EP1446384A1 - Forme polymorphe du rimonabant, son procede de preparation et les compositions pharmaceutiques en contenant - Google Patents

Forme polymorphe du rimonabant, son procede de preparation et les compositions pharmaceutiques en contenant

Info

Publication number
EP1446384A1
EP1446384A1 EP02785580A EP02785580A EP1446384A1 EP 1446384 A1 EP1446384 A1 EP 1446384A1 EP 02785580 A EP02785580 A EP 02785580A EP 02785580 A EP02785580 A EP 02785580A EP 1446384 A1 EP1446384 A1 EP 1446384A1
Authority
EP
European Patent Office
Prior art keywords
temperature
rimonabant
methylcyclohexane
medium
concentration
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Withdrawn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
EP02785580A
Other languages
German (de)
English (en)
French (fr)
Inventor
Alain Alcade
Gilles Anne-Archard
Corinne Gavory
Olivier Monnier
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.)
Sanofi SA
Original Assignee
Sanofi Synthelabo SA
Sanofi Aventis France
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 Sanofi Synthelabo SA, Sanofi Aventis France filed Critical Sanofi Synthelabo SA
Publication of EP1446384A1 publication Critical patent/EP1446384A1/fr
Withdrawn legal-status Critical Current

Links

Classifications

    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
    • C07D401/10—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings linked by a carbon chain containing aromatic rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D231/00—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings
    • C07D231/02—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings not condensed with other rings
    • C07D231/10—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members
    • C07D231/14—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P3/00—Drugs for disorders of the metabolism
    • A61P3/04—Anorexiants; Antiobesity agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • 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 a new polymorph of N-piperidino-5- (4-chlorophenyl) -1- (2,4-dichlorophenyl) -4-methyl-3-pyrazole-carboxamide and a process for its preparation. More particularly, the invention relates to the preparation of this polymorph called form II, as well as to the pharmaceutical compositions containing it.
  • rimonabant in crystalline form which will be called form I. It has now been found that rimonabant can exist in different polymorphic crystalline forms which differ from each other by their stability, their physical properties, their spectral characteristics and their method of preparation.
  • the subject of the present invention is a new polymorphic form of rimonabant, called form II, it also relates to processes for preparing rimonabant in its polymorphic form II, as well as the pharmaceutical compositions containing said form IL
  • European patent EP 0 656 354 does makes no reference to the existence of specific polymorphic forms of rimonabant.
  • the compound is isolated according to conventional techniques; more precisely, according to the embodiments exemplified, the product is obtained after crystallization from isopropyl ether or by cooling a medium containing the product in methylcyclohexane.
  • the crystal form II of rimonabant was characterized and compared to the crystal form I previously described.
  • the infrared (IR) spectra of the 2 crystalline forms of rimonabant were recorded on Perkin Elmer System 2000 FT-IR spectrophotometers, between 400 cm-1 and 4000 cm-1, with a resolution of 4 cm-1, in a potassium bromide tablet, the test compound being at a concentration of 0.5% by mass.
  • X-ray powder diffractograms for crystal forms I and IL were recorded.
  • the crystal form rimonabant II is also characterized by its crystal structure for which the mesh parameters have been determined by X-ray diffraction on a single crystal.
  • the differential enthalpy analysis of the 2 crystal forms was carried out under the same conditions on a differential enthalpy analysis device MDSC 2920, marketed by TA Instruments SARL (PARIS); operating in a nitrogen atmosphere, the initial temperature is 30 ° C, it increases at a rate of 10 ° C / minute.
  • MDSC 2920 differential enthalpy analysis device
  • PARIS TA Instruments SARL
  • the melting peak and the difference in enthalpy of the substance ( ⁇ H) are measured before and after the fusion, in Joule per gram of material.
  • the present invention relates to the crystalline polymorph of rimonabant (form II) characterized by the absorption bands of the infrared spectrum as described in table 2. This polymorph is also characterized by the characteristic lines of the powder X-ray diffractogram as described in Table 4.
  • rimonabant form II is less soluble at all temperatures between 10 ° C and 70 ° C, this shows that rimonabant form II is thermodynamically more stable than rimonabant form I.
  • the process for obtaining the crystalline form II of rimonabant is characterized in that: a) the rimonabant is hot dissolved in a solvent chosen from:
  • the medium is cooled to a temperature between 5 ° C and 25 ° C, c) the crystals formed are filtered at a temperature between 5 ° C and 25 ° C.
  • the medium is seeded with rimonabant having the crystalline form IL
  • the rimonabant which is dissolved in step a) is the rimonabant in crystalline form I as obtained according to patent EP 0 656 354 or the rimonabant form II or a mixture of the two forms.
  • Rimonabant can also be prepared in crystalline form I directly from 5- (4-chlorophenyl) -1- (2,4-dichlorophenyl) -4-methylpyrazole-3-carboxylic acid, according to the process described in EP 0 656 354: the acid is transformed into its acid chloride by the action of thionyl chloride, then the 1-aminopiperidine is made to act in the presence of triethylamine.
  • the present invention presents several particular embodiments.
  • a particular process is characterized in that: a) the rimonabant is dissolved at a concentration of 150 to 220 g / 1, by heating to the reflux temperature of a solvent consisting of methylcyclohexane containing 1 to 10% of water, then , either steps b), c) and d) are carried out below, or steps c) and d) are carried out directly; b) the medium is cooled to a temperature between 40 ° C and 50 ° C, then the medium is warmed to a temperature between 60 ° C and 75 ° C and maintained for 2 hours; c) the temperature is lowered with a cooling ramp from -15 ° C to -20 ° C per hour to a temperature between 5 ° C and 20 ° C; d) the crystals formed are filtered at a temperature between 5 ° C and 20 ° C.
  • this process is characterized in that:
  • step a) the compound is dissolved at a concentration of 200 g / 1 in a solvent consisting of methylcyclohexane containing 1 to 5% of water, while heating to the reflux temperature of the solvent;
  • step b) the medium is cooled to 45 ° C in 30 minutes; then the medium is heated to 70 ° C + 2 ° C and the temperature is maintained for 2 hours;
  • step c) the temperature is lowered with a ramp from -15 ° C to -20 ° C per hour to a temperature between 15 ° C and 20 ° C.
  • the rimonabant is dissolved at a concentration of 50 to 250 g / 1 in a solvent consisting of pure methylcyclohexane or containing 1 to 10% of water; b) the medium is cooled to a temperature between 65 ° C and 75 ° C and left for 2 hours at this temperature; c) the medium is inoculated by adding 1% to 5% by weight of rimonabant, crystalline form II; d) the temperature is lowered with a cooling ramp from -15 ° C to -20 ° C per hour to a temperature between 10 ° C and 20 ° C; e) the crystals formed are filtered at a temperature between 10 ° C and 20 ° C.
  • this process is characterized in that:
  • the rimonabant is at a concentration of 120 to 150 g / 1;
  • step b cooling to 70 ° C;
  • step c) crystallization is initiated with 2% by weight of the rimonabant in crystalline form IL
  • Another embodiment of the process according to the invention is characterized in that: a) the rimonabant is dissolved at a concentration of 120 to 250 g / 1 by heating at the reflux temperature of the solvent which is methylcyclohexane; b) cooling to a temperature between 80 ° C and 90 ° C; c) the medium is seeded by adding 1% to 5% by weight of rimonabant in crystalline form II suspended in methylcyclohexane and the temperature is maintained for one hour between 80 ° C and 90 ° C; d) the temperature is lowered with a cooling ramp from -15 ° C to -20 ° C per hour to a temperature between 10 ° C and 20 ° C; e) the crystals formed are filtered at a temperature between 10 ° C and 20 ° C.
  • this process is characterized in that:
  • the rimonabant is dissolved at a concentration of 200 g / 1 in the solvent;
  • step b in step b), cooling to 85 ° C ⁇ 2 ° C;
  • step c) inoculated with 2% by weight of rimonabant form II, then the temperature of the medium is maintained for one hour at 85 ° C. + 2 ° C.
  • Another particular production process according to the invention is characterized in that: a) the rimonabant is dissolved at room temperature in acetonitrile, until saturation; b) allowed to evaporate at room temperature; c) collecting the crystals formed.
  • a slightly polar solvent such as pure methylcyclohexane and to obtain rimonabant in form II by using a primer of rimonabant form II for crystallization.
  • This process for preparing the compound according to the invention is characterized in that: a) the rimonabant is heated to the concentration of 150 g / 1 to 300 g / 1 in methylcyclohexane, at a temperature between 85 ° C and 95 ° VS ; b) the medium is seeded with 1% to 5% by weight of rimonabant in crystalline form II and the temperature is maintained between 85 ° C and 95 ° C for several hours until disappearance of form I; c) the temperature is lowered with a cooling ramp from -10 ° C to -20 ° C per hour to a temperature of 10 ° C to 20 ° C; d) the crystals formed are filtered at a temperature between 10 ° C and 20 ° C.
  • the rimonabant in step a) is prepared at a concentration of 150g / l to 300g / l in methylcyclohexane by treatment of 5- (4-chlorophenyl) -l- ( 2,4-dichlorophenyl) -4-methylpyrazole-3-carboxylic, with 1-aminopiperidine in a mixture of methylcyclohexane and tetrahydrofuran in the presence of triethylamine.
  • the crystalline form II of rimonabant has a higher stability than that of form I previously described.
  • the crystalline form II of rimonabant can be obtained unequivocally thanks to the process of the invention, this constitutes an advantage for the industrial manufacture of the crystalline form II of rimonabant.
  • the crystalline form II of rimonabant is particularly suitable for the manufacture of pharmaceutical compositions useful for the treatment of all diseases in which a cannabinoid receptor antagonist CBi is indicated.
  • the present invention relates to pharmaceutical compositions containing as active ingredient rimonabant in crystalline form IL
  • the active principle in the pharmaceutical compositions of the present invention for oral, sublingual, subcutaneous, intramuscular, intravenous, transdermal or local administration, can be administered in unit form of administration, in admixture with conventional pharmaceutical carriers, to animals and humans.
  • Appropriate unit administration forms including oral forms such as tablets, capsules, pills, powders, granules and oral solutions or suspensions, sublingual and oral administration forms, aerosols, implants , forms of local, transdermal, subcutaneous, intramuscular, intravenous, intranasal or intraocular administration.
  • the active principle or the active principles are generally formulated in dosage units.
  • the dosage unit contains 0.5 to 300 mg, advantageously from 5 to 60 mg, preferably from 5 to 40 mg per dosage unit, for daily administration, one or more times a day.
  • the appropriate dosage for each patient is determined by the doctor according to the mode of administration, the age, the weight and the response of said patient.
  • a mixture of pharmaceutical excipients which may be composed of diluents such as lactose, mannitol, microcrystalline cellulose, is added to the active principles, micronized or not. , starch, dicalcium phosphate, binders such as, for example, polyvinylpyrrolidone, hydroxypropylmethylcellulose, disintegrants such as crosslinked polyvinylpyrrolidone, crosslinked carboxymethylcellulose, sodium croscarmellose, flow agents such as silica, talc, lubricants such as magnesium stearate, stearic acid, glycerol tribehenenate, sodium stearyl fumarate.
  • diluents such as lactose, mannitol, microcrystalline cellulose
  • binders such as, for example, polyvinylpyrrolidone, hydroxypropylmethylcellulose, disintegrants such as crosslinked polyvinylpyrrolidone, crosslinked carboxymethylcellulose, sodium croscar
  • wetting agents or surfactants such as sodium lauryl sulfate, polysorbate 80, poloxamer 188 can be added to the formulation.
  • the tablets can be produced by different techniques, direct compression, dry granulation, wet granulation, hot melt.
  • the tablets can be naked or coated (with sucrose for example) or coated with various polymers or other suitable materials.
  • the tablets can have a flash, delayed or prolonged release by producing polymer matrices or by using specific polymers in the film coating.
  • the capsules can be soft or hard, film-coated or not so as to have a flash, prolonged or delayed activity (for example by an enteric form). They can contain not only a solid formulation formulated as above for the tablets but also liquids or semi-solids.
  • a preparation in the form of a syrup or elixir may contain the active principle or active principles together with a sweetener, preferably calorie-free, methylparaben and propylparaben as antiseptics, as well as a flavoring agent and an appropriate color.
  • the powders or granules dispersible in water can contain the active principle or the active principles in mixture with dispersing agents or agents wetting agents, or suspending agents, such as polyvinylpyrrolidone or polyvidone, as well as with sweeteners or flavor correctors.
  • Suppositories are used for rectal administration which are prepared with binders which melt at rectal temperature, for example cocoa butter or polyethylene glycols.
  • aqueous suspensions, isotonic saline solutions or sterile injectable solutions which contain pharmacologically compatible dispersing agents and or solubilizing agents, for example propylene glycol or butylene glycol.
  • a cosolvent for example an alcohol such as ethanol or a glycol such as polyethylene glycol or propylene glycol, and a hydrophilic surfactant such as polysorbate 80 or poloxamer 188
  • the active principle can be dissolved by a triglyceride or a glycerol ester.
  • creams, ointments, gels, eye drops, sprays can be used.
  • an aerosol for administration by inhalation, an aerosol is used containing, for example, sorbitan trioleate or oleic acid as well as trichlorofluoromethane, dichlorofluoromethane, dichlorotetrafluoroethane, freon substitutes or any other biologically compatible propellant; one can also use a system containing the active ingredient alone or associated with an excipient, in the form of powder.
  • the active principle or the active principles can also be presented in the form of a complex with a cyclodextrin, for example ⁇ -, ⁇ - or ⁇ -cyclodextrin, 2-hydroxypropyl- ⁇ -cyclodextrin or methyl- ⁇ -cyclodextrin.
  • a cyclodextrin for example ⁇ -, ⁇ - or ⁇ -cyclodextrin, 2-hydroxypropyl- ⁇ -cyclodextrin or methyl- ⁇ -cyclodextrin.
  • the active principle or the active principles can also be formulated in the form of microcapsules or microspheres, optionally with one or more carriers or additives.
  • implants can be used. These can be prepared in the form of an oily suspension or in the form of a suspension of microspheres in an isotonic medium.
  • the rimonabant in crystalline form II is administered orally, in a single dose per day.
  • the invention also relates to a method which consists in administering a therapeutically effective amount of rimonabant in crystalline form IL
  • EXAMPLE 1 obtaining form II without primer in methylcyclohexane at 1.64% water.
  • the reaction medium is brought to reflux in order to obtain homogenization.
  • the heating is interrupted and then the crystallization of the expected product is observed at around 40 ° C. and then left to stir at 20 ° C. + 3 ° C.
  • the crystals formed are filtered, drained and dried under vacuum at 60 ° C.
  • the reaction medium is brought to reflux, the medium is thus homogenized.
  • the heating is then stopped and then cooled to 20 ° C + 3 ° C.
  • the expected product crystallizes.
  • the crystals formed are filtered, drained and then dried under vacuum at 60 ° C.
  • the solution obtained is added over 15 minutes at 12 ° C + 3 ° C to a medium composed of 50.08 g of triethylamine, 55.10 g of 1-aminopiperidine and 460 ml of methylcyclohexane.
  • the temperature is allowed to rise to 20 ° C + 5 ° C and then the organic phase is washed successively at 70 ° C + 3 ° C with deionized water and 4% acetic acid in water.
  • the washes of the organic phase are terminated at 70 ° C. + 3 ° C. with a 1.5% NaOH solution then with deionized water and the tetrahydrofuran and the water are entrained by azeotropic distillation at atmospheric pressure.

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  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Health & Medical Sciences (AREA)
  • General Health & Medical Sciences (AREA)
  • Veterinary Medicine (AREA)
  • General Chemical & Material Sciences (AREA)
  • Medicinal Chemistry (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Animal Behavior & Ethology (AREA)
  • Public Health (AREA)
  • Engineering & Computer Science (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Child & Adolescent Psychology (AREA)
  • Diabetes (AREA)
  • Hematology (AREA)
  • Obesity (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Medicinal Preparation (AREA)
  • Steroid Compounds (AREA)
  • Plural Heterocyclic Compounds (AREA)
  • Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)
EP02785580A 2001-11-08 2002-11-04 Forme polymorphe du rimonabant, son procede de preparation et les compositions pharmaceutiques en contenant Withdrawn EP1446384A1 (fr)

Applications Claiming Priority (3)

Application Number Priority Date Filing Date Title
FR0114579 2001-11-08
FR0114579A FR2831883B1 (fr) 2001-11-08 2001-11-08 Forme polymorphe du rimonabant, son procede de preparation et les compositions pharmaceutiques en contenant
PCT/FR2002/003765 WO2003040105A1 (fr) 2001-11-08 2002-11-04 Forme polymorphe du rimonabant, son procede de preparation et les compositions pharmaceutiques en contenant

Publications (1)

Publication Number Publication Date
EP1446384A1 true EP1446384A1 (fr) 2004-08-18

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EP02785580A Withdrawn EP1446384A1 (fr) 2001-11-08 2002-11-04 Forme polymorphe du rimonabant, son procede de preparation et les compositions pharmaceutiques en contenant

Country Status (33)

Country Link
US (2) US20050043356A1 (sr)
EP (1) EP1446384A1 (sr)
JP (2) JP4181994B2 (sr)
KR (2) KR20050043774A (sr)
CN (1) CN100412063C (sr)
AP (1) AP1830A (sr)
AR (1) AR037253A1 (sr)
AU (1) AU2002350869B2 (sr)
BR (1) BR0213931A (sr)
CA (1) CA2464145A1 (sr)
CO (1) CO5580827A2 (sr)
CR (1) CR7333A (sr)
EA (1) EA006771B1 (sr)
EC (1) ECSP045088A (sr)
FR (1) FR2831883B1 (sr)
GE (1) GEP20063894B (sr)
HR (1) HRP20040403A2 (sr)
HU (1) HUP0402043A3 (sr)
IL (2) IL161533A0 (sr)
IS (1) IS7226A (sr)
MA (1) MA27080A1 (sr)
ME (1) MEP21908A (sr)
MX (1) MXPA04004394A (sr)
NO (1) NO326648B1 (sr)
NZ (1) NZ532369A (sr)
OA (1) OA12721A (sr)
PL (1) PL369372A1 (sr)
RS (1) RS36904A (sr)
TN (1) TNSN04079A1 (sr)
TW (1) TW200302824A (sr)
UA (1) UA76776C2 (sr)
WO (1) WO2003040105A1 (sr)
ZA (1) ZA200402999B (sr)

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US9238027B2 (en) 2009-01-12 2016-01-19 Fundacion Del Hospital Nacional De Paraplejicos Para La Investigacion Y La Integracion (Fuhnpaiin) Use of CB1 antagonists and/or inverse agonists for the preparation of drugs that increase motor neuron excitability

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BAUER M: "LA CRISTALLISATION DES MOLECULES CONSEQUENCES EN TERMES DE POLYMORPHISME ET FACIES APPLIQUEES AU DOMAINE PHARMACEUTIQUE CONCEPTS DE BASE", SCIENCES TECHNIQUES ET PRATIQUES STP PHARMA PRATIQUES, PARIS, FR, vol. 13, no. 2, 1 January 2003 (2003-01-01), pages 47 - 61, XP008141685, ISSN: 1157-1497 *

Cited By (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US9238027B2 (en) 2009-01-12 2016-01-19 Fundacion Del Hospital Nacional De Paraplejicos Para La Investigacion Y La Integracion (Fuhnpaiin) Use of CB1 antagonists and/or inverse agonists for the preparation of drugs that increase motor neuron excitability
US9592237B2 (en) 2009-01-12 2017-03-14 Fundacion Del Hospital Nacional De Paraplejicos Para La Investigacion Y La Integracion (Fuhnpaiin) Use of CB1 antagonists and/or inverse agonists for the preparation of drugs that increase motor neuron excitability

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EA200400491A1 (ru) 2004-12-30
MEP21908A (en) 2010-06-10
CR7333A (es) 2008-09-23
JP4931874B2 (ja) 2012-05-16
HUP0402043A3 (en) 2009-07-28
JP2005508383A (ja) 2005-03-31
IL161533A0 (en) 2004-09-27
US20100190827A1 (en) 2010-07-29
PL369372A1 (en) 2005-04-18
NO326648B1 (no) 2009-01-26
FR2831883B1 (fr) 2004-07-23
RS36904A (sr) 2006-10-27
AR037253A1 (es) 2004-11-03
JP4181994B2 (ja) 2008-11-19
EA006771B1 (ru) 2006-04-28
WO2003040105A1 (fr) 2003-05-15
GEP20063894B (en) 2006-08-10
AP1830A (en) 2008-02-22
FR2831883A1 (fr) 2003-05-09
BR0213931A (pt) 2004-09-08
TNSN04079A1 (fr) 2006-06-01
KR20090089485A (ko) 2009-08-21
NZ532369A (en) 2005-10-28
IL161533A (en) 2010-05-31
CN100412063C (zh) 2008-08-20
ZA200402999B (en) 2005-04-20
JP2009035547A (ja) 2009-02-19
UA76776C2 (uk) 2006-09-15
KR20050043774A (ko) 2005-05-11
ECSP045088A (es) 2004-06-28
MXPA04004394A (es) 2004-08-11
AP2004003024A0 (en) 2004-06-30
IS7226A (is) 2004-04-19
CO5580827A2 (es) 2005-11-30
OA12721A (fr) 2006-06-27
HRP20040403A2 (en) 2004-08-31
CA2464145A1 (en) 2003-05-15
TW200302824A (en) 2003-08-16
AU2002350869B2 (en) 2007-07-26
US20050043356A1 (en) 2005-02-24
CN1582278A (zh) 2005-02-16
NO20041879L (no) 2004-06-08
MA27080A1 (fr) 2004-12-20
NO20041879D0 (no) 2004-05-07

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