EP1615927A2 - Procede de production de riboflavine de la modification b/c sous forme de granules - Google Patents

Procede de production de riboflavine de la modification b/c sous forme de granules

Info

Publication number
EP1615927A2
EP1615927A2 EP04726106A EP04726106A EP1615927A2 EP 1615927 A2 EP1615927 A2 EP 1615927A2 EP 04726106 A EP04726106 A EP 04726106A EP 04726106 A EP04726106 A EP 04726106A EP 1615927 A2 EP1615927 A2 EP 1615927A2
Authority
EP
European Patent Office
Prior art keywords
riboflavin
fluidized bed
range
precipitation
temperature
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Withdrawn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
EP04726106A
Other languages
German (de)
English (en)
Inventor
Dirk Franke
Friedrich Hill
Christoph Martin
Thomas Knebel
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.)
BASF SE
Original Assignee
BASF SE
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 BASF SE filed Critical BASF SE
Publication of EP1615927A2 publication Critical patent/EP1615927A2/fr
Withdrawn legal-status Critical Current

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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
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D475/00—Heterocyclic compounds containing pteridine ring systems
    • C07D475/12—Heterocyclic compounds containing pteridine ring systems containing pteridine ring systems condensed with carbocyclic rings or ring systems
    • C07D475/14—Benz [g] pteridines, e.g. riboflavin
    • A—HUMAN NECESSITIES
    • A23—FOODS OR FOODSTUFFS; TREATMENT THEREOF, NOT COVERED BY OTHER CLASSES
    • A23L—FOODS, FOODSTUFFS, OR NON-ALCOHOLIC BEVERAGES, NOT COVERED BY SUBCLASSES A21D OR A23B-A23J; THEIR PREPARATION OR TREATMENT, e.g. COOKING, MODIFICATION OF NUTRITIVE QUALITIES, PHYSICAL TREATMENT; PRESERVATION OF FOODS OR FOODSTUFFS, IN GENERAL
    • A23L33/00—Modifying nutritive qualities of foods; Dietetic products; Preparation or treatment thereof
    • A23L33/10—Modifying nutritive qualities of foods; Dietetic products; Preparation or treatment thereof using additives
    • A23L33/15—Vitamins

Definitions

  • the present invention relates to an improved process for the production of pure riboflavin (vitamin B2) of the modification B / C in granular form.
  • the invention relates to pure riboflavin in granular form, which is characterized by particularly good dissolution kinetics with a high bulk density.
  • riboflavin vitamin B2
  • vitamin B2 which is intended as an active ingredient or additive for food or pharmaceuticals
  • the highest demands on the purity of the product must be met. This is one of the main requirements for the synthetic or biotechnological processes currently being carried out for the industrial production of riboflavin.
  • a riboflavin produced by biotechnological processes is initially obtained in a purity of about 75%, which is mainly due to impurities typical of biotechnological manufacturing processes, such as cell residues, proteins, peptides or amino acids. Such raw products are therefore not suitable for the above-mentioned applications in humans and require further purification.
  • Riboflavin in modifications B or C especially riboflavin, which is essentially present in modification B and can contain small amounts of riboflavin of modification C, which is difficult to detect (hereinafter referred to as riboflavin of modification B / C).
  • EP-A 0307767 describes a first approach to this goal: To produce a spherulitic form of riboflavin with improved handling and flow properties, riboflavin is dissolved in a solvent and with a second solvent in which riboflavin is not soluble, but which is soluble with the first solvent is miscible, precipitated.
  • EP-A 0457075 describes a process for the production of free-flowing, non-dusting and binder-free riboflavin spray granules or microgranules from pure riboflavin.
  • An aqueous or water-containing suspension of pure, finely divided riboflavin is spray-dried in a fluidized bed, subjected to single-substance atomization drying or disc atomization drying.
  • EP-A 0 995749 describes a cleaning and crystallization process for riboflavin.
  • Riboflavin of modification A is dissolved in aqueous mineral acid and activated carbon is added for cleaning. After filtration, the valuable substance is precipitated and isolated by adding water by the method described in EP-A 0307767. Dendritic spherical crystals of modification B / C are obtained.
  • EP-A 1 048 668 describes a process based on the teaching of EP-A 0457075 for the production of non-dusting and binder-free riboflavin granules with good flow properties.
  • the riboflavin is first purified by activated carbon as described in EP-A 0995749 and then precipitated at a temperature of 0 to 30 ° C. after a subsequent crossflow filtration.
  • the aqueous riboflavin suspension obtained in this way is then filtered, washed and the riboflavin thus isolated of modification B / C is subjected to spray fluidized-bed drying, single-component atomization drying or disk atomization drying.
  • Granules such as B. described in EP-A 1 048668, are usually characterized by good dissolving properties, but have a low bulk density, which makes their handling or further processing considerably more difficult.
  • a) dissolves in aqueous mineral acid
  • b) precipitates directly afterwards, without first treating the resulting mineral acid riboflavin solution with activated carbon, steps a) and b) being carried out at a temperature in the range from 5 to 15 ° C. and c) the riboflavin dries by fluidized bed spray granulation.
  • the riboflavin granules produced in this way are distinguished by particularly advantageous dissolution kinetics (dissolution) and a high bulk density.
  • the granules are so designed that, even after being compressed in tablet form (tableting), they can be quickly dissolved in aqueous media despite their high density.
  • this particularly advantageous combination of properties depends on how long the riboflavin comes into contact with the mineral acid medium used as solvent. A shortening of the contact time leads to an improvement in the product properties according to the invention. Shortening the contact time from
  • Riboflavin and mineral acid medium is u. a. in that the time-consuming cleaning step of adding activated carbon is dispensed with in the process according to the invention and the precipitation is carried out immediately after the dissolving process.
  • Immediate is to be understood here as meaning that between the dissolving process and the precipitation no further process steps or longer standing times of the solution are provided, which are carried out via the necessary transport of the solution from the dissolving kettle to the first felling kettle, e.g. through pipelines.
  • the use of other adsorbents known per se to the person skilled in the art is also not necessary.
  • Dissolving medium the decomposition products which are always present in traces when treated with acid are produced to a lesser extent, which, after precipitation and the subsequent fluidized-bed spray granulation, leads to the particularly advantageous properties of the granular riboflavin prepared according to the invention. It is thus the combination of the process features shown that leads to the advantageous properties of the riboflavin granulate according to the invention.
  • the process according to the invention is suitable for the production of pure riboflavin of the modification B / C in granular form.
  • the starting material used is synthetic or fermentative, but preferably fermentatively produced riboflovin, which after the production may already have at least one cleaning step, e.g. by reprecipitation, with a purity that is usually in the range of 90 to 99%.
  • Riboflavin with a purity of 95 to 99%, particularly preferably with a purity of 97 to 99%, is used as the preferred starting material. This is usually completely or predominantly (i.e. more than about 90%) in the
  • the riboflavin used as the starting material is dissolved in aqueous mineral acid, for example in nitric acid or preferably in hydrochloric acid.
  • aqueous mineral acid for example in nitric acid or preferably in hydrochloric acid.
  • the conc The mineral acid is usually about 10 to about 65% by weight.
  • the concentration is expediently in the range from about 18 to about 28% (% by weight).
  • the dissolving process takes place in the process according to the invention at a temperature of the dissolving medium in the range from approximately 5 ° C. to approximately 15 ° C.
  • Dissolving temperatures in the range from 5 ° C. to 12 ° C. are particularly preferred, very particularly preferably from 6 ° C. to 9 ° C. Solutions are obtained in which up to about 20% by weight of riboflavin is dissolved. In general, the dissolving process is completed after 30 to 150 minutes.
  • the duration of the dissolving process is chosen so that the total time during which the riboflavin is in contact with the mineral acid solvent is as short as possible.
  • the total contact time is to be understood as the time from the start of the dissolving process to the precipitation of the riboflavin from the aqueous hydrochloric acid dissolving medium, that is to say the time during which the riboflavin is dissolved in the aqueous hydrochloric acid solution medium. It is advantageous to work with total contact times of up to about 4 hours. Total contact times of approximately 2.5 to approximately 3 hours are particularly preferred. Since the process according to the invention preferably also includes process steps carried out continuously, the stated contact times, as well as all other time information (e.g. dissolution or precipitation time), are to be interpreted as average time information.
  • the mineral acidic riboflavin solution is mixed with water, usually with about five to ten times the amount (volume / volume).
  • water usually with about five to ten times the amount (volume / volume).
  • the riboflavin can be precipitated continuously or discontinuously in one or more stirred kettles connected in series, a so-called stirred kettle cascade.
  • the precipitation is carried out continuously in a two-stage stirred tank cascade.
  • the temperature during the precipitation is selected according to the invention such that it is in a range from approximately 5 ° C. to approximately 15 ° C., in particular from approximately 6 ° C. to approximately 12 ° C.
  • a falling temperature in the range from approximately 7 ° C. to approximately 10 ° C. is particularly preferred.
  • the average residence times of the riboflavin solution in the case of the continuously carried out precipitation of the riboflavin preferred according to the invention are in the first stirred tank Range from about 1 minute to about 10 minutes, preferably from about 2.5 minutes to about 5 minutes.
  • the residence time in the second kettle can vary more widely, but is expediently chosen in a range from about 5 minutes to about 15 minutes, preferably from about 5 minutes to about 10 minutes.
  • the stirring power in the first and, independently of this, also in the second boiler is advantageously about 0.02 W / I to about 1.0 W / l.
  • a stirring power in the range from about 0.05 to about 0.3 W / l is preferably selected independently for each boiler.
  • the riboflavin that can be produced by the process steps according to the invention is obtained in the form of agglomerates. These have a high density and a smooth surface and are distinguished, above all in view of the processing which is usually still necessary, by considerable advantages over conventional spherical riboflavin crystals.
  • the conventional crystals sometimes have a spiky surface (see EP-A 0995749) and are not very stable to shear. This property, which is unfavorable for the process control, favors the growth of needle-shaped crystals and poor process stability and poor filtration and handling properties.
  • agglomerates can be influenced by the process control of the precipitation. In the case of continuous operation with two boilers, the exact metering of the feed streams must be ensured. The mixing times should be short to avoid local over-concentrations. The latter can be achieved by a suitable choice of the stirrer and the metering points, as is known to the person skilled in the art. It may be advantageous to divide the supply of water and riboflavin solution between the containers. However, no more than 70% of the water should be added to the second reactor. Another option for setting the concentration is the return of suspension from the second precipitation tank and the return of mother liquor after the filtration. The solids concentration is thus freely selectable, which influences the agglomeration kinetics.
  • the second stirred kettle In order to ensure complete conversion, it can make sense to offer a further dwell time after the second stirred kettle.
  • the latter can be carried out in the form of a tubular reactor.
  • the advantageous execution of the felling step can differ between pilot plant and company scale. If the process according to the invention is carried out on an industrial scale, the product properties which are advantageous compared to the prior art become particularly apparent when the process steps connected in series are in a stationary state. This condition is usually reached after about 10 runs. In the case of the process carried out on a smaller scale, for example on a laboratory or pilot plant scale, it may be possible and advantageous to further shorten the total contact time of the riboflavin with the mineral acidic aqueous dissolving medium.
  • the precipitated riboflavin is then separated from the aqueous precipitation medium and washed by filtration methods known per se to the person skilled in the art.
  • the filtration cake obtained by filtration and consisting of solid riboflavin of modification B / C is advantageously suspended by adding water.
  • the amount of water added is chosen so that a riboflavin suspension with a solids content of about 5 to about 15% by weight, preferably from about 8 to about 12% by weight, is obtained. But you can also use a suspension in a not too high boiling solvent if this solvent contains water. The water content in the suspension should then be at least 10% by weight.
  • Suitable solvents are in particular water-miscible solvents, such as, for example, C to C alkanols.
  • the riboflavin suspension is subjected to fluidized-bed spray granulation to dry it.
  • the suspension is sprayed continuously or discontinuously into a fluidized bed of dry reaction product in the fluidized bed spray granulation used according to the invention.
  • the drying device is provided with devices which allow a specific particle size fraction to be obtained and the granulation process to be maintained (cf. K. Kroll, drying technology, Volume II, "Dryer and drying process", Springer, Berlin, 1978, 221-223).
  • Riboflavin in the form of a dry powder or a spray or microgranules in a fluidized bed dryer in a to 20 to 100 ° C, preferably 50 to
  • b) for this purpose adds an aqueous or water-containing suspension of the finely divided riboflavin according to the drying rate in sprayed form, c) after a suitable residence time, the riboflavin particles are removed from the fluidized bed and passed through a separates a suitable device into particle fractions, d) discharges the particle fraction in the particle size range from approximately 50 to approximately 450 ⁇ m, preferably from approximately 80 to approximately 250 ⁇ m, and e) the finely divided particles and / or the finely divided particles obtained by grinding larger particles and / or some of the fraction discharged as the useful fraction with or without grinding back into the spray fluidized bed.
  • the spray fluidized bed drying can be carried out continuously or batchwise. It is particularly advantageous to work continuously.
  • a riboflavin product which is suitable for producing a fluidized bed must first be produced from riboflavin dry powder corresponding to the prior art.
  • a sufficiently fine-particle product such as e.g. obtained by spray drying or agglomerating spray drying, submit in a fluidized bed.
  • a dry product with a smaller or larger particle size range is then obtained. Particles in the size range of approximately 50 to 450 ⁇ m have the desired properties and are therefore obtained as a valuable product. Smaller particles and riboflavin obtained by grinding larger particles are used as fluidized bed material for further batches.
  • the aqueous or water-containing suspension of finely divided riboflavin is continuously sprayed into a fluidized bed.
  • the rate of spraying is adjusted so that the fluidized bed has a temperature corresponding to the desired degree of drying. It is determined by the difference between the inlet and outlet temperatures of the fluidizing gas blown into the dryer. If the process is carried out continuously, fine particle riboflavin in the fluidized bed is assumed only when the fluidized bed dryer is started up for the first time. Then you get a dry product with an almost constant particle size distribution. From this, a certain part of the desired particle size fractions is advantageously taken continuously or intermittently.
  • the particle fraction in the particle size range from approximately 50 to approximately 450 ⁇ m is discharged as a product of value and the fine particles and / or the fine particles obtained by grinding larger particles are continuously returned to the fluidized bed in order to maintain the granulation processes.
  • the ratio of the mass flow returned to the spray fluidized bed to the mass flow which is taken from the process as a valuable product is particularly advantageously selected in the range from about 0 to about 8, preferably from about 0.5 to about 5, particularly preferably from about 1 to about 4.
  • the amount of riboflavin corresponding to the amount removed as the product of value is continuously sprayed into the fluidized bed in the form of an aqueous suspension of finely divided riboflavin, and the amount of riboflavin in the fluidized bed is thus kept constant.
  • the fluidizing gas blown into the dryer to form the fluidized bed generally has an inlet temperature of 60 to 250 ° C., preferably 140 to 185 ° C. and an outlet temperature of 40 to 140 ° C., preferably 60 to 95 ° C. This results in a fluidized bed temperature of approximately 40 to 140 ° C., preferably 60 to 95 ° C., particularly preferably 65 to 95 ° C.
  • Evaporation of the amount of liquid introduced into the fluidized bed with the aqueous riboflavin suspension may require the supply of additional energy.
  • the temperature of these heating surfaces is usually in the range from 100 to 250 ° C., preferably in the range from 140 to 180 ° C.
  • the method used is a dryer which is configured in such a way that the spray nozzle or spray nozzles is or are arranged above the fluidized bed, in the so-called top-spray configuration.
  • the spraying process is controlled in such a way that the ratio of the nozzle air to the sprayed suspension based on the mass is less than about 1.5, preferably less than about 1.
  • the process shown is suitable for the production of pure riboflavin of the modification B / C in granular form. Pure riboflavin is understood to mean a riboflavin which has a degree of purity of more than 96%, preferably more than 98%, particularly preferably more than 99% and has not been mixed with binding or granulating aids or other additives.
  • Another object of the invention relates to pure riboflavin in granular form, which has a bulk density of 0.45 to 0.7 g / ml and after tableting a dissolution rate of at least 80%.
  • the invention preferably relates to pure riboflavin in granular form which has a bulk density of 0.5 to 0.65 g / ml and, after tableting, a dissolution kinetics of at least 80%.
  • the invention particularly preferably relates to pure riboflavin in granular form which has a bulk density of 0.5 to 0.65 g / ml and, after tableting, a dissolution kinetics of at least 85%.
  • Bulk density is to be understood as the quotient of the mass and the volume which a molding compound poured in a certain way (here riboflavin in granular form) takes up.
  • the bulk density of a water-soluble bulk material usually correlates with the dissolution kinetics, i.e. at the rate at which the bulk material dissolves in water or an aqueous dissolving medium in such a way that an increased bulk density allows the person skilled in the art to expect a reduced rate of dissolution.
  • the riboflavin according to the invention in granular form is characterized in that, even after tableting, i.e. after pressing in tablet form, has an unexpectedly good dissolution kinetics (dissolution).
  • a powder mixture consisting of 16.66% by weight of riboflavin, 53.34% by weight of tablettose (Meggle AG), 26.84 is first used wt .-% Avicel ® PH 102 (FMC Corp.), 0.5 wt .-% Ac-Di-Sol ® (FMC Corp.), 2.0 wt.% Aerosil ® 200 (Degussa AG) and 0.66 % By weight magnesium stearate (Bärlocher GmbH).
  • a suitable measure for determining the kinetics of dissolution of the riboflavin granules according to the invention after the tableting carried out as described above is the so-called “dissolution”.
  • a fully automatic U.S.P. release device is used to determine the dissolution of the tableted riboflavin. 26 (Physical Tests / 711 Dissolution, p.2155). The measurement is carried out in a 1 liter measuring cylinder which is filled with 900 ml of 0.1 molar hydrochloric acid. The measuring solution is heated to 36.5 to 37.5 ° C in a water bath and stirred at 75 revolutions / min with a blade stirrer. 30 minutes after the addition of the riboflavin tablet prepared as described above, a sample of the measurement solution is taken, the riboflavin content of which, if appropriate after further dilution, is determined by UV spectroscopy at a wavelength of 267 nm. The proportion of the amount of riboflavin released from the tablet after 30 min is given as a dissolution in [%].
  • the riboflavin granules according to the invention are superior to the previously known administration forms of riboflavin.
  • the granules according to the invention are free-flowing, non-dusting and binder-free. They are preferably obtained without the addition of granulation aids.
  • aqueous suspension containing about 10% by weight of this residue is sprayed at a rate of 4 kg / h and at an inlet air temperature of 180 ° C. from above onto the fluidized receiver of a fluidized bed dryer using a two-fluid nozzle.
  • granules are withdrawn from the product space so that the content of the fluidized bed remains constant.
  • the discharge is fractionated with a sieve (250 ⁇ m).
  • the coarse material is crushed with a universal mill and returned to the fluidized bed, the ratio of the returned product to the discharged product being 1: 1.
  • the spray granulation takes place in a fluidized bed apparatus with an inflow area of 0.07 m 2 .
  • the sprayed mass flow of the suspension is between approx. 12 and 20 kg / h.
  • the product area of the fluidized bed apparatus is provided with heating surfaces heated to 160 ° C.
  • the fluidizing gas is injected at a temperature of 166 ° C.
  • part of the fluidized material is drawn off and separated into two fractions (useful fraction ⁇ 250 ⁇ m, coarse fraction> 250 ⁇ m) using a screening machine.
  • the coarse fraction and, if necessary, part of the useful fraction is ground and returned to the fluidized bed.
  • the ratio of the returned product to the discharged product is the values given in Table 2 under "Return".

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

Abstract

La présente invention concerne un procédé amélioré de production de riboflavine pure (vitamine B2) de la modification B/C sous forme de granulés. L'invention concerne également une riboflavine pure sous forme de granulés ayant une densité en vrac à déterminer selon la norme DIN 53468 de 0,45 à 0,7 g/ml et, après agglomération, une cinétique de dissolution (dissolution) d'au moins 80 % .
EP04726106A 2003-04-11 2004-04-07 Procede de production de riboflavine de la modification b/c sous forme de granules Withdrawn EP1615927A2 (fr)

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
DE2003117051 DE10317051A1 (de) 2003-04-11 2003-04-11 Verfahren zur Herstellung von Riboflavin der Modifikation B/C in Granulatform
PCT/EP2004/003689 WO2004089889A2 (fr) 2003-04-11 2004-04-07 Procede de production de riboflavine de la modification b/c sous forme de granules

Publications (1)

Publication Number Publication Date
EP1615927A2 true EP1615927A2 (fr) 2006-01-18

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Family Applications (1)

Application Number Title Priority Date Filing Date
EP04726106A Withdrawn EP1615927A2 (fr) 2003-04-11 2004-04-07 Procede de production de riboflavine de la modification b/c sous forme de granules

Country Status (8)

Country Link
US (1) US7329748B2 (fr)
EP (1) EP1615927A2 (fr)
JP (1) JP2006522763A (fr)
KR (1) KR20060006028A (fr)
CN (1) CN100334087C (fr)
CA (1) CA2521633A1 (fr)
DE (1) DE10317051A1 (fr)
WO (1) WO2004089889A2 (fr)

Families Citing this family (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN104961740B (zh) * 2015-06-02 2016-04-27 湖北广济药业股份有限公司 一种含核黄素的固体制剂及其制备方法
CN113929683A (zh) * 2021-11-15 2022-01-14 天津大学 一种提高核黄素晶体堆密度和流动性的方法

Family Cites Families (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
ATE91686T1 (de) * 1987-09-18 1993-08-15 Hoffmann La Roche Neue form des riboflavins.
DE4014262A1 (de) 1990-05-04 1991-11-07 Basf Ag Gut rieselfaehige, nichtstaubende bindemittelfreie riboflavinspruehgranulate oder -mikrogranulate aus reinem riboflavin und ein verfahren zu deren herstellung
EP0730034A1 (fr) * 1995-03-03 1996-09-04 F. Hoffmann-La Roche Ag Purification de riboflavine
CA2282908A1 (fr) * 1998-10-19 2000-04-19 F. Hoffmann-La Roche Ag Procede de purification et de cristallisation de la riboflavine
US6723346B1 (en) * 1999-04-30 2004-04-20 Roche Vitamins Inc. Process for preparing spray granules containing riboflavin

Non-Patent Citations (1)

* Cited by examiner, † Cited by third party
Title
See references of WO2004089889A2 *

Also Published As

Publication number Publication date
CA2521633A1 (fr) 2004-10-21
CN100334087C (zh) 2007-08-29
US7329748B2 (en) 2008-02-12
KR20060006028A (ko) 2006-01-18
CN1774438A (zh) 2006-05-17
US20060258664A1 (en) 2006-11-16
WO2004089889A2 (fr) 2004-10-21
WO2004089889A3 (fr) 2005-06-02
JP2006522763A (ja) 2006-10-05
DE10317051A1 (de) 2004-10-21

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