EP1663106A2 - Pharmaceutical composition, method of manufacturing and therapeutic use thereof - Google Patents

Pharmaceutical composition, method of manufacturing and therapeutic use thereof

Info

Publication number
EP1663106A2
EP1663106A2 EP04762305A EP04762305A EP1663106A2 EP 1663106 A2 EP1663106 A2 EP 1663106A2 EP 04762305 A EP04762305 A EP 04762305A EP 04762305 A EP04762305 A EP 04762305A EP 1663106 A2 EP1663106 A2 EP 1663106A2
Authority
EP
European Patent Office
Prior art keywords
oxaliplatin
animal origin
alcoholic
pharmaceutical composition
freeze
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Withdrawn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
EP04762305A
Other languages
German (de)
French (fr)
Inventor
Borek Zaludek
Jan Boleslav
Vladimir Kysilka
Jiri Verner
Hana Brzobohata
Bozena Matejkova
Milan Kakrda
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.)
Pliva Lachema AS
Original Assignee
Pliva Lachema AS
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 Pliva Lachema AS filed Critical Pliva Lachema AS
Publication of EP1663106A2 publication Critical patent/EP1663106A2/en
Withdrawn legal-status Critical Current

Links

Classifications

    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/0012—Galenical forms characterised by the site of application
    • A61K9/0019—Injectable compositions; Intramuscular, intravenous, arterial, subcutaneous administration; Compositions to be administered through the skin in an invasive manner
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/555—Heterocyclic compounds containing heavy metals, e.g. hemin, hematin, melarsoprol
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/06—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
    • A61K47/26—Carbohydrates, e.g. sugar alcohols, amino sugars, nucleic acids, mono-, di- or oligo-saccharides; Derivatives thereof, e.g. polysorbates, sorbitan fatty acid esters or glycyrrhizin
    • 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
    • A61K9/19—Particulate form, e.g. powders, Processes for size reducing of pure drugs or the resulting products, Pure drug nanoparticles lyophilised, i.e. freeze-dried, solutions or dispersions
    • 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
    • A61P31/12—Antivirals

Definitions

  • the invention relates to a pharmaceutical composition which is prepared by freeze-drying and contains oxaliplatin as the active component and a pharmaceutically acceptable carrier, application of this composition reducing the risk of viral contamination, especially by causers of animal spongiform encephalopathy.
  • Oxaliplatin (named according to the INN nomenclature as oxaliplatinum) has been prepared for the first time in the optically pure form in 1978 by isolation from a mixture of isomers [ J. Clin. Hematol. Oncol. 1977, 7(1), 197-210].
  • Oxaliplatin is chemically the ⁇ trans-(-)-l,2-cyclohexanediamine ⁇ -(oxalato)platinum(II) complex of formula I
  • Oxaliplatin is a cytostatic agent used in treatment of testicular and ovarial tumors, malignant melanoma, bronchogenic carcinoma and especially of metastazing colon carcinoma in combination with fiuoropyrimidines. In comparison with the hitherto used cisplatinum, oxaliplatin exhibits lower nefrotoxicity and a broader spectrum of antitumor activity. Oxaliplatin is generally applied in doses 100 to 135 mg/m 2 in the form of 2 to 6 hours' infusion. The infusion solution is prepared by dilution of the final drug form with 5% aqueous solution of glucose.
  • this dry powdery composition contains a carrier consisting of lactose which ensures the cohesion of the dry oxaliplatin matrix formed by freeze-drying in vacuo and prevents its cracking, which otherwise would result in escape of part of the oxaliplatin from vials in which the freeze-drying takes place.
  • lactose carrier which is an animal product
  • the substantial drawback of the hitherto used lactose carrier, which is an animal product is the risk of viral contamination of the pharmaceutical composition by viruses that may be present in lactose.
  • Lactose hitherto employed in oxaliplatin pharmaceutical compositions, exhibits very good cryoprotective effects and its replacement with another suitable carrier under preservation of properties of oxaliplatin lyophilizate and economy of the freeze-drying process so far has not been satisfactorily solved.
  • the pharmaceutical composition according to the present invention prepared by freeze-drying in vacuo, that contains oxaliplatin as the active component together with a pharmaceutically acceptable carrier, the said composition being characterized in that it contains at least one alcoholic sugar of non-animal origin as a carrier, the ratio of oxaliplatin to this alcoholic sugar or alcoholic sugars of non-animal origin being 1:3 to 1:7 by weight.
  • the pharmaceutical composition according to the invention contains oxaliplatin and an alcoholic sugar of non-animal origin or alcoholic sugars of non-animal origin in a ratio 1 :5 by weight.
  • the preferred alcoholic sugar of non-animal origin is mannitol.
  • the present invention also relates to the method of manufacturing of the above mentioned pharmaceutical composition, characterized in that a sterile aqueous solution of oxaliplatin and of at least one alcoholic sugar of non-animal origin, containing oxaliplatin and an alcoholic sugar of non-animal origin or alcoholic sugars of no-animal origin in a weight ratio 1:3 to 1:7 with total concentration of the mentioned compounds 2.8 to 3.2 % by weight, is introduced into a vial in a volume equal to at most 60 % of the available vial volume, whereupon the content of the vial is cooled to 2 to 8 °C, then freezed under linear temperature drop of 0.1 to 0.5 °C/min to a final temperature of -35 to -45 °C, left aside at this temperature for 1 to 6 hours and then subjected to freeze-drying in vacuo.
  • the invention also relates to the above mentioned pharmaceutical composition for application in treatment of tumors sensitive to oxaliplatin.
  • the pharmaceutical composition according to this invention affords a clear solution which contains neither undissolved material nor turbidity and which is thus particularly suitable for parenteral application.
  • the composition according to the invention can be readily prepared, is highly stable and its application does not represent any risk of viral contamination.
  • the method according to the present invention solves problems that would occur in the case of mere replacement of lactose by mannitol without changing the existing mode of working with lactose.
  • the lyophilizate often escapes from the vials and the glass vials crack as the result of increased mechanical tension due to the changing volume of the freezed solution, which is particularly manifested by falling away of the vial bottom during the freeze-drying procedure. It has been found that the temperature mode of the freezing procedure according to the invention significantly eliminates the mentioned vial cracking in the course of the freeze- drying procedure.
  • the total concentration of oxaliplatin and of at least one alcoholic sugar in the aqueous solution before the freeze-drying must be 2.8 to 3.2 % by weight.
  • the vials can be filled with the sterile solution of oxaliplatin and mannitol in the mentioned weight ratio in a volume up to 60 % of the available vial volume without change of the lyophilizate quality, without escape of the lyophilizate from the vials, and without cracking of the vials, which represents a very advantageous solution from the viewpoint of utilization of capacity of the freeze-drying equipment.
  • the pharmaceutical composition according to the invention is particularly suitable for application in treatment of tumors sensitive to oxaliplatin.
  • the solution in the vial is slowly freezed (linear temperature drop of 0.2 °C/min) to the final temperature of -40 °C.
  • the frozen solution is left at this temperature for 4 h, whereupon it is subjected to freeze-drying in vacuo.
  • the obtained lyophilizate has a white compact form and contains 0.8 % by weight of water. Dissolution of the obtained material gives a clear solution, in accord with Ph. Eur. Art. 2.2.1.
  • the solution in the vial is slowly freezed (linear temperature drop of 0.2 °C/min) to the final temperature of -40 °C.
  • the frozen solution is left at this temperature for 4 h, whereupon it is subjected to freeze-drying in vacuo.
  • Example 3 This Example studies the stability of the pharmaceutical composition prepared in Example 1 when stored at 40 °C and 75% relative humidity. The obtained results are given in Table 1 below.
  • Example 4 This Example studies the stability of the pharmaceutical composition prepared in Example 2 when stored at 40 °C and 75% relative humidity. The obtained results are given in Table 2 below.

Landscapes

  • Health & Medical Sciences (AREA)
  • Chemical & Material Sciences (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Veterinary Medicine (AREA)
  • Public Health (AREA)
  • General Health & Medical Sciences (AREA)
  • Medicinal Chemistry (AREA)
  • Animal Behavior & Ethology (AREA)
  • Epidemiology (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • General Chemical & Material Sciences (AREA)
  • Engineering & Computer Science (AREA)
  • Molecular Biology (AREA)
  • Oncology (AREA)
  • Communicable Diseases (AREA)
  • Biochemistry (AREA)
  • Organic Chemistry (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Oil, Petroleum & Natural Gas (AREA)
  • Virology (AREA)
  • Dermatology (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)
  • Medicinal Preparation (AREA)

Abstract

The invention relates to a pharmaceutical composition prepared by freeze-drying in vacuo, containing oxaliplatin as the active component and a pharmaceutically acceptable carrier, wherein the carrier is at least one alcoholic sugar of non-animal origin, the weight ratio of oxaliplatin to the alcoholic sugar of non-animal origin or alcoholic sugars of non-animal origin being 1:3 to 1:7. The invention also relates to the method of manufacturing of said composition and to the use of this composition in the treatment of tumors sensitive to oxaliplatin.

Description

Pharmaceutical Composition, Method of Manufacturing and Therapeutic Use Thereof
Field of the Invention
The invention relates to a pharmaceutical composition which is prepared by freeze-drying and contains oxaliplatin as the active component and a pharmaceutically acceptable carrier, application of this composition reducing the risk of viral contamination, especially by causers of animal spongiform encephalopathy.
Background of the Invention
Oxaliplatin (named according to the INN nomenclature as oxaliplatinum) has been prepared for the first time in the optically pure form in 1978 by isolation from a mixture of isomers [ J. Clin. Hematol. Oncol. 1977, 7(1), 197-210]. Oxaliplatin is chemically the {trans-(-)-l,2-cyclohexanediamine}-(oxalato)platinum(II) complex of formula I
Oxaliplatin is a cytostatic agent used in treatment of testicular and ovarial tumors, malignant melanoma, bronchogenic carcinoma and especially of metastazing colon carcinoma in combination with fiuoropyrimidines. In comparison with the hitherto used cisplatinum, oxaliplatin exhibits lower nefrotoxicity and a broader spectrum of antitumor activity. Oxaliplatin is generally applied in doses 100 to 135 mg/m2 in the form of 2 to 6 hours' infusion. The infusion solution is prepared by dilution of the final drug form with 5% aqueous solution of glucose.
Within the framework of the prior art there was described a series of liquid drug forms of oxaliplatin based on its aqueous solutions which however for their insufficient stability so far have not found application. The cause of this instability is the known fact that oxaliplatin hydrolytically decomposes under formation of toxic platinum aquacomplexes. The only stable drug form of oxaliplatin known so far is a powder composition obtained by freeze-drying in vacuo (lyophilization). Beside oxaliplatin, this dry powdery composition contains a carrier consisting of lactose which ensures the cohesion of the dry oxaliplatin matrix formed by freeze-drying in vacuo and prevents its cracking, which otherwise would result in escape of part of the oxaliplatin from vials in which the freeze-drying takes place. The substantial drawback of the hitherto used lactose carrier, which is an animal product, is the risk of viral contamination of the pharmaceutical composition by viruses that may be present in lactose. Recently, reduction of the risk of such viral contamination, especially of transfer of animal spongiform encephalopathy, represents a current problem concerning most drug forms that contain auxiliary components of animal, particularly bovine origin. Lactose, hitherto employed in oxaliplatin pharmaceutical compositions, exhibits very good cryoprotective effects and its replacement with another suitable carrier under preservation of properties of oxaliplatin lyophilizate and economy of the freeze-drying process so far has not been satisfactorily solved.
Summary of the Invention
The above-mentioned desired replacement of the lactose carrier with another carrier which in principle eliminates the mentioned risk of viral contamination is solved by the pharmaceutical composition according to the present invention, prepared by freeze-drying in vacuo, that contains oxaliplatin as the active component together with a pharmaceutically acceptable carrier, the said composition being characterized in that it contains at least one alcoholic sugar of non-animal origin as a carrier, the ratio of oxaliplatin to this alcoholic sugar or alcoholic sugars of non-animal origin being 1:3 to 1:7 by weight.
Preferably, the pharmaceutical composition according to the invention contains oxaliplatin and an alcoholic sugar of non-animal origin or alcoholic sugars of non-animal origin in a ratio 1 :5 by weight.
In a pharmaceutical composition according to the invention, the preferred alcoholic sugar of non-animal origin is mannitol.
The present invention also relates to the method of manufacturing of the above mentioned pharmaceutical composition, characterized in that a sterile aqueous solution of oxaliplatin and of at least one alcoholic sugar of non-animal origin, containing oxaliplatin and an alcoholic sugar of non-animal origin or alcoholic sugars of no-animal origin in a weight ratio 1:3 to 1:7 with total concentration of the mentioned compounds 2.8 to 3.2 % by weight, is introduced into a vial in a volume equal to at most 60 % of the available vial volume, whereupon the content of the vial is cooled to 2 to 8 °C, then freezed under linear temperature drop of 0.1 to 0.5 °C/min to a final temperature of -35 to -45 °C, left aside at this temperature for 1 to 6 hours and then subjected to freeze-drying in vacuo.
Finally, the invention also relates to the above mentioned pharmaceutical composition for application in treatment of tumors sensitive to oxaliplatin.
After dissolution in a suitable pharmaceutically acceptable solvent, the pharmaceutical composition according to this invention affords a clear solution which contains neither undissolved material nor turbidity and which is thus particularly suitable for parenteral application. The composition according to the invention can be readily prepared, is highly stable and its application does not represent any risk of viral contamination.
The method according to the present invention solves problems that would occur in the case of mere replacement of lactose by mannitol without changing the existing mode of working with lactose. During workup of solutions in which lactose is simply replaced with mannitol, the lyophilizate often escapes from the vials and the glass vials crack as the result of increased mechanical tension due to the changing volume of the freezed solution, which is particularly manifested by falling away of the vial bottom during the freeze-drying procedure. It has been found that the temperature mode of the freezing procedure according to the invention significantly eliminates the mentioned vial cracking in the course of the freeze- drying procedure. Thus, it was found that in order to achieve an optimal freeze-drying rate the total concentration of oxaliplatin and of at least one alcoholic sugar in the aqueous solution before the freeze-drying must be 2.8 to 3.2 % by weight. Further, it was found that the vials can be filled with the sterile solution of oxaliplatin and mannitol in the mentioned weight ratio in a volume up to 60 % of the available vial volume without change of the lyophilizate quality, without escape of the lyophilizate from the vials, and without cracking of the vials, which represents a very advantageous solution from the viewpoint of utilization of capacity of the freeze-drying equipment. For its properties, the pharmaceutical composition according to the invention is particularly suitable for application in treatment of tumors sensitive to oxaliplatin.
In the following part of the description the invention will be explained in detail using individual examples of execution, that are only illustrative, without limiting in any way the scope of the invention.
Examples
Example 1
Under GMP conditions, 0.50 kg of oxaliplatin (pharmacopoeia quality) and 2.50 kg of mannitol (pharmacopoeia quality) are gradually dissolved at 20 to 25 °C in 70 kg of water. The obtained solution is sterilized by filtration through a 0.22 μm filter and filled into colourless clear vials for antibiotics of the first hydrolytic class, type 20 H (Saint Gobain Desjonqueres) the amount of the solution corresponding to 50 mg of the dissolved active component per vial. The filled vials are equipped with stoppers for freeze-drying and placed into a freeze-drying chamber, pre-cooled to 5 °C. After thermal equilibration of the solution in the vial with the environment, the solution in the vial is slowly freezed (linear temperature drop of 0.2 °C/min) to the final temperature of -40 °C. The frozen solution is left at this temperature for 4 h, whereupon it is subjected to freeze-drying in vacuo.
The obtained lyophilizate has a white compact form and contains 0.8 % by weight of water. Dissolution of the obtained material gives a clear solution, in accord with Ph. Eur. Art. 2.2.1.
Example 2
Under GMP conditions, 0.50 kg of oxaliplatin (pharmacopoeia quality) and 2.50 kg of mannitol (pharmacopoeia quality) are gradually dissolved at 20 to 25 °C in 70 kg of water. The obtained solution is sterilized by filtration through a 0.22 μm filter and filled into colourless clear vials for antibiotics of the first hydrolytic class, type 20 H (Saint Gobain Desjonqueres) the amount of the solution corresponding to 100 mg of the dissolved active component per vial. The filled vials are equipped with stoppers for freeze-drying and placed into a freeze-drying chamber, pre-cooled to 5 °C. After thermal equilibration of the solution in the vial with the environment, the solution in the vial is slowly freezed (linear temperature drop of 0.2 °C/min) to the final temperature of -40 °C. The frozen solution is left at this temperature for 4 h, whereupon it is subjected to freeze-drying in vacuo.
The obtained lyophilizate has a white compact form and contains 1.0 % by weight of water. Dissolution of the obtained material gives a clear solution, in accord with Ph. Eur. Art. 2.2.1. Example 3 This Example studies the stability of the pharmaceutical composition prepared in Example 1 when stored at 40 °C and 75% relative humidity. The obtained results are given in Table 1 below.
Table 1
The percentages given in Table 1 are % by weight. Example 4 This Example studies the stability of the pharmaceutical composition prepared in Example 2 when stored at 40 °C and 75% relative humidity. The obtained results are given in Table 2 below.
Table 2
The percentages given in Table 2 are % by weight.

Claims

PATENT CLAIMS
1. A pharmaceutical composition prepared by freeze-drying in vacuo, containing oxaliplatin as the active component and a pharmaceutically acceptable carrier, characterized in that the carrier is at least one alcoholic sugar of non-animal origin, the weight ratio of oxaliplatin to the alcoholic sugar of non-animal origin or alcoholic sugars of non-animal origin being 1:3 to 1:7.
2. The pharmaceutical composition according to Claim 1, characterized in that it contains oxaliplatin and an alcoholic sugar of non-animal origin or alcoholic sugars of non-animal origin in a weight ratio 1:5.
3. The pharmaceutical composition according to Claims l or2, characterized in that the alcoholic sugar of non-animal origin is mannitol.
4. A method of manufacturing of pharmaceutical composition according to Claim 1, characterized in that a sterile aqueous solution of oxaliplatin and of at least one alcoholic sugar of non-animal origin, containing oxaliplatin and an alcoholic suger of non-animal origin or alcoholic sugars of non-animal origin in a weight ratio 1:3 to 1:7, with total concentration of the mentioned compounds 2.8 to 3.2 % by weight, is introduced into a vial in a volume amount equal to at most 60 vol% of the available vial volume, whereupon the content of the vial is cooled to a temperature of 2 to 8 °C, then freezed under linear temperature drop of 0.1 to 0.5 °C/min to a final temperature of -35 to -45 °C, left at this temperature for 1 to 6 hours and then subjected to freeze-drying in vacuo.
5. The pharmaceutical composition according to any of Claims 1 to 3 for use in the treatment of tumors sensitive to oxaliplatin.
EP04762305A 2003-09-02 2004-08-31 Pharmaceutical composition, method of manufacturing and therapeutic use thereof Withdrawn EP1663106A2 (en)

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
CZ20032367A CZ300795B6 (en) 2003-09-02 2003-09-02 Pharmaceutical composition and process for its preparation
PCT/CZ2004/000053 WO2005020876A2 (en) 2003-09-02 2004-08-31 Pharmaceutical composition, method of manufacturing and therapeutic use thereof

Publications (1)

Publication Number Publication Date
EP1663106A2 true EP1663106A2 (en) 2006-06-07

Family

ID=34256928

Family Applications (1)

Application Number Title Priority Date Filing Date
EP04762305A Withdrawn EP1663106A2 (en) 2003-09-02 2004-08-31 Pharmaceutical composition, method of manufacturing and therapeutic use thereof

Country Status (6)

Country Link
EP (1) EP1663106A2 (en)
CA (1) CA2537610A1 (en)
CZ (1) CZ300795B6 (en)
PL (1) PL366975A1 (en)
RU (1) RU2329052C2 (en)
WO (1) WO2005020876A2 (en)

Families Citing this family (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2008089709A2 (en) * 2007-01-22 2008-07-31 Pliva-Lachema A.S. Oxaliplatin pharmaceutical composition with alcoholic sugar-based buffer
CZ300664B6 (en) * 2007-01-22 2009-07-15 Pliva-Lachema A. S. Sterile liquid pharmaceutical composition and process for preparing thereof

Family Cites Families (7)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
GB8810173D0 (en) * 1988-04-29 1988-06-02 Norsk Hydro As Pharmaceutical compositions with anti-cancer activity & method for treatment of cancer
WO1994012193A1 (en) * 1992-11-24 1994-06-09 Debiopharm S.A. Cisplatinum/oxaliplatinum combination
FR2740686B1 (en) * 1995-11-03 1998-01-16 Sanofi Sa STABLE LYOPHILIZED PHARMACEUTICAL FORMULATION
GB9804013D0 (en) * 1998-02-25 1998-04-22 Sanofi Sa Formulations
EP1154796B1 (en) * 1999-02-22 2007-06-20 University of Connecticut Novel albumin-free factor viii formulations
HK1048266B (en) * 1999-08-30 2005-04-01 德比奥法姆股份有限公司 Pharmaceutically stable oxaliplatinum preparation for parenteral administration
DE10314377A1 (en) * 2003-03-28 2004-10-07 Stada Arzneimittel Ag Pharmaceutical composition useful for tumor therapy comprises water, oxaliplatin and an acid other than oxalic acid

Non-Patent Citations (1)

* Cited by examiner, † Cited by third party
Title
See references of WO2005020876A2 *

Also Published As

Publication number Publication date
RU2006110563A (en) 2006-08-10
PL366975A1 (en) 2005-03-07
RU2329052C2 (en) 2008-07-20
CA2537610A1 (en) 2005-03-10
CZ20032367A3 (en) 2005-04-13
WO2005020876A2 (en) 2005-03-10
CZ300795B6 (en) 2009-08-12
WO2005020876A3 (en) 2005-06-09

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