WO2003076474A1 - Process for the physical depolymerization of glycosaminoglycanes and products obtained therefrom - Google Patents
Process for the physical depolymerization of glycosaminoglycanes and products obtained therefrom Download PDFInfo
- Publication number
- WO2003076474A1 WO2003076474A1 PCT/EP2003/002462 EP0302462W WO03076474A1 WO 2003076474 A1 WO2003076474 A1 WO 2003076474A1 EP 0302462 W EP0302462 W EP 0302462W WO 03076474 A1 WO03076474 A1 WO 03076474A1
- Authority
- WO
- WIPO (PCT)
- Prior art keywords
- glycosaminoglycanes
- heparin
- organic compound
- depolymerization
- radiation
- Prior art date
Links
Classifications
-
- C—CHEMISTRY; METALLURGY
- C08—ORGANIC MACROMOLECULAR COMPOUNDS; THEIR PREPARATION OR CHEMICAL WORKING-UP; COMPOSITIONS BASED THEREON
- C08B—POLYSACCHARIDES; DERIVATIVES THEREOF
- C08B37/00—Preparation of polysaccharides not provided for in groups C08B1/00 - C08B35/00; Derivatives thereof
- C08B37/006—Heteroglycans, i.e. polysaccharides having more than one sugar residue in the main chain in either alternating or less regular sequence; Gellans; Succinoglycans; Arabinogalactans; Tragacanth or gum tragacanth or traganth from Astragalus; Gum Karaya from Sterculia urens; Gum Ghatti from Anogeissus latifolia; Derivatives thereof
- C08B37/0063—Glycosaminoglycans or mucopolysaccharides, e.g. keratan sulfate; Derivatives thereof, e.g. fucoidan
-
- C—CHEMISTRY; METALLURGY
- C08—ORGANIC MACROMOLECULAR COMPOUNDS; THEIR PREPARATION OR CHEMICAL WORKING-UP; COMPOSITIONS BASED THEREON
- C08B—POLYSACCHARIDES; DERIVATIVES THEREOF
- C08B37/00—Preparation of polysaccharides not provided for in groups C08B1/00 - C08B35/00; Derivatives thereof
- C08B37/006—Heteroglycans, i.e. polysaccharides having more than one sugar residue in the main chain in either alternating or less regular sequence; Gellans; Succinoglycans; Arabinogalactans; Tragacanth or gum tragacanth or traganth from Astragalus; Gum Karaya from Sterculia urens; Gum Ghatti from Anogeissus latifolia; Derivatives thereof
- C08B37/0063—Glycosaminoglycans or mucopolysaccharides, e.g. keratan sulfate; Derivatives thereof, e.g. fucoidan
- C08B37/0069—Chondroitin-4-sulfate, i.e. chondroitin sulfate A; Dermatan sulfate, i.e. chondroitin sulfate B or beta-heparin; Chondroitin-6-sulfate, i.e. chondroitin sulfate C; Derivatives thereof
-
- C—CHEMISTRY; METALLURGY
- C08—ORGANIC MACROMOLECULAR COMPOUNDS; THEIR PREPARATION OR CHEMICAL WORKING-UP; COMPOSITIONS BASED THEREON
- C08B—POLYSACCHARIDES; DERIVATIVES THEREOF
- C08B37/00—Preparation of polysaccharides not provided for in groups C08B1/00 - C08B35/00; Derivatives thereof
- C08B37/006—Heteroglycans, i.e. polysaccharides having more than one sugar residue in the main chain in either alternating or less regular sequence; Gellans; Succinoglycans; Arabinogalactans; Tragacanth or gum tragacanth or traganth from Astragalus; Gum Karaya from Sterculia urens; Gum Ghatti from Anogeissus latifolia; Derivatives thereof
- C08B37/0063—Glycosaminoglycans or mucopolysaccharides, e.g. keratan sulfate; Derivatives thereof, e.g. fucoidan
- C08B37/0072—Hyaluronic acid, i.e. HA or hyaluronan; Derivatives thereof, e.g. crosslinked hyaluronic acid (hylan) or hyaluronates
-
- C—CHEMISTRY; METALLURGY
- C08—ORGANIC MACROMOLECULAR COMPOUNDS; THEIR PREPARATION OR CHEMICAL WORKING-UP; COMPOSITIONS BASED THEREON
- C08B—POLYSACCHARIDES; DERIVATIVES THEREOF
- C08B37/00—Preparation of polysaccharides not provided for in groups C08B1/00 - C08B35/00; Derivatives thereof
- C08B37/006—Heteroglycans, i.e. polysaccharides having more than one sugar residue in the main chain in either alternating or less regular sequence; Gellans; Succinoglycans; Arabinogalactans; Tragacanth or gum tragacanth or traganth from Astragalus; Gum Karaya from Sterculia urens; Gum Ghatti from Anogeissus latifolia; Derivatives thereof
- C08B37/0063—Glycosaminoglycans or mucopolysaccharides, e.g. keratan sulfate; Derivatives thereof, e.g. fucoidan
- C08B37/0075—Heparin; Heparan sulfate; Derivatives thereof, e.g. heparosan; Purification or extraction methods thereof
-
- C—CHEMISTRY; METALLURGY
- C08—ORGANIC MACROMOLECULAR COMPOUNDS; THEIR PREPARATION OR CHEMICAL WORKING-UP; COMPOSITIONS BASED THEREON
- C08B—POLYSACCHARIDES; DERIVATIVES THEREOF
- C08B37/00—Preparation of polysaccharides not provided for in groups C08B1/00 - C08B35/00; Derivatives thereof
- C08B37/006—Heteroglycans, i.e. polysaccharides having more than one sugar residue in the main chain in either alternating or less regular sequence; Gellans; Succinoglycans; Arabinogalactans; Tragacanth or gum tragacanth or traganth from Astragalus; Gum Karaya from Sterculia urens; Gum Ghatti from Anogeissus latifolia; Derivatives thereof
- C08B37/0063—Glycosaminoglycans or mucopolysaccharides, e.g. keratan sulfate; Derivatives thereof, e.g. fucoidan
- C08B37/0075—Heparin; Heparan sulfate; Derivatives thereof, e.g. heparosan; Purification or extraction methods thereof
- C08B37/0078—Degradation products
Definitions
- Glycosaminoglycanes are natural products of large pharmaceutical interest. Among the most widely used we can mention heparin, dermatan, hep aransulp hate and chondroitines.
- the molecular weight of the natural products varies considerably and normally ranges from 5 to 40 kDa. It is however known that for certain applications lower molecular weights lead to higher pharmacological activity. The high molecular weight of these compounds often renders impossible their oral administration. Furthermore, it is known that specific activities of glycosaminoglycanes are related to relatively short saccharide sequences. Thus, it would be very advantageous to depolymerize glycosaminoglycanes reducing the molecular weight without loosing the active sites present in the molecule. The chemical depolymerization of glycosaminoglycanes is well known in the art and leads to glycosaminoglycanes of lower MW but also with a lower S content.
- EP 394 971 discloses an enzymatic or chemical depolymerization process.
- the obtained heparin oligomers have a sulphur content lower than 9%.
- WO 90/04607 discloses a depolymerization of heparin and dermatansulfate by the use of H 2 O and Cu 2+ .
- the ratio SO 3 7COO " is slightly lower than in the starting heparin.
- US 4,987,222 discloses a method for the depolymerization of heparin by the use of gamma rays.
- the examples disclose the preparation of heparin of Mw around 5,000 Da and with a high S content.
- the heparin produced by this method presents a certain amount of degradation products as a result of uncontrolled side reactions.
- the patent shows a direct relationship between the amount of radiation and the reduction in
- the present invention relates to a physical process for the depolymerization of glycosaminoglycanes in the presence of an organic compound selected from ethers, alcohols, aldeheides, amides and formic acid.
- the present invention provides a physical depolymerization process which reduces the molecular weight of glycosaminoglycanes without substantially modifying the chemical structure of the same.
- heparin as a starting material, this process results in a low to ultra-low molecular weight heparin characterized by low absorbance at 400 nm and high S content.
- the ratio SO 3 7COO " of the depolymerized glycosaminoglycanes according to the invention is higher than the ratio of the starting glycosaminoglycanes; in the case of heparin, it is preferably higher than 2.3, more preferably higher than 2.35.
- the starting materials to be used in the process according to the present invention are natural glycosaminoglycanes such as heparin, heparansulphate, dermatane and chondroitine.
- Other suitable starting materials are derivatives of glycosaminoglycanes obtained by known methods.
- N-acetyl or N-sulphate groups of the residues of hexosamine can be transformed in amino groups through N-desulphation or N-deacetylation reactions and the sulphate groups of the uronic acids through desulphation reactions can give rise to epoxy groups.
- glycosaminoglycane which has already undergone a depolymerization process either chemical or enzymatic or by high-energy radiation.
- the use of partly depolymerized glycosaminoglycanes is for example relevant in case of heparin which has undergone an acid pretreatment that has as a side effect partial depolymerization, or when depolymerizing functionalized glycosaminoglycanes.
- the conditions used for the introduction of functional groups are sometimes also causing reduction of the molecular weight of the polysaccharide.
- micro-heparins M w around 1,200-1,600 Da
- the process of the present invention allows reduction of the molecular weight of the glycosaminoglycane without sensible modification of the chemical structure of the polysaccharide. More specifically, the process of the present invention is characterized by a S content of the low-ultra low molecular weight glycosaminoglycane equal to or higher than the original glycosaminoglycane together with an absorbance at 400 nm preferably lower than 0.300, most preferably lower than 0.200.
- the high-energy radiation used to depolymerize the glycosaminoglycanes can be any radiation which results in the generation of radical on the glycosaminoglycanes; the preferred radiation is gamma radiation, preferably obtained from the following sources: Co Am Cs and Ra; the most preferred gamma radiation is the one obtained from 60 Co as a source. 60 Co has an half life time of 5.3 years and emits two photons with an energy of 1.17 and 1.33 MeN.
- the amount of radiation used in the depolymerization process depends on several factors: the type of glycosaminoglycanes, the desired final Mw, the amount and type of organic compound used. In general, the amount of radiation will vary in the range 50-
- 300 kGy preferably 100-250 kGy, more preferably 120-200 kGy.
- the structure of the glycosaminoglycane influences the efficiency of the depolymerization process.
- the higher the sulfur content the higher the amount of radiation required for the same reduction of molecular weight.
- an increase in the amount of organic compound requires an increase in the amount of radiation to obtain the same reduction of Mw.
- the organic compound according to the invention is selected from the group consisting of alcohols, ethers, aldehydes, amides and formic acid.
- the organic compound is selected from compounds of formula I, II and III.
- each R is independently selected from the group consisting of H, OH, CHO, C ⁇ -C 6 alkyl and acyl, optionally substituted by oxygen atoms; two R groups optionally join together to form a ring.
- alcohols are: methanol, ethanol, n-propanol, isopropanol, n- butanol, isobutanol, glycerol.
- ethers are: tetrahydrofurane, dioxane, diethylether, tertbutylmethylether. dioxolane.
- aldehydes are formaldehyde, glyoxal, acetaldehyde or stabilized forms thereof (trioxane, glyoxal trimeric dihydrate).
- amides are: N,N-dimethylformamide, N,N-dimethylacetamide,
- glycosaminoglycane in the solution to be submitted to radiation can vary in a broad range. Preferably it is comprised between 2 and 25% w/v, more preferably between 5 and 15%.
- the amount of organic compound according to the invention depends on several parameters, but it is generally comprised between 0.1 and 5%. When using an amount of radiation up to 100 kGy, the preferred amount of organic compound is comprised between 0.1 and 1%, while in the case of amount of radiation higher than lOOkGy, the preferred amount of organic compound is comprised between 0.2 and 2%.
- the solutions are optionally discolored either by using an oxidizing treatment or by passing them on proper resins.
- the solution is then generally purified by precipitation in hydrophilic solvent.
- the obtained paste can be redissolved in water and lyophilized by vacuum distillation.
- the system which conveys the products around the source is a "multipass" type: the containers go around a number of times which is directly proportional to the dose the product is to be subjected to.
- the product receives a dose of about 25 kGy.
- the time taken to complete the route once depends on the power (or activity) of the radioactive source; it is periodically adjusted following the natural decay of the source, or taking into account additions of radioactive isotope.
- Anti Xa activity was determined according to the method described in European Pharmacopoeia 4 th ed.: 2.2.30 and 2.2.46 for chromatography techniques and 01/2002:0828 p.1297 for method.
- Sulfate and carboxylate ions were determined by conductimetric techniques according to European Pharmacopoeia 4 th ed.: 2.2.38 and 01/2002:0828 p.1297 for method.
- the intermediate depolymerized heparin was dissolved in a buffer solution and fractionated by Gel Permeation for obtaining the desired Molecular Weight.
- Sodium heparin (100 g, Mw 13,500 Da) was dissolved in 11 of bi-distilled water containing 4 ml of isopropyl alcohol. The solution was poured in a 1.5 1 pyrex glass container, purged with argon and hermetically sealed. The container was irradiated with a total amount of 180 kGy using a 60 Co radiation source. The irradiated solution presented a dark yellow color. It was discolored by adding an oxidative substance, like hydrogen peroxide. The solution was kept at pH 8-8.5 by addition of NaOH 32% and under intensive stirring for 7 h.
- the pH of the solution is then adjusted to 6.5 by using HC1 10%, then treated with
- the intermediate depolymerized heparin was dissolved in a buffer solution and fractionated by Gel Permeation for obtaining the desired Molecular Weight
- the clear solution was neutralized and directly precipitated with acetone.
- the light paste was dissolved in water, distilled off under vacuum and spay-dried.
- the intermediate depolymerized dermatandsulfate presented the following characteristics:
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- Chemical & Material Sciences (AREA)
- Health & Medical Sciences (AREA)
- Life Sciences & Earth Sciences (AREA)
- Biochemistry (AREA)
- Molecular Biology (AREA)
- Engineering & Computer Science (AREA)
- General Health & Medical Sciences (AREA)
- Materials Engineering (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Medicinal Chemistry (AREA)
- Polymers & Plastics (AREA)
- Organic Chemistry (AREA)
- Dermatology (AREA)
- Polysaccharides And Polysaccharide Derivatives (AREA)
- Preparation Of Compounds By Using Micro-Organisms (AREA)
Abstract
Description
Claims
Priority Applications (9)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
EP03711967A EP1404720B1 (en) | 2002-03-12 | 2003-03-11 | Process for the physical depolymerization of glycosaminoglycanes and products obtained therefrom |
DK03711967T DK1404720T3 (en) | 2002-03-12 | 2003-03-11 | Process for the physical depolymerization of glycosaminoglycans and products obtained therefrom |
AU2003218725A AU2003218725A1 (en) | 2002-03-12 | 2003-03-11 | Process for the physical depolymerization of glycosaminoglycanes and products obtained therefrom |
JP2003574689A JP4440650B2 (en) | 2002-03-12 | 2003-03-11 | Process for the physical depolymerization of glycosaminoglycans and the products obtained thereby |
DE60300877T DE60300877T2 (en) | 2002-03-12 | 2003-03-11 | PROCESS FOR DEPOLYMERIZING GLYCOSAMINOGLYCANES AND PRODUCTS MANUFACTURED THEREFOR |
AT03711967T ATE298349T1 (en) | 2002-03-12 | 2003-03-11 | METHOD FOR DEPOLYMERIZING GLYCOSAMINOGLYCANS AND PRODUCTS PRODUCED THEREFORE |
CA002446695A CA2446695C (en) | 2002-03-12 | 2003-03-11 | Process for the physical depolymerization of glycosaminoglycanes and products obtained therefrom |
US10/477,293 US7091337B2 (en) | 2002-03-12 | 2003-03-11 | Process for the physical depolymerization of glycosaminoglycanes and products obtained therefrom |
SI200330075T SI1404720T1 (en) | 2002-03-12 | 2003-03-11 | Process for the physical depolymerization of glycosaminoglycanes and products obtained therefrom |
Applications Claiming Priority (2)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
EP02425142A EP1344781A1 (en) | 2002-03-12 | 2002-03-12 | Process for the depolymerization of glycosaminoglycanes and products obtained therefrom |
EP02425142.3 | 2002-03-12 |
Publications (1)
Publication Number | Publication Date |
---|---|
WO2003076474A1 true WO2003076474A1 (en) | 2003-09-18 |
Family
ID=27763488
Family Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
PCT/EP2003/002462 WO2003076474A1 (en) | 2002-03-12 | 2003-03-11 | Process for the physical depolymerization of glycosaminoglycanes and products obtained therefrom |
Country Status (12)
Country | Link |
---|---|
US (1) | US7091337B2 (en) |
EP (2) | EP1344781A1 (en) |
JP (1) | JP4440650B2 (en) |
AT (1) | ATE298349T1 (en) |
AU (1) | AU2003218725A1 (en) |
CA (1) | CA2446695C (en) |
DE (1) | DE60300877T2 (en) |
DK (1) | DK1404720T3 (en) |
ES (1) | ES2244929T3 (en) |
PT (1) | PT1404720E (en) |
SI (1) | SI1404720T1 (en) |
WO (1) | WO2003076474A1 (en) |
Cited By (3)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
EP1524276A1 (en) * | 2003-10-16 | 2005-04-20 | Laboratori Derivati Organici S.P.A. | Multistep process for the physical depolymerization of heparin and products obtained therefrom |
EP1792621A1 (en) | 2005-11-30 | 2007-06-06 | Debiopharm S.A. | Orally administrable heparin derivatives |
US7939512B2 (en) * | 2004-10-13 | 2011-05-10 | Laboratori Derivati Organici Spa | Multistep process for the physical depolymerization of heparin and products obtained therefrom |
Families Citing this family (2)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
EP1475391A1 (en) * | 2003-05-09 | 2004-11-10 | Laboratori Derivati Organici S.P.A. | Process for the physical depolymerization of glycosaminoglycanes and products obtained therefrom |
EP2109626A1 (en) * | 2007-01-22 | 2009-10-21 | Akzo Nobel N.V. | Process for preparing cellulose ether |
Citations (4)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
EP0269937A2 (en) * | 1986-11-24 | 1988-06-08 | MEDIOLANUM FARMACEUTICI s.r.l. | Process for the controlled preparation of low molecular weight glucosaminoglycans |
WO1990004607A2 (en) * | 1988-10-21 | 1990-05-03 | Opocrin S.P.A. Laboratorio Farmacobiologico | Novel dermatan sulfate and heparin oligosaccharides having antiatherosclerotic activity |
JP2000237294A (en) * | 1999-02-18 | 2000-09-05 | Denki Kagaku Kogyo Kk | Medical material containing hyaluronic acid gel |
WO2000069444A1 (en) * | 1999-05-14 | 2000-11-23 | Umberto Cornelli | Glycosaminoglycans having an average molecular weight equal to 2400 d suitable for the treatment of senile dementia |
Family Cites Families (1)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US6383344B1 (en) * | 2000-07-19 | 2002-05-07 | Genzyme Corporation | Molecular weight reduction of polymer using irradiation treatment |
-
2002
- 2002-03-12 EP EP02425142A patent/EP1344781A1/en not_active Withdrawn
-
2003
- 2003-03-11 DK DK03711967T patent/DK1404720T3/en active
- 2003-03-11 EP EP03711967A patent/EP1404720B1/en not_active Expired - Lifetime
- 2003-03-11 SI SI200330075T patent/SI1404720T1/en unknown
- 2003-03-11 DE DE60300877T patent/DE60300877T2/en not_active Expired - Lifetime
- 2003-03-11 ES ES03711967T patent/ES2244929T3/en not_active Expired - Lifetime
- 2003-03-11 PT PT03711967T patent/PT1404720E/en unknown
- 2003-03-11 CA CA002446695A patent/CA2446695C/en not_active Expired - Lifetime
- 2003-03-11 AU AU2003218725A patent/AU2003218725A1/en not_active Abandoned
- 2003-03-11 WO PCT/EP2003/002462 patent/WO2003076474A1/en active IP Right Grant
- 2003-03-11 AT AT03711967T patent/ATE298349T1/en active
- 2003-03-11 US US10/477,293 patent/US7091337B2/en not_active Expired - Lifetime
- 2003-03-11 JP JP2003574689A patent/JP4440650B2/en not_active Expired - Lifetime
Patent Citations (5)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
EP0269937A2 (en) * | 1986-11-24 | 1988-06-08 | MEDIOLANUM FARMACEUTICI s.r.l. | Process for the controlled preparation of low molecular weight glucosaminoglycans |
US4987222A (en) * | 1986-11-24 | 1991-01-22 | Mediolanum Farmaceutici Spl | Process for the controlled preparation of low molecular weight glucosaminoglycans |
WO1990004607A2 (en) * | 1988-10-21 | 1990-05-03 | Opocrin S.P.A. Laboratorio Farmacobiologico | Novel dermatan sulfate and heparin oligosaccharides having antiatherosclerotic activity |
JP2000237294A (en) * | 1999-02-18 | 2000-09-05 | Denki Kagaku Kogyo Kk | Medical material containing hyaluronic acid gel |
WO2000069444A1 (en) * | 1999-05-14 | 2000-11-23 | Umberto Cornelli | Glycosaminoglycans having an average molecular weight equal to 2400 d suitable for the treatment of senile dementia |
Non-Patent Citations (5)
Title |
---|
BAQUEY C ET AL: "ESR STUDY OF GAMMA-IRRADIATED SODIUM HEPARINATE", RADIATION RESEARCH, ACADEMIC PRESS INC, US, vol. 1, no. 70, 1977, pages 82 - 90, XP008005918, ISSN: 0033-7587 * |
DATABASE CHEMABS [online] CHEMICAL ABSTRACTS SERVICE, COLUMBUS, OHIO, US; "Radiochemical destruction of cellulose and other polysaccharides", XP002209916, retrieved from STN Database accession no. 129:42412 * |
DATABASE WPI Week 200062, Derwent World Patents Index; AN 2000-641802, XP002205793, "Medicinal material used as adhesion prevention or wound treatment material, contains hyaluronic acid gel obtained by irradiating water insoluble hyaluronic acid by electron beam, gamma ray, plasma or light pulse." * |
ERSHOV B.G., USPEKHI KHIMII, vol. 67, no. 4, 1998, pages 353 - 375 * |
JOOYANDEH F ET AL: "CHEMICAL EFFECTS OF GAMMA-IRRADIATION OF AQUEOUS SOLUTIONS OF HEPARIN AND KERATAN SULPHATE", RADIATION RESEARCH, ACADEMIC PRESS INC, US, vol. 3, no. 45, 1971, pages 455 - 461, XP008005919, ISSN: 0033-7587 * |
Cited By (5)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
EP1524276A1 (en) * | 2003-10-16 | 2005-04-20 | Laboratori Derivati Organici S.P.A. | Multistep process for the physical depolymerization of heparin and products obtained therefrom |
WO2005035587A2 (en) * | 2003-10-16 | 2005-04-21 | Laboratori Derivati Organici Spa | Multistep process for the physical depolymerization of heparin and products obtained therefrom |
WO2005035587A3 (en) * | 2003-10-16 | 2005-06-16 | Derivati Organici Lab | Multistep process for the physical depolymerization of heparin and products obtained therefrom |
US7939512B2 (en) * | 2004-10-13 | 2011-05-10 | Laboratori Derivati Organici Spa | Multistep process for the physical depolymerization of heparin and products obtained therefrom |
EP1792621A1 (en) | 2005-11-30 | 2007-06-06 | Debiopharm S.A. | Orally administrable heparin derivatives |
Also Published As
Publication number | Publication date |
---|---|
US7091337B2 (en) | 2006-08-15 |
JP4440650B2 (en) | 2010-03-24 |
EP1404720B1 (en) | 2005-06-22 |
SI1404720T1 (en) | 2005-12-31 |
ES2244929T3 (en) | 2005-12-16 |
CA2446695C (en) | 2008-10-07 |
EP1404720A1 (en) | 2004-04-07 |
DK1404720T3 (en) | 2005-10-24 |
JP2005520005A (en) | 2005-07-07 |
ATE298349T1 (en) | 2005-07-15 |
AU2003218725A1 (en) | 2003-09-22 |
US20040186279A1 (en) | 2004-09-23 |
EP1344781A1 (en) | 2003-09-17 |
PT1404720E (en) | 2005-11-30 |
DE60300877D1 (en) | 2005-07-28 |
CA2446695A1 (en) | 2003-09-18 |
DE60300877T2 (en) | 2006-07-27 |
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