WO1999011261A1 - Granules exempts d'excipients - Google Patents

Granules exempts d'excipients Download PDF

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Publication number
WO1999011261A1
WO1999011261A1 PCT/EP1998/005902 EP9805902W WO9911261A1 WO 1999011261 A1 WO1999011261 A1 WO 1999011261A1 EP 9805902 W EP9805902 W EP 9805902W WO 9911261 A1 WO9911261 A1 WO 9911261A1
Authority
WO
WIPO (PCT)
Prior art keywords
granules
anyone
amoxicillin
sieving
excipients
Prior art date
Application number
PCT/EP1998/005902
Other languages
English (en)
Inventor
Jan Willem Groenendaal
Original Assignee
Dsm N.V.
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 Dsm N.V. filed Critical Dsm N.V.
Priority to EP98948983A priority Critical patent/EP1023065A1/fr
Priority to AU95408/98A priority patent/AU9540898A/en
Publication of WO1999011261A1 publication Critical patent/WO1999011261A1/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
    • A61K9/20—Pills, tablets, discs, rods
    • A61K9/2095—Tabletting processes; Dosage units made by direct compression of powders or specially processed granules, by eliminating solvents, by melt-extrusion, by injection molding, by 3D printing
    • 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
    • A61K31/425—Thiazoles
    • A61K31/429—Thiazoles condensed with heterocyclic ring systems
    • A61K31/43—Compounds containing 4-thia-1-azabicyclo [3.2.0] heptane ring systems, i.e. compounds containing a ring system of the formula, e.g. penicillins, penems
    • 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
    • A61K9/1688—Processes resulting in pure drug agglomerate optionally containing up to 5% of excipient

Definitions

  • the present invention relates to granules free of excipients and a process to prepare the same.
  • crystalline antibiotic powder itself is not suitable for the manufacturing of tablets and capsules containing oral grade antibiotics such as penicillins or cephalosporins 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 first by mixing the crystalline product ( 1 -30 ⁇ m) with a small amount of organic solvent (e.g. alcohol and/or water) . It is preferred then to admix other components as binders (e.g. PVP) and fillers (e.g. lactose) for obtainment of granulates with satisfactory particle size distribution and strength. However, it will not be possible to achieve a high dosage per tablet unless relatively large tablets are made.
  • organic solvent e.g. alcohol and/or water
  • the granulation process generally takes place in a high shear mixer granulator by which dense particles of a suitable particle size distribution are produced. After the granulation process the material (particles of approximately 400-500 ⁇ m average diameter) is dried. It is found that while using only water as binding agent (i.e. no alcohol, no further binding agents) the batch-wise operated high shear granulators can not give a satisfactory particle size distribution while excessive fouling of the apparatus occurs.
  • Difficulties one may encounter by using dry granulation are: - a lot of dust is produced during the slugging or roller compaction process and in some cases, for example such as amoxicillin, this dust sticks to the coarser particles and can not be separated by currently applied vibrating sieves,
  • 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 (5-1 5%) amount 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.
  • the present invention provides granules being free of excipients, for instance antibiotic and antihypercholesterolemic ones and preferably also substantially free of solvents. These granules are of a particle size between about 50 ⁇ m and 1 500 ⁇ m, preferably between about 1 25 ⁇ m and 1 000 ⁇ m.
  • antibiotic granules are those of penicillins, cephalosporins, tetracyclines and macrolides.
  • penicillins are preferably amoxicillin, ampicillin, penicillin V, oxacillin, cloxacillin, flucloxacillin, dicloxacillin and pharmaceutically acceptable salts thereof, preferably potassium salt of penicillin V, sodium salt of cloxacillin, sodium salt of flucloxacillin and sodium salt of dicloxacillin.
  • cephalosporins are preferably cephalexin, cefaclor, cefadroxil and cephradine.
  • tetracyclines are tetracycline, chlorotetracycline, oxytetracycline, doxycycline, minocycline, demeclocycline and acid salts thereof, preferably the HCI salts.
  • macrolides are preferably erythromycin, clarithromycin, roxithromycin, azithromycin and stearates, estolates, propionates, ethylsuccinates thereof.
  • antihypercholesterolemic compounds are lovastatin, simvastatin and pravastatin.
  • the process comprises of feeding, for example, an antibiotic powder corresponding to said granules to a roller compactor to produce compacts, followed by milling to give granules. These granules are, then, sieved with a sieving device to separate the granules from fine particles with a size of ⁇ 1 50 ⁇ m, preferably ⁇ 1 25 ⁇ m.
  • the sieving device preferably comprises an air jet system. The fine particles are optionally recirculated to the roller compactor.
  • the granules, prepared according to the present invention are suitable to prepare oral dosage forms such as tablets, capsules, syrups, sachets, dry instant or ready to use and multiple or single dose.
  • the oral dosage form, comprising granules free of excipients also contain a ⁇ -lactamase inhibitor such as potassium clavulanate, preferably in granule form. Said granules can also be used in Dose Sipping devices.
  • the granulation method wherein the use of excipients has been avoided, 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 sieving or wet sieving procedure.
  • the sieving device comprises preferably an air jet system. Furthermore, the sieving device can be coupled directly to the roller compactor or stand separately from the same.
  • the application of this granulation method results in granules of penicillins, cephalosporins, tetracyclines, macrolides and antihypercholesterol compounds with a satisfactory particle size distribution, viz. between 50 ⁇ m and 1 500 ⁇ m, preferably between 1 25 ⁇ 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 are usually avoided.
  • the only traces of solvent(s) that may be present in the said granules are either already present in the starting compound or result from wet sieving operation.
  • a certain amount of antibiotic powder to be granulated for instance amoxicillin trihydrate, is fed to a roller compactor.
  • 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 free of excipients 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.
  • These granules can also be used, for instance, in a pharmaceutical composition as a tablet of amoxicillin trihydrate produced from granules of amoxicillin trihydrate and potassium clavulanate (in ratio of 1 -20: 1 as, for example, described in European patent EP 49061 and International patent application WO 9709042) as a powder or in granule form.
  • 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.
  • the resulting granulates containing antibiotics or antihypercholesterol compounds show all-around technological properties for the production of all oral dosage forms like tablets, capsules, syrups, sachets, dry instant or ready to use, multi dose or single dose and for dose sipping devices,
  • a pharmaceutical composition of granules of ⁇ -lactams for instance amoxicillin trihydrate and a ⁇ -lactam inhibitor, for instance clavulanic acid or a pharmaceutical acceptable salt thereof, or sulbactam, preferably in the granule form, have been provided for.
  • the granules of the ⁇ -lactam inhibitor optionally contain an excipient.
  • 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.
  • Example 1 Production of amoxicillin granulate by roller compacting using air sieving.
  • a Minox sieve type MTS 1 200 equipped with an air jet system was used instead of a vibrating sieve.
  • 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.
  • the fine particles were blown of 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.
  • Vibrating sieve The following three analytical sieving methods were used to separate fine from coarse particles amoxicillin granulate: Vibrating sieve:
  • Air sieve A sieve with a diameter of 20 cm, known weight and apertures of 1 25 ⁇ m was put on a Hosokawa Alpine air sieve type 200 LS-N, 20 g amoxicillin granulate was weighed and put on the sieve. The air sieve was activated during 3 minutes, whereafter the amount of amoxicillin was determined by weighing the sieve. The test was repeated with a 250 and 1 000 ⁇ m sieve.
  • Example 3 Flowability of amoxicillin granulate of preparation 1 .
  • the class of flowability was determined using the classification of table 2.
  • amoxicillin granulate of example 1 did not flow through the funnel with a diameter of 1 8 mm so this material shows a poor flowability.
  • a graduated cylinder of 250 ml was filled carefully with amoxicillin granulate up to the 250 ml mark, the weight of the amoxicillin was determined and the loose bulk density was calculated in g/ml.
  • the cylinder was tapped using an Engelsmann Volumeter until the volume did not change more than 2 ml after 1 00 taps, the decreased volume was determined and the tapped bulk density was calculated in g/ml.
  • the compressibility was calculated according to the following formula: (tapped bulk density - loose bulk density) x 1 00%
  • the class of flowability was determined using the classification of table 3.
  • amoxicillin granulate of example 1 showed the following results:
  • Example 4 Separation of fine from coarse amoxicillin granulate particles of example 1
  • Example 5 Flowability of amoxicillin granulate of example 1
  • the flowability method using the funnels according to Lerk mentioned in example 3 was used.
  • the amoxicillin granulate of example 1 did flow smoothly through the funnel with a diameter of 5 mm so this material showed a good flowability.
  • amoxicillin granulate of example 1 showed the following results:
  • Example 6 Production of tablets containing amoxicillin granulate of example 1
  • Example 7 Production of four different formulations of tablets containing amoxicillin granulate of example 1
  • compositions of the tablet formulations are provided.
  • Amoxicillin granules and the excipients were weighed according to the above compositions and mixed during 5 minutes in a Turbula mixer, the total weight of the materials was about 100 g.
  • Amoxicillin granulate (prepared from amoxicillin trihydrate according to example 1 ) was filled into hard gelatine capsules on a Robert Bosch GKF 1 200 S capsule filling machine using continuous motion with tamping and a speed of about 65,000 capsules per hour.
  • the temperature was between 20 and 25 °C and the relative humidity ⁇ 20%.
  • Amoxicillin granules were prepared according to example 1 , the water activity of the granules was less than 0.2 at 25 ° C, which was obtained by drying the granules during 30 minutes at 40 °C and reduced pressure in a rotating mixer.
  • Potassium clavulanate granules were prepared as follows:
  • Potassium clavulanate powder with a water activity of less than 0.2 at 25 ° C 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 then fed to a roller compactor. The produced compacts were milled with an oscillating Frewitt sieve equipped with a screen with 1 000 ⁇ m apertures.
  • the milled material was classified using a vibration sieve equipped with a 420 ⁇ m screen on top and a 1 50 ⁇ m screen equipped with an air jet system on the bottom.
  • the material coming from the top of the 420 ⁇ m screen and from the top of the 1 50 ⁇ m screen was transferred to a batch mixer, the fine material from the bottom of the sieve was transferred back to the roller compactor.
  • the granules were ready for further processing into tablets.
  • the tablets were prepared as follows:
  • Potassium granulate granules ( 1 .52 kg) with a potency of 41 .1 % clavulanic acid, amoxicillin trihydrate granules (2.925 kg) with a potency of 85.5% amoxicillin, 0.047 kg magnesium stearate, and 0.1 62 kg microcrystalline cellulose (Avicel ® PH 1 1 2 with a water activity of less than 0.2 at 25 °C) . were mixed.
  • Tablets were pressed using a Korsch EKO excenter tablet press with the following characteristics: diameter 1 8 mm, weight 950 mg, thickness 6 mm, hardness between 1 1 0 and 1 50 N, disintegration in water of 20 °C in less than 60 seconds, dissolution of the labelled amount of amoxicillin within 30 minutes by using the method as described in the U.S. Pharmacopoeia XXIII 1 994, The United States Pharmacopoeial Convention Inc. Rochville MD, USA.

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  • Health & Medical Sciences (AREA)
  • Epidemiology (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Chemical & Material Sciences (AREA)
  • Medicinal Chemistry (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Engineering & Computer Science (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 des granules exempts d'excipients pouvant être mis en application dans toutes les formulations pharmaceutiques. Elle concerne également un procédé servant à préparer ces granules au moyen d'un dispositif de tamisage comportant, de préférence, un système à jet d'air.
PCT/EP1998/005902 1997-08-29 1998-08-27 Granules exempts d'excipients WO1999011261A1 (fr)

Priority Applications (2)

Application Number Priority Date Filing Date Title
EP98948983A EP1023065A1 (fr) 1997-08-29 1998-08-27 Granules exempts d'excipients
AU95408/98A AU9540898A (en) 1997-08-29 1998-08-27 Granules free of excipients

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
EP97202651.2 1997-08-29
EP97202651 1997-08-29

Publications (1)

Publication Number Publication Date
WO1999011261A1 true WO1999011261A1 (fr) 1999-03-11

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Application Number Title Priority Date Filing Date
PCT/EP1998/005902 WO1999011261A1 (fr) 1997-08-29 1998-08-27 Granules exempts d'excipients

Country Status (5)

Country Link
EP (1) EP1023065A1 (fr)
CN (1) CN1268888A (fr)
AU (1) AU9540898A (fr)
TR (1) TR200000529T2 (fr)
WO (1) WO1999011261A1 (fr)

Cited By (28)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2001043766A1 (fr) * 1999-12-14 2001-06-21 Asahi Kasei Kabushiki Kaisha Granules de sulfate de colistine
WO2003063820A2 (fr) * 2002-02-01 2003-08-07 Sandoz Gmbh Granulats stables a la segregation
WO2004082661A1 (fr) * 2003-03-21 2004-09-30 Dsm Ip Assets B.V. Poudre de trihydrate d'amoxicilline cristallin
AT412344B (de) * 2001-04-12 2005-01-25 Sandoz Ag Hydrophobisierte teilchen von k-clavulanat
AT500133A1 (de) * 2002-02-06 2005-11-15 Sandoz Ag Verfahren zur herstellung eines entmischungsstabilen granulats
AT500131A1 (de) * 2002-02-01 2005-11-15 Sandoz Ag Organische verbindungen
AT500132A1 (de) * 2002-02-06 2005-11-15 Sandoz Ag Organische verbindungen
AT500134A1 (de) * 2002-02-01 2005-11-15 Sandoz Ag Verfahren zur herstellung eines entmischungsstabilen granulats
US6979735B1 (en) 1999-04-01 2005-12-27 Dsm N.V. Agglomerates by crystallization
WO2006003152A1 (fr) * 2004-06-30 2006-01-12 Dsm Ip Assets B.V. GRANULES COMPRENANT UN ANTIBIOTIQUE ß-LACTAME
AT413983B (de) * 2001-04-12 2006-08-15 Sandoz Ag K-clavulanat in der form eines granulates
US7534781B2 (en) 2003-03-21 2009-05-19 Dsm Ip Assets B.V. Crystalline amoxicillin trihydrate powder
WO2009101258A1 (fr) * 2008-02-15 2009-08-20 Atacama Labs Oy Nouvelle préparation pharmaceutique
WO2009135949A2 (fr) * 2008-05-09 2009-11-12 Atacama Labs Oy Procédé pour préparer un comprimé à forte charge en substance médicamenteuse
WO2009135950A2 (fr) * 2008-05-09 2009-11-12 Atacama Labs Oy Procédé pour préparer un comprimé contenant des excipients
WO2009135951A2 (fr) * 2008-05-09 2009-11-12 Atacama Labs Oy Procédé pour préparer un comprimé contenant de la metformine
WO2009135947A2 (fr) * 2008-05-09 2009-11-12 Atacama Labs Oy Procédé de préparation d'un comprimé à faible charge de médicament
WO2009135948A2 (fr) * 2008-05-09 2009-11-12 Atacama Labs Oy Procédé pour préparer un comprimé à forte charge en substance médicamenteuse
GB2456989B (en) * 2006-11-10 2010-12-15 Atacama Labs Oy Granules, tablets and granulation
US20110140298A1 (en) * 2006-11-10 2011-06-16 Atacama Labs Oy Method and apparatus or dry granulation
US8110702B2 (en) 2007-01-26 2012-02-07 Dsm Ip Assets B.V. Process for the manufacture of substituted 2-cyano cinnamic esters
US8138334B2 (en) 2005-03-03 2012-03-20 Janssen Pharmaceutica N.V. Substituted oxa-diaza-spiro-[5.5]-undecanone derivatives and their use as neurokinin antagonists
US8581134B2 (en) 2006-11-10 2013-11-12 Giovanni Politi Method and apparatus for dry granulation
US8590818B2 (en) 2008-11-05 2013-11-26 Polibiotech Srl Dry granulation in a gas stream
US8604200B2 (en) 2005-03-08 2013-12-10 Janssen Pharmaceutica N.V. Diaza-spiro-{4,4}-nonane derivatives as neurokinin (NK1) antagonists
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
BE1021312B1 (nl) * 2014-07-30 2015-10-28 Nordic Specialty Pharma Bvba Dicloxacillin capsule
US9314475B2 (en) 2008-03-28 2016-04-19 Paratek Pharmaceuticals, Inc. Oral and injectable formulations of tetracycline compounds

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FI20060990A0 (fi) * 2006-11-10 2006-11-10 Iprbox Oy Rakeita, tabletteja ja rakeistusmenetelmä
CN105832694A (zh) * 2016-03-25 2016-08-10 海南汤臣史克生物科技有限公司 一种青霉素类药物胶囊及其制法
CN106088893B (zh) * 2016-07-28 2017-11-28 谭芳 隐藏式闭门器

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WO1997033564A1 (fr) * 1996-03-13 1997-09-18 Biochemie Gesellschaft Mbh Agglomerats renfermant des composes de betalactamines

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DE2251250A1 (de) * 1972-10-19 1974-05-02 Hoechst Ag Verfahren zur herstellung hochdosierter antibiotica-tabletten
EP0194880A2 (fr) * 1985-03-12 1986-09-17 Sankyo Company Limited Préparation polyvitaminée
EP0281200A1 (fr) * 1987-03-02 1988-09-07 Yamanouchi Europe B.V. Composition pharmaceutique, granulé pharmaceutique et leur procédé de fabrication
EP0414115A1 (fr) * 1989-08-23 1991-02-27 BASF Aktiengesellschaft Granulés de riboflavine sans excipients
WO1991016893A1 (fr) * 1990-04-27 1991-11-14 Beecham Group Plc Formulation pharmaceutique
WO1992019227A2 (fr) * 1991-05-08 1992-11-12 Laboratorios Beecham Sa Preparations pharmaceutiques
WO1995028927A1 (fr) * 1994-04-23 1995-11-02 Smithkline Beecham Corporation Comprime enrobe d'un polymere, comprenant de l'amoxycilline et du clavulanate
WO1997033564A1 (fr) * 1996-03-13 1997-09-18 Biochemie Gesellschaft Mbh Agglomerats renfermant des composes de betalactamines

Cited By (45)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP1165049B2 (fr) † 1999-04-01 2011-07-06 DSM IP Assets B.V. Agglomerats obtenus par cristallisation
US6979735B1 (en) 1999-04-01 2005-12-27 Dsm N.V. Agglomerates by crystallization
WO2001043766A1 (fr) * 1999-12-14 2001-06-21 Asahi Kasei Kabushiki Kaisha Granules de sulfate de colistine
AT413983B (de) * 2001-04-12 2006-08-15 Sandoz Ag K-clavulanat in der form eines granulates
AT412344B (de) * 2001-04-12 2005-01-25 Sandoz Ag Hydrophobisierte teilchen von k-clavulanat
AT500134A1 (de) * 2002-02-01 2005-11-15 Sandoz Ag Verfahren zur herstellung eines entmischungsstabilen granulats
AT500131A1 (de) * 2002-02-01 2005-11-15 Sandoz Ag Organische verbindungen
WO2003063820A3 (fr) * 2002-02-01 2004-01-15 Sandoz Ag Granulats stables a la segregation
WO2003063820A2 (fr) * 2002-02-01 2003-08-07 Sandoz Gmbh Granulats stables a la segregation
AT500132A1 (de) * 2002-02-06 2005-11-15 Sandoz Ag Organische verbindungen
AT500133A1 (de) * 2002-02-06 2005-11-15 Sandoz Ag Verfahren zur herstellung eines entmischungsstabilen granulats
WO2004082661A1 (fr) * 2003-03-21 2004-09-30 Dsm Ip Assets B.V. Poudre de trihydrate d'amoxicilline cristallin
JP2006520765A (ja) * 2003-03-21 2006-09-14 デーエスエム アイピー アセッツ ベー． ヴェー． アモキシシリン三水和物
JP2006523188A (ja) * 2003-03-21 2006-10-12 デーエスエム アイピー アセッツ ベー． ヴェー． アモキシシリン三水和物結晶性粉末
US7534781B2 (en) 2003-03-21 2009-05-19 Dsm Ip Assets B.V. Crystalline amoxicillin trihydrate powder
WO2006003152A1 (fr) * 2004-06-30 2006-01-12 Dsm Ip Assets B.V. GRANULES COMPRENANT UN ANTIBIOTIQUE ß-LACTAME
US8138334B2 (en) 2005-03-03 2012-03-20 Janssen Pharmaceutica N.V. Substituted oxa-diaza-spiro-[5.5]-undecanone derivatives and their use as neurokinin antagonists
US8604200B2 (en) 2005-03-08 2013-12-10 Janssen Pharmaceutica N.V. Diaza-spiro-{4,4}-nonane derivatives as neurokinin (NK1) antagonists
US10265272B2 (en) 2006-11-10 2019-04-23 Atacama Labs Oy Method and apparatus for dry granulation
EP2081669B1 (fr) 2006-11-10 2018-10-17 Atacama Labs Oy Procédé et dispositif pour produire des granules
US20150238427A1 (en) * 2006-11-10 2015-08-27 Atacama Labs Oy Method and apparatus for dry granulation
US8968788B2 (en) 2006-11-10 2015-03-03 Atacama Labs Oy Granules, tablets and granulation
US9700513B2 (en) 2006-11-10 2017-07-11 Atacama Labs Oy Method and apparatus for dry granulation
US8951562B2 (en) 2006-11-10 2015-02-10 Atacama Labs Oy Method and apparatus or dry granulation
KR101487565B1 (ko) * 2006-11-10 2015-01-29 아타카마 랩스 오이 과립, 정제 및 과립화
US8052999B2 (en) 2006-11-10 2011-11-08 Atacama Labs Granules, tablets and granulation
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EP1023065A1 (fr) 2000-08-02
CN1268888A (zh) 2000-10-04
TR200000529T2 (tr) 2000-08-21
AU9540898A (en) 1999-03-22

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