EP1720884A1 - Pharmakologisch akzeptierbare salze von clopidogrel - Google Patents

Pharmakologisch akzeptierbare salze von clopidogrel

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Publication number
EP1720884A1
EP1720884A1 EP05700370A EP05700370A EP1720884A1 EP 1720884 A1 EP1720884 A1 EP 1720884A1 EP 05700370 A EP05700370 A EP 05700370A EP 05700370 A EP05700370 A EP 05700370A EP 1720884 A1 EP1720884 A1 EP 1720884A1
Authority
EP
European Patent Office
Prior art keywords
clopidogrel
solvent
water
isopropanol
hydrobromide
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Withdrawn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
EP05700370A
Other languages
German (de)
English (en)
French (fr)
Inventor
Beat T. Weber
Michael Karl Levis
Hon Quang Ly
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.)
Siegfried Generics International AG
Original Assignee
Siegfried Generics International AG
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 Siegfried Generics International AG filed Critical Siegfried Generics International AG
Publication of EP1720884A1 publication Critical patent/EP1720884A1/de
Withdrawn legal-status Critical Current

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Classifications

    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D495/00—Heterocyclic compounds containing in the condensed system at least one hetero ring having sulfur atoms as the only ring hetero atoms
    • C07D495/02—Heterocyclic compounds containing in the condensed system at least one hetero ring having sulfur atoms as the only ring hetero atoms in which the condensed system contains two hetero rings
    • C07D495/04—Ortho-condensed systems
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00

Definitions

  • the present invention relates to salts of clopidogrel, in particular new polymorphic forms of clopidogrel hydrobride, and salts of clopidogrel with benzenesulfonic acid (besylate), with para-toluenesulfonic acid (tosylate), with naphthalene-2-sulfonic acid (napsylate) and with oxalic acid (Oxalate).
  • Clopidogrel is a pharmaceutically active compound and is known per se. Clopidogrel is the right-turning S-enantiomer of alfa (2-chlorophenyl) -6, 7-dihydro-thieno [3, 2-c] pyidin-5 (4H) methyl acetate.
  • the present invention also relates to processes for the preparation of these compounds and pharmaceutically active compositions which contain at least one compound according to the invention in known concentrations.
  • the present invention also relates to the use of the new compounds and forms for the production of pharmaceutically active compositions which contain at least one compound according to the invention in a pharmaceutically active concentration.
  • EP 0 099 802 discloses the racemic mixture and the two enantiomeric forms of clopidogrel.
  • EP 1 087 976 describes further salts of clopidogrel.
  • the present invention relates to six new polymorphic forms of (+) - (S) -clopidogrel hydrogen bromide, which are referred to herein as polymorphic "" Form A, polymorphic "" Form B ' 1 , polymorphic "" Form C M , polymorphic “” Form D M , as polymorphic "" form E 11 , and as polymorphic "” form F M , and two new polymorphic forms of (+) - (S) -clopidogrel napsylate, which are referred to here as polymorphic "form A” and polymorphic " Form B "are designated.
  • These polymorphic forms differ each other in their powder X-ray diagrams (XRPD).
  • the polymorphic forms of the Clopidogrel Hydrobromides also differ in the infrared spectrum. In the present description, the XRPD peaks are used for differentiation.
  • the characteristic XRPD peaks of clopidogrel hydrobromide of the polymorphic forms A, B, C, D, E and F and clopidogrel napsylate of the polymorphic forms A and B are expressed in degrees 2 ⁇ with an accuracy of ⁇ 0.2 degrees 2 ⁇ , and are at the following scattering angles listed in Table 1 and Table 2.
  • Form A clopidogrel hydrobromide is obtained either by combining hydrogen bromide (HBr) and clopidogrel base in a suitable solvent and subsequent crystallization, or by recrystallization or by crystal transformation from the suspension of any form of clopidogrel hydrobromide from a suitable solvent or solvent mixture.
  • Suitable solvents are acetone, ethyl acetate, diisopropyl ether, tert-butyl methyl ether, methyl isobutyl ketone, dichloromethane, toluene, isobutyronitrile, isopropanol, preferably at temperatures between 18 and 22 ° C. using a solvent mixture of methyl isobutyl ketone and isopropanol, preferably in a mass ratio from 4: 1.
  • the invention relates to a process for the preparation of clopidogrel hydrobromide of the form A, which is characterized in that clopidogrel hydrobromide of any crystal form from a solvent or solvent mixture containing acetone, ethyl acetate, diisopropyl ether, tert. -Butyl methyl ether, methyl isobutyl ketone, dichloromethane, toluene, isobutyronitrile and / or isopropanol, preferably methyl isobutyl ketone and / or isopropanol, preferably in a mass ratio of 4: 1, in the temperature range from 18 ° C. to 22 ° C.
  • Clopidogrel hydrobromide of form B is obtained by combining HBr and clopidogrel base in a suitable solvent and subsequent crystallization and advantageously by crystallization from this solution by rapidly exceeding the saturation curves by techniques such as the rapid addition of a counter solvent (antisolvent) or by evaporative crystallization, or by very rapid cooling of the crystallization solution (shock cooling).
  • Suitable solvents are acetone and dichloromethane.
  • Suitable counter solvents are aliphatic hydrocarbons such as heptane or hexane.
  • the invention relates to a process for the preparation of clopidogrel hydrobromide of the form B, which is characterized in that clopidogrel hydrobromide of any crystal form from a suitable solvent, preferably acetone and / or dichloromethane, by rapidly exceeding the saturation curve, preferably by rapidly adding a counter solvent (Antisolvent), preferably an aliphatic hydrocarbon, preferably heptane and / or hexane, or by evaporation crystallization, or by very rapid cooling of the crystallization solution (shock cooling).
  • a suitable solvent preferably acetone and / or dichloromethane
  • Antisolvent preferably an aliphatic hydrocarbon, preferably heptane and / or hexane
  • evaporation crystallization or by very rapid cooling of the crystallization solution (shock cooling).
  • Form C clopidogrel hydrobromide is obtained either by combining HBr and clopidogrel base in a suitable solvent or by recrystallization or by crystal transformation from the suspension of any form of clopidogrel hydrobromide from a suitable solvent or solvent mixture.
  • a suitable solvent is acetonitrile.
  • the invention relates to a method for producing clopidogrel hydrobromide of the form C, which is characterized in that clopidogrel hydrobromide is a known any crystal form by crystallization from acetonitrile.
  • Form D clopidogrel hydrobromide is obtained either by combining HBr and clopidogrel base in a suitable solvent and subsequent crystallization or by recrystallization or by crystal conversion from the suspension of any form of clopidogrel hydrobromide from a suitable solvent or solvent mixture containing acetone, ethyl acetate, diisopropyl ether, tert.
  • the invention relates to a process for the preparation of clopidogrel hydrobromide of the form D, which is characterized in that clopidogrel hydrobromide of any crystal form from a solvent or solvent mixture containing acetone, ethyl acetate, diisopropyl ether, is tert.
  • clopidogrel hydrobromide of any crystal form from a solvent or solvent mixture containing acetone, ethyl acetate, diisopropyl ether is tert.
  • -Butyl methyl ether, methyl isobutyl ketone, dichloromethane, toluene, isobutyronitrile and / or isopropanol preferably methyl isobutyl ketone and / or isopropanol, preferably in a mass ratio of 4: 1, in the temperature range from 30 ° C. to 60 ° C.
  • Form E clopidogrel hydrobromide is obtained either by combining HBr and clopidogrel base in a suitable solvent and subsequent crystallization, or by crystallizing any form of clopidogrel hydrobromide from a suitable solvent or solvent mixture.
  • suitable solvents are mixtures of dichloromethane and aliphatic hydrocarbons. Long crystallization times of up to 24 hours are particularly preferred den, a working temperature range from 0 ° C to 25 ° C and crystallization of the form E by slow evaporation of the lower-silk solvent from the solvent mixture.
  • the invention relates to a process for the preparation of clopidogrel hydrobromide of the form E, which is characterized in that clopidogrel hydrobromide of any crystal form of dichloromethane and / or an aliphatic hydrocarbon with a boiling point of preferably 60 ° C. to 125 ° C., preferably hexane, Heptane or octane, crystallized, preferably in a temperature range from 0 ° C to 25 ° C, or by crystallization by slowly evaporating the lower-boiling solvent from the solvent mixture at temperatures in the temperature range from 0 ° C to 25 ° C. Long crystallization times of up to 24 hours are preferred.
  • Clopidogrel hydrobromide of form F is obtained by combining HBr and clopidogrel base in a suitable solvent and subsequent crystallization or by recrystallization of any form of clopidogrel hydrobromide from a suitable solvent or solvent mixture containing acetone, ethyl acetate, diisopropyl ether and tert. -Butyl methyl ether, methyl isobutyl ketone, dichloromethane, toluene, isobutyronitrile and / or isopropanol.
  • Methyl isobutyl ketone and / or isopropanol is preferred, preferably in a mass ratio of 4: 1, with crystallization in the temperature range from -5 ° C. to + 15 ° C. Long crystallization and stirring times of the solutions and suspensions are preferred, preferably longer than 24 hours.
  • the invention relates to a process for producing clopidogrel hydrobromide of the form F, which is characterized in that Clopidogrel hydrobromide of any crystal form from a solvent or solvent mixture containing acetone, ethyl acetate, diisopropyl ether, tert. -Butyl methyl ether, methyl isobutyl ketone, dichloromethane, toluene, isobutyronitrile and / or isopropanol, preferably methyl isobutyl ketone and / or isopropanol, preferably in a mass ratio of 4: 1, in the temperature range from -5 ° C. to + 15 ° C. ,
  • Clopidogrel also forms salts with selected organic sulfonic acids.
  • the present invention also relates to the salts clopidogrel besylate, clopidogrel tosylate, and clopidogrel napsylate as form A and form B, and also clopidogrel oxalate.
  • Clopidogrel besylate is prepared by reacting equimolar amounts of benzenesulfonic acid and clopidogrel base in a suitable solvent.
  • suitable solvents are, for example, alcohols, ethers and / or nitriles. Methanol is preferred as the solvent.
  • the compound is isolated by solvent abstraction, i.e. for example by removing the solvent by distillation or spray drying.
  • Clopidogrel tosylate is prepared by reacting equimolar amounts of para-toluenesulfonic acid with clopidogrel base in a suitable solvent.
  • suitable solvents are, for example, alcohols, ethers and / or nitriles. Methanol is preferred as the solvent at a working temperature of 20-25 ° C.
  • the compound is preferably isolated by solvent abstraction.
  • Clopidogrel napsylate form A is prepared by mixing equimolar amounts of naphthalene-2-sulfonic acid with clopidogrel Absorbs base in a suitable solvent and brings the crystallization solution to crystallization by inoculation with clopidogrel napsylate form A.
  • suitable solvents are, for example, primary and secondary alcohols, ethers, nitriles, toluene and water-containing solvent mixtures, preferably of these solvents and their mixtures, with a water content of preferably less than 10% by weight ( ⁇ 10% by weight).
  • the suitable temperature working range is between 20 ° C and 60 ° C.
  • Preferred solvents are isopropanol, diisopropyl ether, and aqueous solvents, preferably of these solvents and mixtures thereof, and isopropanol is particularly preferred.
  • clopidogrel napsylate form A is also formed by salting out clopidogrel salts (for example clopidogrel hydrobromide) and naphthalene-2-sulfonic acid salts (for example sodium 2-naphthyl sulfonate).
  • Suitable solvents are: isopropanol, diisopropyl ether, and water-containing solvent mixtures, preferably of these solvents and their mixtures, with a water content of preferably less than 10% by weight of water.
  • the temperature working range is also preferably 20 ° C to 60 ° C here.
  • Clopidogrel napsylate form A is obtained directly and without seeding if equimolar amounts of naphthalene-2-sulfonic acid are reacted with clopidogrel base in a suitable solvent, as described above, the naphthalene-2-sulfonic acid used having a purity of at least 99.5 Has wt .-% and especially if their content of naphthalene-1-sulfonic acid is less than 0.5 wt .-%.
  • Clopidogrel napsylate form B is prepared by dissolving equimolar amounts of naphthalene-2-sulfonic acid with clopidogrel base in a suitable solvent and crystallizing with clopidogrel napsylate form B by seeding.
  • suitable solvents are primary and secondary alcohols, nitriles, toluene and / or water-containing solvent mixtures, preferably of these solvents and their mixtures, with a water content of preferably less than 10% by weight of water.
  • Isopropanol is particularly preferred as the solvent, a strongly supersaturated crystallization solution (> 20%), a temperature working range from 15 ° C to 20 ° C, and long stirring times of up to 24 hours (crystallization and stirring of the suspension).
  • clopidogrel napsylate form B is also formed by salting out clopidogrel salts (eg clopidogrel hydrobromide) and naphthalene-2-sulfonic acid salts (eg sodium 2-naphthylsulfonate) and by recrystallization from clopidogrel napsylate form A by inoculating the solution with form B.
  • Suitable ones Solvents are isopropanol, diisopropyl ether, and water-containing solvent mixtures, preferably of these solvents and their mixtures, with a water content of preferably less than 10% by weight ( ⁇ 10% by weight) of water, with a preferred temperature operating range of 15 ° C. up to 20 ° C and long stirring times of up to 24 hours (crystallization and stirring of the suspension).
  • Clopidogrel napsylate form B can be obtained directly and without seeding if equimolar amounts of naphthalene-2-sulfonic acid are reacted with clopidogrel base in a suitable solvent, as described above, the naphthalene-2-sulfonic acid used having a purity of less than 99.0 wt .-% and in particular if their content of naphthalene-1-sulfonic acid is higher than 1.0 wt .-%.
  • the present invention also relates to the connection
  • Clopidogrel oxalate is produced by reacting equimolar amounts of oxalic acid with clopidogrel base in a suitable solvent.
  • suitable solvents are, for example, alcohols, ethers, nitriles, and / or water-containing solvent mixtures, preferably from these solvents and mixtures thereof, with a water content of preferably less than 10% by weight of water.
  • Preferred solvents are isopropanol, diisopropyl ether and solvent mixtures with a water content of preferably less than 10% by weight ( ⁇ 10% by weight).
  • the compound is advantageously isolated by solvent abstraction. In the foregoing cases, the condition that the water content is lower than 10% by weight is only preferable. This limit is not critical.
  • Figures 1-11 show the XRPD diagrams of Clopidogrel HBr Form A ( Figure 1), Form B ( Figure 2), Form C ( Figure 3),
  • Example 1 (Clopidogrel Hydrobromide of Form A) 160 g of Clopidogrel Base are dissolved in 260 g of acetone. While cooling with ice (internal temperature: 0 ° C - 5 ° C), this solution is fed with hydrogen bromide gas until the pH of the solution (measured with moist indicator paper) is 2 (two). The resulting suspension is allowed to warm to 20 ° C. and stirred for two hours. The solid is isolated by vacuum filtration and washed with cold acetone. The damp goods are dried in vacuo to constant weight. 130 g of clopidogrel hydrobromide of form A are obtained with the following properties: HPLC content of clopidogrel HBr: 100% DSC: maximum endothermic temperature: 143 ° C.
  • Example 2 (Clopidogrel Hydrobromide Form B) 10 g of Clopidogrel Hydrobromide are completely dissolved in 60 g of acetone with gentle heating. This solution is evacuated in a large round-bottom flask with stirring. A white residue of 10 g of clopidogrel hydrobromide of amorphous form B remains with the following properties: HPLC content of clopidogrel HBr: 100% DSC: endothermic maximum: weak minimum at approx. 130 ° C.
  • Example 3 (Clopidogrel Hydrobromide Form C) 13 g of Clopidogrel Hydrobromide are stirred in 30 ml of acetonitrile for several hours at room temperature. The solid is then isolated by means of vacuum filtration. The damp goods are dried to constant weight in a vacuum. 11 g of clopidogrel hydrobromide form C are obtained with the following properties: HPLC content of clopidogrel HBr: 100% DSC: maximum endothermic temperature: 145 ° C.
  • Example 4 (Clopidogrel Hydrobromide of Form D) 1 g of Clopidogrel Hydrobromide is stirred at 40 ° C. overnight in 2 ml of isopropanol. The solid is then isolated by means of vacuum filtration. The damp goods are dried to constant weight in a vacuum. 0.8 g of clopidogrel hydrobromide of form D are obtained with the following properties: HPLC content of clopidogrel HBr: 100% DSC: maximum endothermic temperature: 14 ° C.
  • Example 5 (Clopidogrel Hydrobromide of Form E) 13.5 g of Clopidogrel Hydrobromide are dissolved in 140 g of dichloromethane. 82 g of heptane (isomer mixture) are added to the solution at room temperature and stirred overnight under a gentle stream of nitrogen. The solid is isolated from the resulting suspension by means of vacuum filtration and dried to constant weight. 13 g of clopidogrel hydrobromide of form E are obtained with the following properties: HPLC content of clopidogrel HBr: 100% DSC: Endothermic maximum: 125 ° C
  • Example 6 (Clopidogrel Hydrobromide Form F) A mixture of 3500g isopropanol and 620g Clopidogrel Hydrobromide Form A are heated until a clear, slightly yellow solution is obtained (internal temperature (IT): 60-65 ° C.). After rapid cooling to an internal temperature of 10 ° C, a white, powdery mass crystallizes spontaneously or after inoculation, which can be achieved by vacuum filtration isolated and dried to constant weight. 361 g of clopidogrel hydrobromide form F are obtained with the following properties: HPLC content of clopidogrel HBr: 100%; DSC: Endothermic maximum: 107.6 ° C
  • Example 7 (Clopidogrel Besylate) 3.0 g of benzenesulfonic acid and 5.5 g of clopidogrel base are dissolved in 30 ml of methanol. The solvent is removed in vacuo. There remain 8.5 g of clopidogrel besylate with the following properties: HPLC content of clopidogrel besylate: 100% DSC: maximum endothermic energy: none
  • Example 8 (Clopidogrel Tosylate) 3.2 g of para-toluenesulfonic acid and 5.5 g of clopidogrel base are dissolved in 30 ml of methanol. The solvent is removed in vacuo. There remain 8.7 g of clopidogrel tosylate with the following properties: HPLC content of clopidogrel besylate: 100% DSC: Endothermic maximum: none
  • Example 10 (Clopidogrel Napsylate, Form A) 2.5 g of sodium 2-naphthylsulfonate are dissolved in 60 ml of water. Suspended matter is separated by clear filtration. Then 30 ml of methanol and 2.9 g of clopidogrel hydrobromide are added. The resulting solution is under vigorous stirring slowly removed about 50% of the solvent under a slight vacuum at room temperature. The white solid formed is isolated by vacuum filtration, washed with water and dried in vacuo to constant weight. 3 g of clopidogrel napsylate form A are obtained.
  • Example 11 (Clopidogrel Napsylate, Form B) A previously prepared hot solution (approx. 65 ° C.) of 462 g of isopropanol and 82 g of Clopidogrel napsylate Form A is cooled to 20-25 ° C. and inoculated with Clopidogrel napsylate Form B. The mixture is stirred well at 15-20 ° C. for 24 hours and the suspension is isolated by means of vacuum filtration. The filter cake is washed with isopropanol at 15-20 ° C and dried in an air stream at IT 20-25 ° C to constant weight. 70 g of clopidogrel napsylate form B are obtained. DSC: Endothermic maximum: 114.4 ° C.
  • Example 13 (Clopidogrel Napsylate Form A) 170 g of clopidogrel base and 115 g of naphthalene-2-sulfonic acid monohydrate are dissolved in 600 ml of isopropanol at 60 ° C. and slowly cooled. The clear solution is inoculated with clopidogrel napsylate form A at 50 ° C. and cooled to room temperature at 10 ° C./h. The crystals are isolated by vacuum filtration and dried in vacuo. 223 g of clopidogrel napsylate form A are obtained.

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  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
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  • Veterinary Medicine (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Heterocyclic Carbon Compounds Containing A Hetero Ring Having Oxygen Or Sulfur (AREA)
  • Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
EP05700370A 2004-02-24 2005-02-16 Pharmakologisch akzeptierbare salze von clopidogrel Withdrawn EP1720884A1 (de)

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
CH3002004 2004-02-24
PCT/CH2005/000086 WO2005080890A1 (de) 2004-02-24 2005-02-16 Pharmakologisch akzeptierbare salze von clopidogrel

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EP1720884A1 true EP1720884A1 (de) 2006-11-15

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US (1) US20070249660A1 (ja)
EP (1) EP1720884A1 (ja)
JP (1) JP2007523203A (ja)
CN (1) CN1922188A (ja)
AU (1) AU2005214469A1 (ja)
CA (1) CA2557256A1 (ja)
NO (1) NO20064332L (ja)
RU (1) RU2006133842A (ja)
TW (1) TW200540171A (ja)
WO (1) WO2005080890A1 (ja)

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EP1732932B1 (en) * 2004-04-09 2012-03-21 Hanmi Holdings Co., Ltd. Crystalline clopidogrel naphthalenesulfonate or hydrate thereof, method for preparing same and pharmaceutical composition containing same
ZA200608569B (en) * 2004-04-20 2007-12-27 Sanofi Aventis Polymorphic forms of methyl (+)-(S)-alpha- (2-chlorophenyl)-6, 7-dinydrothieno[3,2-C] pyridine-5(4H) acetate hydrobromide, clopidrogel hydrobromide
ZA200608035B (en) 2004-04-20 2008-07-30 Sanofi Aventis Clopidogrel salt and polymorphic forms thereof
GB0418580D0 (en) * 2004-08-21 2004-09-22 Ivax Pharmaceuticals Sro Clopidogrel salt
EP1934229B1 (en) * 2005-09-05 2012-09-26 Cadila Healthcare Limited Processes for the preparation of different forms of (s)-(+)-clopidogrel besylate
KR100945062B1 (ko) 2006-03-22 2010-03-05 한미약품 주식회사 클로피도그렐 1,5-나프탈렌디술폰산염 및 이의 수화물의제조방법
EP2107061A1 (en) 2008-04-02 2009-10-07 Krka Tovarna Zdravil, D.D., Novo Mesto Process for the preparation of optically enriched clopidogrel
HUE031738T2 (en) * 2009-02-27 2017-07-28 Janssen Pharmaceuticals Inc Amorphous salts of the HCV macrocyclic inhibitor
CN102199161B (zh) * 2011-03-30 2013-07-03 天津红日药业股份有限公司 一种苯磺酸氯吡格雷晶型ⅰ及其制备方法和用途
CN104193762B (zh) * 2014-08-04 2017-02-15 浙江车头制药股份有限公司 一种制备苯磺酸氯吡格雷晶型ⅲ的方法
CN104610275B (zh) * 2015-02-06 2017-07-07 符健 一种2，5‑二羟基苯磺酸氯吡格雷及其制备方法

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FR2623810B2 (fr) * 1987-02-17 1992-01-24 Sanofi Sa Sels de l'alpha-(tetrahydro-4,5,6,7 thieno(3,2-c) pyridyl-5) (chloro-2 phenyl) -acetate de methyle dextrogyre et compositions pharmaceutiques en contenant
FR2779726B1 (fr) * 1998-06-15 2001-05-18 Sanofi Sa Forme polymorphe de l'hydrogenosulfate de clopidogrel
DE10305984A1 (de) * 2003-02-13 2004-09-02 Helm Ag Salze organischer Säuren mit Clopidogrel und deren Verwendung zur Herstellung phamazeutischer Formulierungen
EP1618111B1 (en) * 2003-04-25 2014-12-24 Cadila Healthcare Limited Salts of clopidogrel and process for preparation

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NO20064332L (no) 2006-11-21
WO2005080890A9 (de) 2005-11-17
WO2005080890A1 (de) 2005-09-01
US20070249660A1 (en) 2007-10-25
CA2557256A1 (en) 2005-09-01
JP2007523203A (ja) 2007-08-16
RU2006133842A (ru) 2008-03-27
CN1922188A (zh) 2007-02-28
AU2005214469A1 (en) 2005-09-01
TW200540171A (en) 2005-12-16

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