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WO2002038183A2 - Dispositifs d'administration - Google Patents

Dispositifs d'administration Download PDF

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Publication number
WO2002038183A2
WO2002038183A2 PCT/GB2001/004982 GB0104982W WO0238183A2 WO 2002038183 A2 WO2002038183 A2 WO 2002038183A2 GB 0104982 W GB0104982 W GB 0104982W WO 0238183 A2 WO0238183 A2 WO 0238183A2
Authority
WO
WIPO (PCT)
Prior art keywords
glycolic acid
polymer
solvent
active compound
pharmaceutically active
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.)
Ceased
Application number
PCT/GB2001/004982
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English (en)
Other versions
WO2002038183A3 (fr
Inventor
Ruth Elizabeth Cameron
Kirsten Joanne Dickers
Georgina Emily Milroy
Hiep Huatan
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.)
Cambridge University Technical Services Ltd CUTS
Original Assignee
Cambridge University Technical Services Ltd CUTS
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
Priority claimed from GB0027583A external-priority patent/GB0027583D0/en
Application filed by Cambridge University Technical Services Ltd CUTS filed Critical Cambridge University Technical Services Ltd CUTS
Priority to AU2002212551A priority Critical patent/AU2002212551A1/en
Publication of WO2002038183A2 publication Critical patent/WO2002038183A2/fr
Publication of WO2002038183A3 publication Critical patent/WO2002038183A3/fr
Anticipated expiration legal-status Critical
Ceased legal-status Critical Current

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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
    • A61K9/0024—Solid, semi-solid or solidifying implants, which are implanted or injected in body tissue
    • 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
    • A61K9/20—Pills, tablets, discs, rods
    • A61K9/2004—Excipients; Inactive ingredients
    • A61K9/2022—Organic macromolecular compounds
    • A61K9/2031—Organic macromolecular compounds obtained otherwise than by reactions only involving carbon-to-carbon unsaturated bonds, e.g. polyethylene glycol, polyethylene oxide, poloxamers
    • A61K9/204—Polyesters, e.g. poly(lactide-co-glycolide)

Definitions

  • the present invention relates to delivery devices for materials such as drugs based upon the biodegradable polymer, polyglycolide.
  • materials such as drugs based upon the biodegradable polymer, polyglycolide.
  • polyglycolide relates to processes for the production of polyglycolide impregnated with pharmaceutically active compounds. It also relates to methods of use of such products and further to novel implants based upon polyglycolide.
  • Various polymers are known to be suitable in this area and include polymers of lactic acid and glycolic acid. These can be polylactide (substantial homopolymer of lactic acid) , polyglycolide (substantial homopolymer of glycolic acid) or poly (lactide-co- glycolide) (copolymer of lactic acid and glycolic acid) . Also known are block copolymers containing blocks of glycolide homopolymer, as disclosed in for example US 4,429,080. Sutures formed from polyglycolide homopolymer are disclosed in US 3,297,033.
  • US 3,896,813 and US 4,024,871 each discuss sutures impregnated with antimicrobial agents. Sutures formed from silk and polyethylene terephthalate having antimicrobials impregnated therein are disclosed in US 3,896,813. US 4,024,871 discloses a variety of suture materials including homopolymers and copolymers of hydroxy carboxylic acid esters in general. The exemplified sutures are based on
  • polyester and coated with polyurethane . They are impregnated with antimicrobial .
  • Polyglycolide is suitable for use in forming implants because it exhibits convenient degradation time and is non- toxic, biocompatible and degrades to inert products which make it suitable for use in both human and veterinary medicine.
  • hitherto use of polyglycolide has been limited due to problems with processing polyglycolide to provide suitable implants.
  • Known techniques for incorporating drugs in biodegradable polymers include processes in which the polymer is melted.
  • polyglycolide has a melting temperature of above 200°C, at which many drugs are decomposed or degraded.
  • polyglycolide dissolves in very few solvents. These include hexafluoroisopropanol
  • US 3,297,033 generally discusses the inclusion of "other substances", such as dyes, antibiotics, .antiseptics, anaethestics and antioxidant in sutures but it is unclear whether these are added during polymerisation or after polymerisation. No methods of impregnation are given or exemplified.
  • US 4,429,080 generally mentions polymers containing dispersed drug for continuous administration but again no methods for obtaining this are disclosed or exemplified. Consequently, use of biodegradable polymer based drug delivery devices has previously focused upon other polymers such as polylactide and poly (lactide-co-glycolide) .
  • the intrauterine contraceptive device Progestasert (trade name, product supplied by Alza) .
  • Progestasert (trade name, product supplied by Alza)
  • This consists of a progesterone core surrounded by a cylindrical non-biodegradable polymer membrane. This releases about 60 micrograms drug per day for one year and is then replaced.
  • Norplant (trade name, product supplied by yeth-Ayerst) is another contraceptive implant, consisting of levonorgestrel-filled inert polymer capsules. These are implanted into the upper arm, so that steroid is administered continuously for up to five years. Glaucoma can be controlled by the Ocusert (trade name, product supplied by Alza) device, which is placed under the eyelid.
  • the device which has a pilocarpine core between two polymer membranes, releases drug for one week and can then be replaced. These systems are non-resorbable .
  • the product Capronor (trade name) is a capsule formed from polycaprolactone and contains the contraceptive steroid levonorgestrel . It releases drug for about one year and is completely degraded by the end of three years . Each of these types of reservoir system exhibits a release profile in which the drug is released continuously and steadily over a period of time.
  • a process for impregnating a polymer of glycolic acid selected from substantial homopolymers of glycolic acid and block copolymers comprising at least 40 mol . % glycolic acid monomer as blocks which are substantial homopolymers of glycolic acid with a pharmaceutically active compound the process comprising dissolving the pharmaceutically active compound in a solvent to form a solution of pharmaceutically active compound, contacting the solution with the polymer and allowing the solution to penetrate the polymer, characterised in that the solvent is liquid at 20°C at atmospheric pressure and is capable of penetrating the polymer and is not capable of dissolving the polymer.
  • the polymer impregnated is preferably a substantial homopolymer of glycolic acid.
  • substantially homopolymer we mean that substantially all of the monomers are glycolic acid monomers.
  • a low amount (up to 5%) of other monomers such as lactic acid may be included but preferably the amount of other monomers is not more than 3%, preferably not more than 1% (by weight based on monomer mixture) .
  • the polymer is formed from 100% glycolic acid monomer.
  • the polymer impregnated can be a block copolymer having blocks which are substantial homopolymers of glycolic acid. Preferably at least 40 mol . % of the block copolymer is formed of such blocks, more preferably at least 50%, in particular at least 55%. These polymers will be referred to below as polyglycolides .
  • the monomers are underivatised glycolic acid.
  • Derivatives of glycolic acid may also be used if appropriate but preferably the monomers are underivatised glycolic acid.
  • the homopolymer is impregnated with an additive.
  • an additive may be any suitable compound, for example therapeutically active agents and nutritional compounds for both human and veterinary use; or others such as fragrances, pesticides and biocides, etc., wherein the polymer as described in this invention could function as a carrier to control the release of the said agents.
  • Suitable therapeutically active agents are those which alter the physiological function of the target species in a beneficial or therapeutic manner. These agents are well described in the art and can be categorised according to their chemical classes such as inorganic molecules, organic heterocycles and macromolecules, for example, proteins and peptides.
  • the therapeutic agents as described in the above chemical classes have utility in the treatment of medical conditions, for example in the following categories: (1) gastrointestinal dysfunction, (2) cardiovascular diseases, (3) respiratory diseases, (4) central and peripheral nervous system diseases, (5) infective disorders, (6) inflammatory disorders, (7) oncology diseases, (8) endocrine diseases, (9) anaesthetic therapy and (10) immune • diseases or modifications.
  • the precise and predictable release kinetics afforded by the delivery systems as described in this invention render them particularly useful for the delivery of agents which have a narrow therapeutic window i.e., where the difference between the efficacious dose and toxic dose of the agent is low (ca. ⁇ 5-fold) .
  • Such agents include, in particular, those used to treat cardiovascular diseases, oncology diseases and endocrine diseases .
  • Additional benefits may also be gained in the use of these systems for the delivery of agents requiring non- continuous or pulsatile release profiles to achieve therapeutic efficacy.
  • classes therein include in particular macromolecules, such as hormonal proteins and peptides such as antiagents, antibodies, cytokines and growth promotants.
  • bioactive agents include cancer cell inhibitory molecules, antimicrobials and antivirals derived from any native, synthetic or recombinant methods.
  • Suitable nutritional compounds which are referred to in the art as “nutra-ceuticals” , include native and synthetic compounds such as vitamins, minerals, nutritional supplements and herbal agents.
  • the pharmaceutically active compound is dissolved in a solvent.
  • the solvent is capable of penetrating the polyglycolide but is not capable of dissolving the polyglycolide.
  • a solvent is considered capable of penetrating if it is capable of penetrating the polyglycolide to a degree of at least 1% measured as the mass increase when the polymer is immersed in the solvent, as a percentage of its initial mass. If it cannot penetrate to this degree it is considered incapable of penetrating.
  • a solvent is considered capable of dissolving the polyglycolide if it is capable of dissolving 0.2 grams polyglycolide in 100 ml solvent.
  • the known systems involving HFIP are such that the solvent is capable of dissolving the polyglycolide and are excluded from the present invention.
  • the solvent used in the invention is not capable of dissolving more than O.lg, more preferably not more than 0.05g, polyglycolide in 100 ml solvent .
  • the solvent is liquid at atmospheric pressure and 20°C.
  • the solvent may be an organic solvent . We have found that in some cases the solubility parameter S of the solvent can be used to predict whether it is likely to be suitable for use in the invention.
  • the solubility parameter is, in the present invention, not the only indicator of suitability, and the essential characteristics are that the solvent should be capable of penetrating but not dissolving the polyglycolide.
  • the solvent whether organic or inorganic, can have any suitable solubility parameter provided the essential requirement is met, eg the solubility parameter can be from 18 to 50.
  • solubility parameters of from 18.5 to 28.0 Mpa 12 , preferably 19.0 to 27.5 MPa 12 , are especially suitable.
  • the organic solvent is physiologically acceptable or pharmaceutically precedented.
  • the known solvents which dissolve polyglycolide, such as HFIP are excluded from this preferred class of polymers.
  • Preferred solvents include dimethylsulphoxide, ⁇ butyrolactone, N-methyl-2-pyrrolidone, dichloromethane, dimethyl malonate, propylene carbonate, acetone and chloroform, in particular dichloromethane and dimethyl malonate.
  • the pharmaceutically active compound is dissolved in the solvent to form a solution of the pharmaceutically active compound.
  • the solvent is water, which is also incapable of dissolving polyglycolide but is capable of penetrating it.
  • the polymer may be formed into any suitable form or shape prior to impregnation, according to the intended form of the final implant to be produced.
  • it may be in the form of films, sheets, membranes, rods, rings, tubes, porous structures, foams, meshes, moulded or extruded shaped objects (eg pins for bone or tissue fixation, screws or other designed shapes) , device components, staples, textiles, woven or knitted fabrics, feltworks, powders, beads, compressed tablets, monofilaments or braided sutures, and coatings.
  • Impregnation of the polyglycolide with the solution of pharmaceutically active compound is generally carried out at a temperature of from 15 to 50°C, preferably 20 to 45°C, more preferably 25 to 40°C. 50°C is the maximum preferred temperature since this minimises degradation of the pharmaceutically active compound.
  • Contact of the solution with the polyglycolide is usually carried out for not more than 5 days, preferably not more than 3 days, and often not more than one day. In some cases impregnation may take less than 12 hours or less than 6 hours .
  • the polyglycolide is dried to remove substantially all the solvent. Preferably drying is carried out at a temperature of not more than 70°C, more preferably not more than 60°C, in particular not more than 50°C. Preferably drying is carried out for not more than 1 month, more preferably not more than two weeks, and in particular not more than one week.
  • Suitable impregnation times and drying times may be selected by the person skilled in the art. In particular, impregnation and drying may be monitored by weighing the sample.
  • the polymer is preferably not subjected to melting at any stage after initiation of contact with the solution of pharmaceutically active compound, and in particular is not subjected to any temperature above 100°C, preferably not subjected to any temperature above 70°C.
  • the onset and duration of release of the pharmaceutically active compound when the product is in use can be controlled by selection of the molecular weight of the polyglycolide and the implant size and geometry, as discussed below.
  • the invention provides a convenient process for impregnating polyglycolide with drug and thus in a second aspect of the invention the product of the process of the first aspect of the invention is used as an implant.
  • a pharmaceutically active compound to the body of a human or other animal subject by placing in the body of the subject an implant comprising an impregnated substantial homopolymer of glycolic acid produced by the process of the first aspect of the invention.
  • the implant may be applied to the body of the subject in any known manner, for instance surgical insertion, by mouth or powder injection.
  • An advantage of the invention is that it is possible to achieve pulsatile release. That is, the release profile is such that in the initial stages there is little if any release of pharmaceutical active and after a period of time a large amount of active is released over a short period.
  • This type of release can advantageously be combined with an initial dose given by conventional means so that the product of the invention may be provided to give a "booster" dose of the same active or a different active.
  • the invention also allows for the achievement of non- pulsatile release.
  • a product suitable for implantation in the body of a human or other animal subject comprising a pharmaceutically active compound encapsulated by a casing which forms a barrier between the pharmaceutically active compound and the environment, wherein at least part of the barrier is formed from a membrane of substantial homopolymer of glycolic acid.
  • the reservoir devices containing pharmaceutically active compound in which the casing or barrier of the reservoir device is at least in part formed from polyglycolide.
  • the reservoir device is such that the only barrier between the pharmaceutically active compound and the environment is formed from a membrane of polyglycolide.
  • devices of this type are capable of providing an entirely different release profile from those of the known reservoir devices.
  • these devices can exhibit low or negligible drug release initially and a burst of pharmaceutically acceptable compound is released after a defined period of time.
  • the pharmaceutically active compound may be formulated in any suitable manner. Generally it is formulated with a pharmaceutically acceptable excipient . It may be in solid form (eg tablets, powders, granules) , semi-solid (eg creams, gels, ointments) or as a liquid, solution, suspension or emulsion.
  • the device may be in any suitable form, for instance a sealed tube formed from a polyglycolide membrane. It may be in the form of small capsules or packets.
  • the entire casing may be formed from polyglycolide membrane.
  • at least part of the casing may be formed from other common non-biodegradable material, provided at least part of the barrier is polyglycolide only.
  • a silicone O-ring sandwiched between two polyglycolide membranes may be used.
  • polyglycolide (PGA) powder was purchased from Medisorb Technologies International, Ohio, lot number 97-12-143. Before processing, the molecular weight was 86,300. The manufacturer's data sheet gives the intrinsic viscosity as 1.3 dL/g, the glass transition temperature as 46.2°C and the melting point as 219°C. Samples contained theophylline, a bronchodilator used in the treatment of asthma. Theophylline was obtained in an anhydrous state from Sigma-Aldrich. Sample degradation
  • PBS phosphate-buffered saline solution
  • the buffer solution was prepared from tablets purchased from Sigma- Aldrich, and contained 0.01 M phosphate buffer, 0.0027 M potassium chloride, and 0.137 M sodium chloride, with a. pH of 7.4. It was prepared with distilled water, and autoclaved at 120°C and 1 bar for 30 minutes before use.
  • the buffer solution was filled into plastic bottles, which had first been autoclaved as described above, and the samples were suspended using cotton or nylon thread, or placed in Perspex sample holders. When samples were stirred during degradation this was done using a Variomag submersible magnetic stirrer. All samples were degraded in a water bath held at 37°C.
  • PGA discs were manufactured on a Magnus compressible hot press, heated to 236 ⁇ 2°C. Circular discs (diameter 15 mm) were pressed in an aluminium mould, of thickness 0.3 mm, which was placed between sheets of aluminium foil lubricated with PTFE spray to prevent the polymer from sticking to the press.
  • An alternative method is to use a polyimide mould release film. The PGA was allowed to melt before pressing, to ensure that it filled the mould completely. The press was then closed, and the pressure was increased to 10 bar. The discs were pressed for 30 seconds, followed by immediate quenching in iced water. The samples obtained were amorphous and translucent, with a mass of approximately 80 mg. Samples prepared to any chosen size or geometry may be used, however.
  • the solvents used in the penetration tests may be compared with PGA in terms of solubility parameters.
  • the solubility parameter of PGA was calculated using two different methods as approximately 24.4 (Coleman, .M. et al (1990) Polymer 31 1187-1203) or 25.0 (van Krevelen, D. W. (1990) Properties of Polymers 3rd Edition, Elsevier) MPa 12 .
  • Those of the solvents used are listed in Table 1 (Brandrup, J & Immergut, E.H. (1989) Polymer Handbook 3rd Edition, Wiley) .
  • Table 1 Table 1
  • the three solvents with the closest solubility parameters to PGA are able to penetrate the polymer, and the best penetration is given by DMSO, with the closest solubility parameter.
  • Figure 1 shows the release profile obtained when dimethyl malonate is used as the solvent. Impregnation was carried out with the sample suspended using cotton thread.
  • Degradation was carried out in 27 ml PBS with the sample suspended using nylon thread, with stirring.
  • Figure 2 shows the release profile obtained when dichloromethane is used as the solvent. Impregnation was carried out with the sample suspended in a copper wire basket. Degradation was carried out in 15ml PBS with the sample held in a perspex sample holder, without stirring. Each of these figures shows two sets of data, which are repeat experiments.
  • the solvent used for incorporation of theophylline into PGA is water.
  • the PGA is partially hydrolysed at the same time as impregnation occurs.
  • PGA discs prepared as in Example 1 and cut in half were suspended in approximately 20 ml of theophylline solution, using cotton thread. They were immersed for 2 days, and held at 37°C in a water bath, without stirring. The immersion time ensured that degradation was minimal, while the temperature was used to encourage ingress of water into the polymer. After impregnation, the samples were washed with distilled water to remove any drug left on the surface. Samples were dried under vacuum at room temperature for 3 days .
  • Figure 3 shows the drug release profile from one sample (dried before degradation) . Degradation was carried out in 15ml PBS with the sample suspended using cotton thread, without stirring.
  • reservoir devices are demonstrated.
  • the devices should be a way of giving a dose of a drug after a defined time period, determined by the thickness and molecular weight of the PGA film. This could be used to give a booster dose of a vaccine after a defined time period, of particular use in animal health applications. This removes the need for two treatments since both the initial dose and the reservoir device are applied at the same time.
  • Experimental Reservoir membranes were produced on a hot press . A specific amount of polymer (measured by powder volume) was placed onto a certain surface area of PTFE-coated aluminium foil for pressing and films of chosen thickness made. A 20mm square of the polymer film was cut and folded in half, to form a pouch shape.
  • a soldering iron at 230°C was used to seal the sides of the pouch. Contacting the soldering iron with the polymer caused rapid melting of the edges, and the molten polymer could then be smoothed down to effect a seal. The soldering iron did not appear to cause significant heating in the rest of the sample.
  • the pouches were then filled with approximately 10 mg theophylline, and the soldering iron was used to seal the top of the pouch in the same way as the sides. Many other ways of producing the required reservoir topology may be used. These involve other geometries such as cylinders, and other methods of sealing. Drug release
  • Figure 4 shows the theophylline release profile from reservoir sample of thickness 0.18mm.
  • the four data sets are repeat experiments .
  • One sample shows a rapid change from very low to 100 % drug release, which can be attributed to the sample having prematurely broken apart .
  • the PGA membranes begin to erode after around 7 to 10 days, for the molecular weight studied. Substantial drug release begins when the membranes are fully porous and the time at which this occurs is related to the thickness of the membranes and the molecular weight of the polymer.

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  • Health & Medical Sciences (AREA)
  • Chemical & Material Sciences (AREA)
  • Medicinal Chemistry (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Epidemiology (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Animal Behavior & Ethology (AREA)
  • General Health & Medical Sciences (AREA)
  • Public Health (AREA)
  • Veterinary Medicine (AREA)
  • Engineering & Computer Science (AREA)
  • Biomedical Technology (AREA)
  • Neurosurgery (AREA)
  • Dermatology (AREA)
  • Medicinal Preparation (AREA)

Abstract

L'invention concerne un procédé d'imprégnation d'un homopolymère substantiel d'acide glycolique, sélectionné parmi des homopolymères substantiels d'acide glycolique et des copolymères séquencés, comportant un monomère à au moins 40 % en moles d'acide glycolique comme blocs constituant des homopolymères substantiels d'acide glycolique avec un composé pharmaceutiquement actif. Ce procédé consiste à dissoudre le composé pharmaceutiquement actif dans un solvant afin de former une solution de composé pharmaceutiquement actif, à mettre en contact la solution avec le polymère et à permettre à la solution de pénétrer dans le polymère, étapes se caractérisant par le fait que le solvant est liquide dans des conditions de pression atmosphérique et à 20 °C et qu'il peut pénétrer dans le polymère, mais qu'il ne peut pas dissoudre ce polymère. Le solvant peut être, par exemple, de l'eau ou un solvant organique présentant un paramètre de solubilité S compris entre 18,5 et 28,0 Mpa½. Le produit peut être utilisé pour être implanté dans un sujet humain ou dans un autre sujet animal. L'invention concerne également un produit pouvant être implanté dans le corps d'un sujet humain ou d'un autre sujet animal, comportant un composé pharmaceutiquement actif encapsulé dans une enveloppe qui forme une barrière entre le composé pharmaceutiquement actif et le milieu ambiant, une partie au moins de la barrière étant formée par une membrane de polymère d'acide glycolique sélectionné parmi des homopolymères substantiels d'acide glycolique et des copolymères séquencés, comportant un monomère à au moins 40 % en moles d'acide glycolique comme blocs constituant des homopolymères substantiels d'acide glycolique.
PCT/GB2001/004982 2000-11-10 2001-11-09 Dispositifs d'administration Ceased WO2002038183A2 (fr)

Priority Applications (1)

Application Number Priority Date Filing Date Title
AU2002212551A AU2002212551A1 (en) 2000-11-10 2001-11-09 Delivery devices

Applications Claiming Priority (4)

Application Number Priority Date Filing Date Title
GB0027583A GB0027583D0 (en) 2000-11-10 2000-11-10 Delivery devices
GB0027583.4 2000-11-10
US25336800P 2000-11-28 2000-11-28
US60/253,368 2000-11-28

Publications (2)

Publication Number Publication Date
WO2002038183A2 true WO2002038183A2 (fr) 2002-05-16
WO2002038183A3 WO2002038183A3 (fr) 2003-01-23

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PCT/GB2001/004982 Ceased WO2002038183A2 (fr) 2000-11-10 2001-11-09 Dispositifs d'administration

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AU (1) AU2002212551A1 (fr)
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Family Cites Families (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US3991766A (en) * 1973-05-31 1976-11-16 American Cyanamid Company Controlled release of medicaments using polymers from glycolic acid
DE3841397A1 (de) * 1988-12-08 1990-06-21 Melzer Wolfgang Poroeser resorbierbarer arzneistofftraeger
US5340614A (en) * 1993-02-11 1994-08-23 Minnesota Mining And Manufacturing Company Methods of polymer impregnation
AUPM897594A0 (en) * 1994-10-25 1994-11-17 Daratech Pty Ltd Controlled release container
AUPO431596A0 (en) * 1996-12-20 1997-01-23 Scientec Research Pty Ltd Apparatus and method for coating a material

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AU2002212551A1 (en) 2002-05-21
WO2002038183A3 (fr) 2003-01-23

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