EP1768676A1 - Verwendung von thiolgruppen-haltigen verbindungen als efflux-pumpen-hemmer - Google Patents

Verwendung von thiolgruppen-haltigen verbindungen als efflux-pumpen-hemmer

Info

Publication number
EP1768676A1
EP1768676A1 EP05771836A EP05771836A EP1768676A1 EP 1768676 A1 EP1768676 A1 EP 1768676A1 EP 05771836 A EP05771836 A EP 05771836A EP 05771836 A EP05771836 A EP 05771836A EP 1768676 A1 EP1768676 A1 EP 1768676A1
Authority
EP
European Patent Office
Prior art keywords
thiol group
use according
glutathione
thiolated
containing compounds
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Withdrawn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
EP05771836A
Other languages
German (de)
English (en)
French (fr)
Inventor
Martin Hoffer
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.)
MucoBiomer Biotechnologische Forschungs- und Entwicklungs GmbH
ThioMatrix Forschungs- und Beratungs GmbH
Original Assignee
MucoBiomer Biotechnologische Forschungs- und Entwicklungs GmbH
ThioMatrix Forschungs- und Beratungs GmbH
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 MucoBiomer Biotechnologische Forschungs- und Entwicklungs GmbH, ThioMatrix Forschungs- und Beratungs GmbH filed Critical MucoBiomer Biotechnologische Forschungs- und Entwicklungs GmbH
Publication of EP1768676A1 publication Critical patent/EP1768676A1/de
Withdrawn legal-status Critical Current

Links

Classifications

    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K45/00—Medicinal preparations containing active ingredients not provided for in groups A61K31/00 - A61K41/00
    • A61K45/06—Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
    • 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
    • A61K31/70—Carbohydrates; Sugars; Derivatives thereof
    • A61K31/7042—Compounds having saccharide radicals and heterocyclic rings
    • A61K31/7048—Compounds having saccharide radicals and heterocyclic rings having oxygen as a ring hetero atom, e.g. leucoglucosan, hesperidin, erythromycin, nystatin, digitoxin or digoxin
    • 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
    • A61K31/70—Carbohydrates; Sugars; Derivatives thereof
    • A61K31/715—Polysaccharides, i.e. having more than five saccharide radicals attached to each other by glycosidic linkages; Derivatives thereof, e.g. ethers, esters
    • A61K31/716—Glucans
    • 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
    • A61K31/70—Carbohydrates; Sugars; Derivatives thereof
    • A61K31/715—Polysaccharides, i.e. having more than five saccharide radicals attached to each other by glycosidic linkages; Derivatives thereof, e.g. ethers, esters
    • A61K31/716—Glucans
    • A61K31/717—Celluloses
    • 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
    • A61K31/74—Synthetic polymeric materials
    • A61K31/795—Polymers containing sulfur
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K38/00—Medicinal preparations containing peptides
    • A61K38/03—Peptides having up to 20 amino acids in an undefined or only partially defined sequence; Derivatives thereof
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K38/00—Medicinal preparations containing peptides
    • A61K38/04—Peptides having up to 20 amino acids in a fully defined sequence; Derivatives thereof
    • A61K38/06—Tripeptides
    • A61K38/063—Glutathione
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K38/00—Medicinal preparations containing peptides
    • A61K38/04—Peptides having up to 20 amino acids in a fully defined sequence; Derivatives thereof
    • A61K38/12—Cyclic peptides, e.g. bacitracins; Polymyxins; Gramicidins S, C; Tyrocidins A, B or C
    • A61K38/13—Cyclosporins
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K38/00—Medicinal preparations containing peptides
    • A61K38/16—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof
    • A61K38/17—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from animals; from humans
    • A61K38/33—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from animals; from humans derived from pro-opiomelanocortin, pro-enkephalin or pro-dynorphin
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P27/00—Drugs for disorders of the senses
    • A61P27/02—Ophthalmic agents
    • 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
    • A61P31/04—Antibacterial agents

Definitions

  • non-invasive dosage forms are far more pleasant for the patient.
  • Tablets or nasal sprays may cause pain and risks associated with e.g. Injections and infusions are avoided. Accordingly, the compliance is greater for non-invasive forms of administration.
  • many classes of drugs such as chemotherapeutics for the treatment of cancer, can usually only be administered parenterally because their uptake via mucous membranes by various efflux pumps, such as e.g. P-glycoprotein greatly reduced [Hunter, J. and Hirst, B.H. (1997). In ⁇ testinal secretion of drugs. The role of P-glycoprotein and related drug efflux in limiting oral drug absorption. Adv. Drug Deliv.
  • the oral bioavailability could be increased from 28.6% to 52.7% [Yang, S., Gursoy RN, Lambert G. and Benita S., En- oral absorption of padlitaxel in a novel self-microemulsifying drug delivery system of P-glycoprotein inhibitors. Pharm. Res. 21 (20024) 261-270].
  • the oral bioavailability of cyclosporin was markedly increased by the use of a nanoparticulate dosage form [Beckerman T., Golenser J. and Domb A., Cyclosporin nanoparticulate lipospheres for oral administration. J. Pharm.
  • the object of the present invention therefore relates to the provision of pharmaceutical dosage forms for active substances whose uptake via mucous membranes is reduced by efflux pumps, these new dosage forms counteracting the reduction in uptake.
  • the invention disclosed here relates to the field of pharmaceutical technology and is based on completely novel dosage forms which, in addition to the respective active ingredient, contain at least one adjuvant which has a large number of thiol groups in its chemical structure.
  • Permeation studies have shown completely unexpectedly that efflux pumps can be very efficiently inhibited on mucous membranes by the addition of such polythiol compounds. This effect can be further enhanced by the additional use of glutathione. Furthermore, glutathione per se shows a marked inhibitory effect against efflux pumps on mucous membranes.
  • these may preferably have a molecular weight of more than 2 kDa, but in particular more than 100 kDa.
  • Glutathione is generally scarcely absorbed by mucous membranes [Langoth N., Deve- lopment of Buccal Drug Delivery Systems for Peptide Drugs, Dissertation, University of Vienna, 2003].
  • dosage forms which contain polythiol compounds and / or glutathione in addition to the active ingredient, matrix tablets, eye drops and microparticles have been developed. Only through the combined use of active ingredients and excipients in the appropriate Darreichungs ⁇ form the desired effect can be achieved.
  • compositions which contain glutathione as stabilizer are described inter alia in WO 95/19177 A, JP 1/203336 A, JP 1/022817 A and JP 57/058616 A.
  • the present invention accordingly also relates to pharmaceutical dosage forms for improved drug absorption, these containing one or more active substances whose absorption via mucous membranes is reduced by efflux pumps, as well as glutathione or a derivative thereof and / or at least one compound contained as an adjuvant, which is composed of not more than 10 different subunits and having at least 10 covalently bonded thiol groups in their structure.
  • the pharmaceutical dosage forms according to the invention contain, in addition to glutathione or a derivative, thereof and / or in addition to the polythiol compound, no further thiol compound.
  • a combination of glutathione or a derivative thereof and a polythiol compound is particularly preferred since this combination has a particularly good action with regard to the inhibition of efflux pumps.
  • the present invention is suitable for all active substances whose uptake is hindered or at least reduced by efflux pumps, but particularly preferred are compounds whose parenteral intake is disadvantageous or unpleasant for patients.
  • the tics from the group chemotherapeutic agents, antiarrhythmic agents, antibiotics, anti-inflammatories, LokalanITAhe ⁇ , hormones, antifungals, ⁇ anticoagulants, antimalarial agents, calcium channel blockers, immunosuppressants and fluorescence Rescue marker are selected, in particular the active ingredients Taxol, cyclosporin, saquinavir or ritonavir.
  • polythiol compound (s) thiol group carrying derivatives of carbomer, polymethacrylic acid, poly (D-glucosamine), cellulose and polylysines or polyarginines which have more than 10, in particular more than 100, thiol groups in their structure are preferred embodiments of the present invention. These have an outstanding effect on the inhibition of the efflux pumps and thus the active substances in these dosage forms can be taken up particularly well and in high doses.
  • the polythiol compound (s) used preferably have a molecular weight which is greater than 2 kDa, in particular greater than 100 kDa.
  • Preferred dosage forms according to the present invention include nanoparticles, microparticles, matrix tablets, emulsions, solutions, suspensions, eye drops or capsules, as well as pharmaceutical dosage forms which are prepared for oral, nasal, pulmonary, vaginal, buccal, rectal and ocular administration.
  • the present invention relates to the use of pharmaceutically acceptable thiol group-containing compounds for the production of medicaments for inhibiting efflux pumps, the medicaments containing active substances whose mucosal uptake is hindered by efflux pumps, if the thiol group-containing compounds are missing.
  • a combination medicine comprising at least two active ingredient components: a first component which comprises a specific active ingredient for a specific purpose for the prevention or treatment of a particular disease or disorder of an individual; and a second component which ensures that the efflux pumps, which counteract uptake of the first component, are inhibited, so that the first component can be absorbed more efficiently into the body of the individual.
  • Preferred efflux pumps which can be inhibited by the present invention are those described as pharmaceutically relevant. Particularly preferred is the inhibition of P-glycoprotein, ABCG2, ABCCl and ABCC2, in particular of P-glycoprotein. Accordingly, either the effective dose of the first component in the body can be increased or the amount of this first component in a particular drug can be reduced without thereby reducing effectiveness.
  • the active ingredient or a composition of active ingredients is provided as the first component, the (usually) absorption of which is reduced by efflux pumps (ie without the presence of the thiol group-containing compounds to be used according to the invention).
  • the compounds are expelled from the individual via the mucous membranes or other biological separating layers which have efflux pumps (eg blood-brain barrier, tumor cells, etc.) (systemically or locally). be supplied).
  • efflux pumps eg blood-brain barrier, tumor cells, etc.
  • this reflux of the active ingredient is now inhibited or reduced and an increased uptake of the active ingredient occurs (compared with the intake without thiol group-containing compound).
  • an efflux rate secretory permeation coefficient / absorptive permeation coefficient
  • an efflux rate secretory permeation coefficient / absorptive permeation coefficient
  • Particularly suitable thiol group-containing compounds according to the invention have a molecular weight of at least 250 g / mol. Compounds which have a lower molecular weight are less advantageous in their thiol group-dependent, efflux-pump-inhibiting properties.
  • the thiol group-containing compounds preferred according to the invention have, on the one hand, at least one thiol group per 1000 g / mol molecular weight, in particular at least one thiol group per 500 g / mol molecular weight. On the other hand, especially when larger molecules are used, these thiol group-containing compounds should have at least 10 thiol groups per molecule.
  • compounds may be used which are composed of one or more monomer units, wherein at least one of the monomer units is thiolierbar.
  • the thiol group-containing compounds according to the invention are composed of not more than 10 different subunits, in particular one, two or three different subunits. different monomer units.
  • Particularly suitable are compounds whose suitability as pharmaceutical formulation substances is already known and proven or their physiologically tolerated thiolated derivatives, ie those compounds which can be prepared from the known pharmaceutical formulation substances by introduction of free thiol groups.
  • Preferred thiol-containing compounds according to the invention are selected from thiolated carbomer, thiolated polymethacrylic acid, thiolated cellulose, thiolated polyglucosamines, thiolated polylysines, thiolated polyarginines or glutathione or glutathione derivatives, preferably those glutathione derivatives in which the -SH and - COOH group, in particular both -COOH groups, are obtained (for example, compounds such as Glu-Cys-Val-Gly, Glu-Cys-Lys-Gly, Glu-Cys-Ala-Cys-Gly).
  • the present combination drug is also administered as a mixture of drug and thiol group containing compound (in an efficient dose to achieve both sufficient effect and sufficient efflux pump inhibition), used in separate form (or eg as a kit ) is also possible, in which the active ingredient and the efflux pump inhibitors are administered separately.
  • Fig. 1 Results of permeation studies with rhodamine 123; Transport through the mucous membrane in the absorptive direction (apical to basolateral, black symbols) and in the lateral direction (basolateral to apical, white symbols) in the absence (... O) or presence (.PHI., .DELTA.) Of glutathione in a concentration of 0.5% (m / v);
  • Fig. 2 Results of permeation studies with rhodamine 123; Transport through the mucous membrane in the absorptive direction (apical to basolateral, black symbols) and in the lateral direction (basolateral to apical, white symbols) in the absence (B 7 O) or presence (+, A) of poly (D-glucosamine) cysteine in a concentration of 0.5% (m / v);
  • Fig. 3 Results of permeation studies with rhodamine 123; Transport through the mucosa in the absorptive direction (apical to basolateral, black symbols) and in the lateral direction (basolateral to apical, white symbols) in the absence (B, O) or presence (+, A) of poly (D. Glucosamine) cysteine (0.5%, m / v) in combination with glutathione (0.5%, m / v).
  • the small intestine of guinea pigs was taken immediately after the animals were euthanized, cut lengthwise and washed in sterile 0.9% saline. Subsequently, this was clamped in Ussing chambers.
  • the incubation a buffer was used containing 250 mM NaCl, 2.6 mM MgSO 4, 10 mM KCl, 40 mM glucose, 50 mM NaHCO 3 and 50 mM Bis-Tris buffer pH 6.0 containing.
  • the Ussing chambers were gassed with a mixture of 95% .O 2 and 5% CO 2 and kept at a temperature of 37 ° C.
  • rhodamine 123 was described in the literature as the substrate for the efflux pump P-glycoprotein [eg: Tang F, Ouyang H, Yang JZ, Borchardt RT, Bidirectional transport of rhodamine 123 and Hoechst 33342 , fluorescence probes of the binding sites on P-glycoprotein, across MDCK-MDRl cell monolayers. J Pharm Be. 2004 May; 93 (5): 1185-94] at a final concentration of 0.001% (w / v) in the donor compartment facing the apical side of the mucosa.
  • FIG. 1 The results of these permeation studies are shown in FIG.
  • the values shown relate to the percentage of rhodamine used (0.001%, w / v) which is able to permeate the mucous membrane.
  • the values are the mean values ⁇ standard deviation from at least 3 test repetitions.
  • cyclosporin swollen with 1 g of the polythiol compound carbomer cysteine (MucoBiomer, Leobendorf, A) in demineralized water. Subsequently, 100 ml of this solution were precipitated in one liter of acetone and the precipitate was washed several times with acetone. Subsequently, it was lyophilized and finely ground the coagulum in the mortar. The corresponding microparticles had a size in the middle micron range and showed good drug release.
  • carbomer cysteine MocoBiomer, Leobendorf, A
  • erythromycin 0.3 g are dissolved with 0.1 g of poly (D-glucosamine) -crystal (MucoBiomer GmbH, Leobendorf, A) and 0.5 g of glutathione (Sigma, Vienna, A) in 100 ml of water for injection purposes. Following this, isotonicity was introduced by addition of NaCl. provides. The solution was germ-filtered and bottled in 10 ml eye dropper bottles.

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  • Health & Medical Sciences (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • General Health & Medical Sciences (AREA)
  • Chemical & Material Sciences (AREA)
  • Medicinal Chemistry (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Veterinary Medicine (AREA)
  • Animal Behavior & Ethology (AREA)
  • Public Health (AREA)
  • Epidemiology (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Engineering & Computer Science (AREA)
  • Proteomics, Peptides & Aminoacids (AREA)
  • Immunology (AREA)
  • Molecular Biology (AREA)
  • Gastroenterology & Hepatology (AREA)
  • Organic Chemistry (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • General Chemical & Material Sciences (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • Zoology (AREA)
  • Communicable Diseases (AREA)
  • Oncology (AREA)
  • Ophthalmology & Optometry (AREA)
  • Medicinal Preparation (AREA)
  • Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
EP05771836A 2004-07-22 2005-07-14 Verwendung von thiolgruppen-haltigen verbindungen als efflux-pumpen-hemmer Withdrawn EP1768676A1 (de)

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
AT12502004 2004-07-22
PCT/EP2005/053395 WO2006008270A1 (de) 2004-07-22 2005-07-14 Verwendung von thiolgruppen-hältigen verbindungen als efflux-pumpen-hemmer

Publications (1)

Publication Number Publication Date
EP1768676A1 true EP1768676A1 (de) 2007-04-04

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EP05771836A Withdrawn EP1768676A1 (de) 2004-07-22 2005-07-14 Verwendung von thiolgruppen-haltigen verbindungen als efflux-pumpen-hemmer

Country Status (7)

Country Link
US (1) US20080200563A1 (enrdf_load_stackoverflow)
EP (1) EP1768676A1 (enrdf_load_stackoverflow)
JP (1) JP2008506750A (enrdf_load_stackoverflow)
CN (1) CN101035547A (enrdf_load_stackoverflow)
AU (1) AU2005263729B2 (enrdf_load_stackoverflow)
CA (1) CA2574232A1 (enrdf_load_stackoverflow)
WO (1) WO2006008270A1 (enrdf_load_stackoverflow)

Families Citing this family (14)

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Publication number Priority date Publication date Assignee Title
ES2391862T3 (es) 2006-12-22 2012-11-30 Croma-Pharma Gesellschaft M.B.H. Uso de polisacaridos tiolados para el aumento de tejido
CN102216381B (zh) 2008-04-24 2016-06-15 麦德托尼克公司 可再水化的多糖颗粒和海绵体
US9433636B2 (en) 2008-04-24 2016-09-06 Medtronic, Inc. Protective gel based on chitosan and oxidized polysaccharide
WO2009132228A1 (en) 2008-04-24 2009-10-29 Medtronic, Inc. Chitosan-containing protective composition
AU2009240509B2 (en) 2008-04-24 2014-08-21 Medtronic, Inc. Rehydratable thiolated polysaccharide particles and sponge
RU2537181C2 (ru) 2009-03-12 2014-12-27 Нордик Байосайенс А/С Лечение диабета и метаболического синдрома
WO2013067357A1 (en) 2011-11-02 2013-05-10 Nu-Co Development Gmbh Peptide analogs for treating diseases and disorders
ES2586805T3 (es) 2011-11-02 2016-10-19 Keybioscience Ag Análogos de péptidos para tratar enfermedades y trastornos
DK3321278T3 (en) 2013-11-14 2019-03-25 Keybioscience Ag CALCITONIN MIMETICS FOR THE TREATMENT OF DISEASES AND DISORDERS
GB201500263D0 (en) 2015-01-08 2015-02-25 Keybioscience Ag Calcitonin analogues for treating diseases and disorders
GB201704429D0 (en) 2017-03-21 2017-05-03 Keybioscience Ag Calcitonin mimetics for treating diseases and disorders
GB201707955D0 (en) 2017-05-18 2017-07-05 Keybioscience Ag Dual amylin and calcitonin receptor agonists for treating diseases and disorders
GB201813677D0 (en) 2018-08-22 2018-10-03 Keybioscience Ag Calcitonin mimetics for treating diseases and disorders
GB201813678D0 (en) 2018-08-22 2018-10-03 Keybioscience Ag Acylated calcitonin mimetics

Family Cites Families (7)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
SE420733B (sv) * 1974-05-30 1981-10-26 Exploaterings Ab Tbf Gelprodukt, innehallande tiosulfatgrupper samt sett for framstellning derav
US5618823A (en) * 1992-06-24 1997-04-08 Boehringer Mannheim Italia S.P.A. Glutathione as chemoprotective agent
US5523316A (en) * 1994-06-23 1996-06-04 Alcon Laboratories, Inc. Intraocular irrigating solution containing agent for controlling IOP
IT1282625B1 (it) * 1996-02-14 1998-03-31 Zambon Spa Composizione farmaceutica atta ad inibire la formazione di metastasi tumorali
US5696152A (en) * 1996-05-07 1997-12-09 Wisconsin Alumni Research Foundation Taxol composition for use as organ preservation and cardioplegic agents
GB0017060D0 (en) * 2000-07-11 2000-08-30 Hunter Fleming Ltd Production, stabilisation and use of reduced forms of pharmaceutical compounds
JP4827385B2 (ja) * 2004-04-07 2011-11-30 ロート製薬株式会社 アズレン含有水性液剤

Non-Patent Citations (1)

* Cited by examiner, † Cited by third party
Title
See references of WO2006008270A1 *

Also Published As

Publication number Publication date
JP2008506750A (ja) 2008-03-06
AU2005263729B2 (en) 2011-01-06
CN101035547A (zh) 2007-09-12
WO2006008270A1 (de) 2006-01-26
AU2005263729A1 (en) 2006-01-26
US20080200563A1 (en) 2008-08-21
CA2574232A1 (en) 2006-01-26

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