 at 25°C, most preferably Avicel ® PH 1 1 2.
  • the ratio of potassium clavulanate related to microcrystalline cellulose such as Avicel ® PH 1 1 2 is 1 : 5 - 0.2 wt%, preferably 1 : 2-0.5 wt% and more preferably about 1 : 1 wt%.
  • These granules are of a particle size between 50 ⁇ m and 1 500 ⁇ m, preferably between 1 25 ⁇ m and 1 000 ⁇ m.
  • the process comprises of feeding, for example, potassium clavulanate powder and inert excipients to a roller compactor to produce compacts, followed by milling said compacts to give granules.
  • These granules are, then, sieved with a sieving device to separate the granules from fine particles, preferably fine particles of ⁇ 1 50 ⁇ m, more preferably fine particles of ⁇ 1 25 ⁇ m.
  • the sieving device comprises a tumbler or vibratory sieving machine, preferably a tumbler sieving machine equipped with an air jet system. The fine particles are optionally recirculated to the roller compactor.
  • the present invention also provides a pharmaceutical composition prepared from blending granules of potassium clavulanate of the invention together with crystals or granules of amoxicillin trihydrate optionally containing excipients and specific excipients specifically used for the preparation of compositions of oral dosage forms like tablets with or without coating, disperse tablets, chewable tablets and oral dry suspension.
  • a pharmaceutical composition prepared from blending granules of potassium clavulanate of the invention together with crystals or granules of amoxicillin trihydrate optionally containing excipients and specific excipients specifically used for the preparation of compositions of oral dosage forms like tablets with or without coating, disperse tablets, chewable tablets and oral dry suspension.
  • the granulation method wherein clavulanate with inert excipients are used, consists of dry granulation by using compaction forces to build up agglomerates. This may be performed by slugging or roller compacting. The compacts are milled and, then, sieved with a sieving device. The separation of fine particles from coarse granules may be carried out by a dry air sieving procedure. In dry air sieving, the milled compacts are placed on the sieve and air is blown through the bed of milled compacts to separate the granules from the fine particles.
  • the sieving device comprises preferably an air jet system using air with a relative humidity of ⁇ 30%, preferably ⁇ 20% and a temperature between 1 5 and 25 °C. Furthermore, the sieving device can be coupled directly to the roller compactor or stands separately from the same.
  • this granulation method results in granules with a satisfactory particle size distribution, viz. between 50 ⁇ m and 1 500 ⁇ m, preferably between 1 25 ⁇ m and 1 000 ⁇ m.
  • these granules are preferably substantially free of organic solvents and/or water, because during the process of compaction use of these solvents is usually avoided. The only traces of solvent(s) which may be present in the said granules are already present in the starting compound.
  • the present technique eliminates problems in granulation processes due to heat and moisture because potassium clavulanate should be processed in an environment with a relative humidity of 20% or lower at a temperature between 20 and 25 °C because higher humidities start decomposition processes with small amounts of water as reaction products which on their turn continue the decomposition reaction. Since potassium clavulanate is dry granulated together with an inert excipient, preferably Avicel ® PH 1 1 2 this has strongly reduced the run-away hazard in comparison with that of the unblended potassium clavulanate. The unblended potassium clavulanate is classified as highly flammable, both according to the European notification directories and the UN transport recommendations.
  • the blend potassium clavulanate in the concentration with Avicel ® PH 1 1 2 1 : 1 weight ratio is not flammable.
  • the inert excipients with sufficient binding properties also increase the flowability of the blend with potassium clavulanate to improve the flow through the compacting equipment.
  • the dry granulation of potassium clavulanate according to the present invention results in granules with a sufficient high density. This is an advantage because potassium clavulanate is always used in admixture with amoxicillin in relatively high dosages resulting in large tablets. A too low density of the granules would further enlarge the large, difficult swallowable tablets.
  • the clavulanate granules also allow for disintegration of dosage forms into primary drug particles followed by a high dissolution rate because no wet binders are used. This is especially important when dispersable tablets are produced which should have a disintegrating time less than a few minutes.
  • the resulting potassium clavulanate granules showing excellent flow properties and almost no dust can be mixed with amoxicillin, preferably amoxicillin granules as mentioned in European patent application No. PCT/EP 98/05902 filed on 27-08-1 998, which granules possess the same particle size forming a mixture of both granules not susceptible to segregation.
  • clavulanate powder for instance potassium clavulanate and the excipients, for instance Avicel® PH 1 1 2 with a water activity of less than 0.2 measured at a temperature of 25 ° C
  • the compact materials are milled and, thereafter, sieved by using an air jet system.
  • the sieving device is coupled directly to the roller compactor in order to avoid extra steps or stands separately.
  • the fine particles preferably the material ⁇ 1 25 ⁇ m, are recycled to the roller compacting process.
  • the granules of clavulanate preferably of potassium clavulanate in combination with granules of amoxicillin, preferably of amoxicillin trihydrate as described in European patent application No. PCT/EP 98/05902 indicated above can be used for all formulations to produce chew, swallow, disperse, effervescent or normal tablets of all sizes, forms and weights, also to fill hard gelatin capsules and to formulate dry syrups and for administering drugs with the help of a dose sipping device. To produce tablets, only excipients have to be mixed with the granules and tablets can be pressed.
  • the granules can directly be filled into capsules or when fast running capsules filling machines are used, some lubricant like magnesium stearate can be mixed with the granules to facilitate the filling process.
  • flavours To formulate dry oral syrups, flavours, bulking agents such as sugars and preservatives are often used. These excipients are mixed with the granules and bottles for multi dosage use or sachets for single dosage use. Optionally a premix of excipients is prepared and filled into bottles or sachets after which the granules are added separately.
  • the granules can be placed over a support in a tube having a liquid inlet end and a liquid outlet end; excipients can also be placed over the support, together with the drug granules.
  • Oral administration of therapeutical agents with the help of a dose sipping device has been described in European patent application EP 383503.
  • Slugs were pressed with a thickness of about 3 mm, and a hardness of about 25 N measured with an Erweka ® TBH28 hardness tester.
  • the slugs were crushed using an Erweka T32 tablet crusher followed by a milling process using a Peppink ® N 1 00 hammer mill equipped with a 3 mm sieve.
  • the milled material (30 g) was treated as presented below:
  • the coarse particles and the fines were separated from the milled material using a Retsch Vibro vibrating-sieve working with a vibration amplitude of 2 mm, during 1 0 minutes, and using a 1 000 ⁇ m and a 1 25 ⁇ m sieve.
  • the amount of fines ⁇ 1 25 ⁇ m was 1 9 % w/w.
  • the amount of coarse particles > 1 000 ⁇ m was 8 % w/w.
  • the yield of granules between 1 25 and 1 000 ⁇ m was 73 % w/w.
  • the flowability was determined using flow funnels with the following size of apertures: 1 8 - 1 2 - 8 - 5 and 2.5 mm.
  • the granules flowed freely through a funnel with an aperture of 1 2 mm but not through 8 mm, which indicates just sufficient flowability.
  • the coarse particles and the fines were separated from the milled material using an Alpine ® 200LS-N air-sieve working with an under pressure of 2000 Pa during 3 minutes, and using a 1 000 and a 1 25 ⁇ m sieve.
  • the used air had a relative humidity of ⁇ 20% and a temperature of 25°C.
  • the amount of fines ⁇ 1 25 ⁇ m was 42 % w/w.
  • the amount of coarse particles > 1 000 ⁇ m was 7 % w/w.
  • the yield of granules between 1 25 and 1 000 ⁇ m was 51 % w/w.
  • the flowability was determined using flow funnels with the following size of apertures: 1 8 - 1 2 - 8 - 5 and 2.5 mm.
  • the granules flowed freely through a funnel with an aperture of 5 mm but not through 2.5 mm, which indicates good flowability.
  • Potassium clavulanate powder was mixed with microcrystalline cellulose (Avicel ® PH 1 1 2), with a water activity of less than 0.2 at 25 °C. The mixture was fed to a roller compactor. The produced compacts were milled and sieved with an air jet system using a sieve with apertures of 1 50 ⁇ m. The particles ⁇ 1 50 ⁇ m were recycled to the roller compactor.
  • the amount of fines ⁇ 1 50 ⁇ m was 32 % w/w.
  • the amount of coarse particles > 1 000 ⁇ m was 5 % w/w.
  • the yield of granules between 1 50 and 1000 ⁇ m was 63 % w/w.
  • the flowability was determined using flow funnels with the following size of apertures: 1 8 - 1 2 - 8 - 5 and 2.5 mm.
  • amoxycillin trihydrate granules were prepared as follows:
  • Amoxicillin trihydrate powder was fed to a Fitzpatrick roller compacter type Chilsonator 4L X 1 0D.
  • the used rolls had a diameter of 25.4 cm and a roll wide of 1 0.2 cm, the roll surface was sinus waved grooved, the roll gap was 3.1 mm.
  • the roll speed was 1 1 rpm
  • the horizontal feeder speed was 1 7 rpm
  • the applied roll pressure 1 1 00 psi.
  • the compacts were milled using a Minox sieve type MTS 1 200 equipped with an air jet system.
  • the sieve applied had a diameter of 1 20 cm and apertures of 1 50 ⁇ m.
  • the air was escaping upwards from a rotating perforated blade fixed horizontal under the sieve. By this action the fine particles were blown off from the coarse particles and sucked downwards through the sieve to the receiver by the action of an under pressure.
  • the fines ⁇ 1 50 ⁇ m were recycled from the receiver to the roller compacting process, the material > 1 50 ⁇ m, collected from the 1 50 ⁇ m sieve, was the final product.

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  • Health & Medical Sciences (AREA)
  • Engineering & Computer Science (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Animal Behavior & Ethology (AREA)
  • General Health & Medical Sciences (AREA)
  • Public Health (AREA)
  • Veterinary Medicine (AREA)
  • Chemical & Material Sciences (AREA)
  • Medicinal Chemistry (AREA)
  • Epidemiology (AREA)
  • Communicable Diseases (AREA)
  • Oncology (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • General Chemical & Material Sciences (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Organic Chemistry (AREA)
  • Medicinal Preparation (AREA)
  • Nitrogen And Oxygen Or Sulfur-Condensed Heterocyclic Ring Systems (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Investigating Or Analysing Biological Materials (AREA)

Abstract

L'invention concerne des granulés de clavulanate contenant des excipients inertes pour des formulations pharmaceutiques, ainsi qu'un procédé pour leur fabrication faisant intervenir un dispositif de tamisage utilisant de préférence un système à jet d'air.
EP98956907A 1997-11-17 1998-11-09 Granules comprenant du clavulanate et un ou plusieurs excipients Withdrawn EP0973520A1 (fr)

Priority Applications (1)

Application Number Priority Date Filing Date Title
EP98956907A EP0973520A1 (fr) 1997-11-17 1998-11-09 Granules comprenant du clavulanate et un ou plusieurs excipients

Applications Claiming Priority (4)

Application Number Priority Date Filing Date Title
EP97203576 1997-11-17
EP97203576 1997-11-17
EP98956907A EP0973520A1 (fr) 1997-11-17 1998-11-09 Granules comprenant du clavulanate et un ou plusieurs excipients
PCT/EP1998/007225 WO1999025343A1 (fr) 1997-11-17 1998-11-09 Granules comprenant du clavulanate et un ou plusieurs excipients

Publications (1)

Publication Number Publication Date
EP0973520A1 true EP0973520A1 (fr) 2000-01-26

Family

ID=8228930

Family Applications (1)

Application Number Title Priority Date Filing Date
EP98956907A Withdrawn EP0973520A1 (fr) 1997-11-17 1998-11-09 Granules comprenant du clavulanate et un ou plusieurs excipients

Country Status (13)

Country Link
EP (1) EP0973520A1 (fr)
JP (1) JP2001516365A (fr)
CN (1) CN1242705A (fr)
AU (1) AU1337999A (fr)
BR (1) BR9806280A (fr)
CA (1) CA2272402A1 (fr)
CO (1) CO4980893A1 (fr)
JO (1) JO2082B1 (fr)
NO (1) NO993467L (fr)
PL (1) PL334517A1 (fr)
TR (1) TR199901584T1 (fr)
WO (1) WO1999025343A1 (fr)
ZA (1) ZA9810499B (fr)

Families Citing this family (23)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US6294199B1 (en) 1999-04-13 2001-09-25 Beecham Pharmaceuticals (Pte) Limited Method of treating a bacterial infection comprising administering amoxycillin
US7250176B1 (en) 1999-04-13 2007-07-31 Beecham Pharmaceuticals (Pte) Limited Method of treating a bacterial infection
US6878386B1 (en) 1999-04-13 2005-04-12 Beecham Pharmaceuticals (Pte) Limited Method of treating a bacterial infection comprising amoxycillin and potassium clavulanate
US6756057B2 (en) 2000-10-12 2004-06-29 Beecham Pharmaceuticals (Pte) Limited Amoxicillin and potassium clavulanate dosage form
AU2001292185A1 (en) 2000-10-12 2002-04-22 Beecham Pharmaceuticals (Pte) Limited Formulation containing amoxicillin
GB0031267D0 (en) * 2000-12-21 2001-01-31 Smithkline Beecham Plc Novel compositions
AT412344B (de) * 2001-04-12 2005-01-25 Sandoz Ag Hydrophobisierte teilchen von k-clavulanat
AT413983B (de) * 2001-04-12 2006-08-15 Sandoz Ag K-clavulanat in der form eines granulates
US8293272B2 (en) * 2003-05-02 2012-10-23 Globopharm Pharmazeutische Produktions-Und Handelsgesellschaft M.B.H. Solid pharmaceutical preparation containing levothyroxine and/or liothyronine salts
BRPI0410021A (pt) * 2003-05-02 2006-04-25 Globopharm Pharmazeutische Pro preparação farmacêutica sólida, que contém sais levotiroxina e/ou liotironina como substáncia ativa
FI20080355A0 (fi) * 2008-05-09 2008-05-09 Atacama Labs Oy Prosessi metforminia käsittävien tablettien valmistamiseksi
FI20080352A0 (fi) * 2008-05-09 2008-05-09 Atacama Labs Oy Prosessi korkean lääkepitoisuuden tabletin valmistamiseksi
FI20080351A0 (fi) * 2008-05-09 2008-05-09 Atacama Labs Oy Prosessi matalan lääkepitoisuuden tabletin valmistamiseksi
US8951562B2 (en) 2006-11-10 2015-02-10 Atacama Labs Oy Method and apparatus or dry granulation
FI20080346A0 (fi) * 2008-05-09 2008-05-09 Atacama Labs Oy Prosessi lisäaineita sisältävän tabletin valmistamiseksi
FI20070521L (fi) 2006-11-10 2008-05-11 Atacama Labs Oy Rakeita, tabletteja ja rakeistusmenetelmä
FI20080353A0 (fi) * 2008-05-09 2008-05-09 Atacama Labs Oy Prosessi erittäin korkean lääkepitoisuuden tabletin valmistamiseksi
EP2291233B1 (fr) 2008-05-09 2019-09-04 Atacama Labs Oy Procédé de granulation par voie sèche
WO2014033077A1 (fr) * 2012-08-28 2014-03-06 Dsm Sinochem Pharmaceuticals Netherlands B.V. Composition comprenant un antibiotique et un inhibiteur de la bêta-lactamase, au moins l'un d'entre eux se trouvant sous la forme de mini-comprimés
JP2014062064A (ja) * 2012-09-21 2014-04-10 Ohara Yakuhin Kogyo Kk バルサルタン含有錠剤の製造方法
JP6141472B2 (ja) * 2016-03-02 2017-06-07 大原薬品工業株式会社 バルサルタン含有錠剤の製造方法
CN110831582B (zh) * 2017-07-05 2023-08-11 诺华股份有限公司 药物组合物
CN110051637A (zh) * 2019-05-21 2019-07-26 葵花药业集团北京药物研究院有限公司 阿莫西林克拉维酸钾制剂及其制备方法

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NZ187013A (en) * 1977-04-27 1985-04-30 Beecham Group Ltd 9-amino-9-deoxy-clavulanic acid derivatives and pharmaceutical compositions
NZ189022A (en) * 1977-12-08 1981-11-19 Beecham Group Ltd Pharmaceutically acceptable particles of clavulanates dispersed in a polymeric binder
EP0281200B1 (fr) * 1987-03-02 1994-01-19 Yamanouchi Europe B.V. Composition pharmaceutique, granulé pharmaceutique et leur procédé de fabrication
IL109770A0 (en) * 1993-05-29 1994-11-28 Smithkline Beecham Corp Thermal infusion process for preparing controlled release solid dosage forms of medicaments for oral administration and controlled release solid dosage forms of medicaments prepared thereby

Non-Patent Citations (1)

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Also Published As

Publication number Publication date
CN1242705A (zh) 2000-01-26
JP2001516365A (ja) 2001-09-25
NO993467D0 (no) 1999-07-14
ZA9810499B (en) 1999-05-24
CA2272402A1 (fr) 1999-05-27
AU1337999A (en) 1999-06-07
NO993467L (no) 1999-07-14
WO1999025343A1 (fr) 1999-05-27
PL334517A1 (en) 2000-02-28
TR199901584T1 (xx) 2000-01-21
JO2082B1 (en) 2000-05-21
BR9806280A (pt) 2000-02-15
CO4980893A1 (es) 2000-11-27

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