EP1274412A1 - Formulation pharmaceutique - Google Patents

Formulation pharmaceutique

Info

Publication number
EP1274412A1
EP1274412A1 EP00975935A EP00975935A EP1274412A1 EP 1274412 A1 EP1274412 A1 EP 1274412A1 EP 00975935 A EP00975935 A EP 00975935A EP 00975935 A EP00975935 A EP 00975935A EP 1274412 A1 EP1274412 A1 EP 1274412A1
Authority
EP
European Patent Office
Prior art keywords
compound
formula
bulk
forming agent
pharmaceutically acceptable
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Withdrawn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
EP00975935A
Other languages
German (de)
English (en)
Inventor
Karrar A. Khan
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.)
Abbott GmbH and Co KG
Original Assignee
Abbott GmbH and Co KG
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 Abbott GmbH and Co KG filed Critical Abbott GmbH and Co KG
Publication of EP1274412A1 publication Critical patent/EP1274412A1/fr
Withdrawn legal-status Critical Current

Links

Classifications

    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K45/00—Medicinal preparations containing active ingredients not provided for in groups A61K31/00 - A61K41/00
    • A61K45/06—Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/13—Amines
    • A61K31/135—Amines having aromatic rings, e.g. ketamine, nortriptyline
    • 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
    • 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
    • A61K9/16—Agglomerates; Granulates; Microbeadlets ; Microspheres; Pellets; Solid products obtained by spray drying, spray freeze drying, spray congealing,(multiple) emulsion solvent evaporation or extraction
    • A61K9/1605—Excipients; Inactive ingredients
    • A61K9/1617—Organic compounds, e.g. phospholipids, fats
    • A61K9/1623—Sugars or sugar alcohols, e.g. lactose; Derivatives thereof; Homeopathic globules
    • 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
    • A61K9/16—Agglomerates; Granulates; Microbeadlets ; Microspheres; Pellets; Solid products obtained by spray drying, spray freeze drying, spray congealing,(multiple) emulsion solvent evaporation or extraction
    • A61K9/1605—Excipients; Inactive ingredients
    • A61K9/1629—Organic macromolecular compounds
    • A61K9/1652—Polysaccharides, e.g. alginate, cellulose derivatives; Cyclodextrin
    • 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
    • A61K9/2013—Organic compounds, e.g. phospholipids, fats
    • A61K9/2018—Sugars, or sugar alcohols, e.g. lactose, mannitol; Derivatives thereof, e.g. polysorbates
    • 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
    • A61K9/205—Polysaccharides, e.g. alginate, gums; Cyclodextrin
    • A61K9/2054—Cellulose; Cellulose derivatives, e.g. hydroxypropyl methylcellulose

Definitions

  • This invention relates to pharmaceutical formulations suitable for use in treating obesity and related conditions. More particularly, the invention relates to a pharmaceutical formulation comprising sibutramine and analogues thereof and a bulk-forming agent.
  • Sibutramine is a 5-hydroxytryptamine and noradrenaline reuptake inhibitor in vivo (Buckett, W.R., Thomas, P.C. & Luscombe, G.P. (1988). Prog. Neuro- Psychopharmacol. Biol. Psychiat. 2, 575-584 and Luscombe, G.P., Hopcroft, R.H., Thomas, P.C. & Buckett, W.R. (1989). Neuropharmacology, 28, 129-134.) Studies have shown that it reduces body weight by a dual mode of action; it decreases food intake by enhancing satiety (Fantino, M. & Souquet, A.-M. (1995). Int. J.
  • a typical formulation might include a rapidly absorbed sugar as a source of energy to assist with appetite suppression, in addition to the centrally acting anorectic sibutramine and an absorptive bulk-forming agent that hydrates and swells in contact with water.
  • the present invention provides a pharmaceutical formulation comprising a compound of formula I
  • R, and R 2 are independently H or methyl and a bulk-forming agent.
  • the present invention may provide the following advantages. Firstly, the maximum weight loss achieved is greater than that achieved by the sole administration of either a compound of formula 1 the bulk-forming agent. Secondly, a synergistic weight loss is achieved in which the weight loss obtained by the administration of a compound of formula I and the bulk-forming agent to a first test group (for example mammals eg rodents or human beings) is greater than the total weight loss achieved by administration of the compound of formula I to a second test group of the same species and the weight loss achieved by administration of a bulk- forming agent to a third test group of the same species. Thirdly, when weight loss has reached a plateau after administration of either a compound of formula I or the bulk-forming agent, a further weight loss is achieved by administering the other compound. Fourthly, lower doses of the compound of formula I and the bulk-forming agent may be used in the present invention to enhance duration of satiety action, and efficacy and to reduce the side-effects associated with administration of a higher dose of each compound.
  • Suitable bulk-forming agents comprise one or more of the following agents: methylcellulose, sterculia, wheat fibre/bran, isphagula husk, carboxymethylcellulose hydroxyethylcellulose, hydroxypropylmethylcellulose, guar gum, xanthan gum, carrageenan gum, tragaca ⁇ th, carob, agar, locust bean gum, sodium alginate, alginic acid or Matricor.
  • the formulation comprises a compound of formula I and a bulk- forming agent.
  • the formulation additionally comprises one or more phamaceutically acceptable excipients.
  • the formulation comprises: compound of formula I 0.01 to 5% bulk-forming agent 10.0 to 90% excipients 5.00 to 89.9%. More preferably the formulation comprises: compound of formula I 0.05 to 3% bulk-forming agent 40.0 to 80% excipients 17.0 to 59.5%.
  • the formulation comprises: compound of formula I 0.1 to 2% bulk-forming agent 50.0 to 75% excipients 23.0 to 49.9%.
  • excipients employed are those known to those skilled in the art of pharmaceutical formulation and include but are not limited to diluents, binders, disintegrants, lubricants, flavours, colouring, sweet ⁇ ers, preservatives and anti- oxidants and mixtures thereof.
  • Formulations in the form of tablets, powders, capsules, oral liquids and granules optionally comprise one or more of the following: diluents for example lactose, microcrystalline cellulose, mannitol, maize starch or sorbitol; binders for example hydroxypropyl methyicellulose or polyvinyipyrrolidone; disintegrants for example croscarmellose sodium; lubricants for example magnesium stearate or stearic acid; flavour for example orange flavour; sweeteners for example sodium saccharin or aspartame and colouring agents.
  • diluents for example lactose, microcrystalline cellulose, mannitol, maize starch or sorbitol
  • binders for example hydroxypropyl methyicellulose or polyvinyipyrrolidone
  • disintegrants for example croscarmellose sodium
  • lubricants for example magnesium stearate or stearic acid
  • flavour for example orange flavour
  • the bulk-forming agent is selected from methyicellulose, sterculia, wheat fibre, isphagula husk, guar gum, carrageenan, xanthan gum and carboxymethylcellulose. More preferably the . bulk-forming agent is selected from methyicellulose, sterculia, wheat fibre or isphagula husk.
  • the present invention provides a method of treating obesity or related conditions wherein the compound of formula I and the bulk forming agent are administered simultaneously, separately or sequentially.
  • a preferred compound of formula I is - ⁇ 1-[1-(4-chlorophenyl)cyclobutyl]-3- methylbutyl ⁇ -N,N-dimethylarnine or a salt thereof, for example the hydrochloride salt, known as sibutramine hydrochloride.
  • a preferred form of this hydrochloride is its monohydrate, known as sibutramine hydrochloride monohydrate.
  • N- ⁇ 1- [1-(4-chlorophenyl)cyclobutyl]-3-methylbutyl ⁇ -N,N-dimethylamine and salts thereof in the treatment of cerebral function disorders is described in US Patent 4939175.
  • the use of N- ⁇ 1 -[1 -(4-chlorophenyl)cyclobutyl]-3-methylbutyl ⁇ -N, N-dimethyiamine hydrochloride in the treatment of obesity is described in European Patent Number 397831.
  • a particularly preferred form of this compound is N- ⁇ 1-[1-(4- chlorophenyl)cyclobutyl]-3-methylbutyl ⁇ -N,N-dimethylamine hydrochloride monohydrate (sibutramine hydrochloride monohydrate) which is described in European Patent Number 230742.
  • the use of N- ⁇ 1-[1-(4-chlorophenyl)cyclobutyl]-3- methylbutyl ⁇ -N,N-dimethylamine and salts thereof for improving the glucose tolerance of humans having Impaired Glucose Tolerance or Non-Insulin Dependent Diabetes Mellitus is described in published PCT application WO95/20949.
  • the enantiomers may be resolved by methods known to those skilled in the art, for example by formation of diastereoisomeric salts or complexes which may be separated, for example, by crystallisation; via formation of diastereoisomeric derivatives which may be separated, for example, by crystallisation, gas-liquid or liquid chromatography; selective reaction of one enantiomer with an enantiomer-specific reagent, for example enzymatic oxidation or reduction, followed by separation of the modified and unmodified enantiomers; or gas-liquid or liquid chromatography in a chiral environment, for example on a chiral support, for example silica with a bound chiral ligand or in the presence of a chiral solvent.
  • enantiomers of formula I can also be prepared by preparing the primary amine racemate, resolving this mixture into its individual enantiomers and then converting the relevant optically pure primary amine enantiomer into the desired secondary amine product.
  • Preferred compounds of formula I are N- ⁇ 1-[1-(4-chlorophenyl)cyclobutyl]-3- methylbutyl ⁇ -N,N-dimethylamine, N- ⁇ 1 -[1 -(4-chlorophenyl)cyclobutyl]-3-methylbutyl ⁇ - N- methylamine, and 1-[1-(4-chIorophenyl)cyclobutyl]-3-methylbutylamine including racemates, individual enantiomers and mixtures thereof, and pharmaceutically acceptable salts thereof.
  • a compound of formula I and the bulk- forming agent may be administered concomitantly or concurrently, for example in the form of separate dosage units to be used simultaneously, separately or sequentially.
  • the present invention provides a compound of formula I including enantiomers and pharmaceutically acceptable salts thereof, in which R-i and R 2 are independently H or methyl and the. bulk-forming agent for simultaneous, separate or sequential use for the treatment of obesity.
  • the present invention provides a compound of formula I including enantiomers and pharmaceutically acceptable salts thereof, in which RT and R are independently H or methyl and the bulk-forming agent as a combined preparation for simultaneous, separate or sequential use for the treatment of obesity.
  • the present invention provides a product containing a compound of formula I including enantiomers and pharmaceutically acceptable salts thereof, in which Ri and R 2 are independently H or methyl and a bulk-forming agent as a combined preparation for simultaneous, separate or sequential use for the treatment of obesity.
  • the present invention provides the use of a compound of formula I including enantiomers and pharmaceutically acceptable salts thereof, in which R-i and R 2 are independently H or methyl in the manufacture of a medicament for the treatment of obesity or a related condition in a patient who is also receiving treatment with a bulk-forming agent.
  • the present invention provides a method of treating obesity comprising the administration of an adjunctive therapy comprising a therapeutically effective amount of a compound of formula I and a bulk-forming agent to a patient in need thereof.
  • the invention also provides the use of the above combination of a compound of formula I and a bulk-forming agent in the manufacture of a medicament for the treatment of obesity and related conditions. Additionally, it provides the combination for use in the treatment of obesity.
  • the amount of each compound to be administered will depend on a number of factors including the age of the patient, the severity of the condition and the past medical history of the patient and always lies within the sound discretion of the administering physician but it is generally envisaged that the dosage of the compound of formula I to be administered will be in the range 0.1 to 50 mg preferably 1 to 30 mg per day given in one or more doses and more preferably 5 mg, 10 mg, 15 mg, 20 mg, 25 mg or 30 mg per day and most preferably 20 mg.
  • the dosage of bulk-forming agent to be administered will be in the range of 100mg to 10g given in one or more doses, preferably two or three times daily, more preferably in the range of 500mg to 8g and most preferably in the range of 1g to 4g .
  • the compound of formula I preferably sibutramine hydrochloride monohydrate, may be administered in any of the known pharmaceutical dosage forms.
  • sibutramine hydrochloride monohydrate is administered once or twice daily, preferably once first thing in the morning, and the bulk-forming agent is administered twice or three times daily before meals.
  • the dose of sibutramine hydrochloride monohydrate is 10 mg, 15 mg, 20 mg or 30 mg administered once or twice daily and the dose of bulk-forming agent is in the range of from 100 mg to 10g for example 100 mg, 200 mg, 300 mg, 400 mg, 500 mg, 600 mg, 700 mg, 800 mg, 900 mg, 1000 mg, 1250 mg, 1500mg, or 2000 mg , 3000 mg, 4000 mg, 5000mg, 6000mg, 7000mg, 8000mg or 9000mg administered three times before meals.
  • the dose of the bulk-forming agent is given prior to the first dose of the compound of formula I, preferably in the range of 5 minutes to 3.5 hours before the first dose the compound of formula I, for example 30 minutes, 1 hour, 1.5 hours, 2 hours, 2.5 hours or 3 hours, before the first dose the compound of formula I. More preferably the dose of the bulk-forming agent is given with the compound of formula I.
  • Oral dosage forms are the preferred compositions for use in the present invention and these are the known pharmaceutical forms for such administration, for example tablets, capsules, granules, liquids and aqueous or oil suspensions.
  • the excipients used in the preparation of these compositions are the excipients known in the pharmacist's art.
  • Tablets may be prepared from a mixture of the active compounds with fillers, for example microcrystalline cellulose; disintegrating agents, for example maize starch; lubricating agents, for example magnesium stearate; binders, for example polyvinyipyrrolidone and other optional ingredients known in the art to permit tableting the mixture by known methods.
  • the tablets may, if desired, be coated using known methods and excipients which may include enteric coating using for example hydroxypropylmethylcellulose phthalate.
  • the tablets may be formulated in a manner known to those skilled in the art so as to give a sustained release of the compounds of the present invention.
  • Such tablets may, ifdesired, be provided with coatings for example, film or sugar coatings or enteric coatings by known methods, for example by the use of cellulose acetate phthalate.
  • capsules for example hard or soft gelatin capsules, containing the active compound with or without added excipients, may be prepared by known methods and, if desired, provided with enteric coatings in a known manner.
  • the contents of the capsule may be formulated using known methods so as to give sustained release of the active compound.
  • the tablets and capsules may conveniently each contain 1 to 50 mg of the compound of formula I and 50 to 2500 mg mg mg of the bulk-forming agent.
  • dosage forms for oral administration include, for example, liquids or aqueous suspensions containing the active compounds in an aqueous medium in the presence of a non-toxic suspending agent such as sodium carboxy- methyicellulose, and oily suspensions containing the active compounds in a suitable vegetable oil, for example arachis oil.
  • the active compounds may be formulated into powders or granules with or without additional excipients.
  • the powders or granules may be ingested directly by the patient or they may be added to a suitable liquid carrier (for example, water) before ingestion.
  • the powders or granules may contain disintegrants, eg an effervescent couple formed from an acid and a carbonate or bicarbonate salt to facilitate dispersion in the liquid medium.
  • the compounds of the present invention in the form of particles of very small size, for example as obtained by fluid energy milling.
  • compositions of the present invention optionally contain one or more of the following ingredients: flavourings, colouring, sweeteners for example
  • the pharmaceutical formulation When the pharmaceutical formulation is in the form of a liquid it optionally contains a preservative.
  • the preservative is a benzoate or an anti-oxidant or an anti-oxidant synergist or mixtures thereof.
  • the preparation may also include an antioxidant, or antioxidant synergists, to prevent oxidative degradation. Any of the known antioxidants may be used, for example alpha tocopherol, ascorbic acid, ascorbyl palmitate, butylated hydroxyanisole, butylated hydroxytoluene, fumaric acid, malic acid, propyl gallate, sodium ascorbate or sodium metabisulphite or their synergists for example disodium edetate. More preferably the antioxidant is sodium metabisulphite.
  • the level of antioxidant used will be optimised for each formulation, for example for sodium metabisulphite is in the range 0.01 to 1.0% w/v, more preferably in the range 0.075 to 0.2% w/v.
  • the liquid pharmaceutical formulation contains one or more flavouring agents.
  • the flavouring agent is a fruit flavour for example lemon, lime, apple and/or a sweetening agent for example sugar or aspartame.
  • the flavouring agent is present in an amount of from 0.1 % to 5% w/v, more preferably from 0.5% to 1.5% w/v of the formulation.
  • the liquid pharmaceutical formulation contains a surfactant which is pharmaceutically acceptable.
  • the surfactant is a hydrophilic non-ionic surfactant. More preferably the surfactant is polysorbate 80 for example Tween® 80.
  • the surfactant is present in an amount of from 0.1 % to 2% w/v, more preferably from 0.2 to 1 % w/v of the formulation.
  • related conditions means medical conditions known to those skilled in the art to be associated with body weight disorders.
  • the term includes but is not limited to the following: diabetes including non-insulin dependent diabetes mellitus, impaired glucose tolerance, lipid syndromes, cachexia, hyperglycaemia and hyperlipidaemia, high uric acid levels and lipid levels, in mammals particularly humans.
  • the present invention may be useful in identifying compounds for the treatment or prevention of metabolic diseases and conditions arising therefrom, for example non exercise activity thermogenesis and increased metabolic rate, weight gain associated with drug treatment, osteoarthritis and gout, cancers associated with weight gain, menstrual dysfunction or gallstones.
  • the present invention may be useful in identifying compounds for preventing cardiovascular disease, in aiding weight loss after pregnancy and in aiding weight loss after smoking cessation.
  • compositions incorporating both a compound of formula I and the bulk-forming agent are important embodiments of the present invention.
  • Such pharmaceutical compositions contain a therapeutically effective amount of each of the compounds.
  • Each dosage unit may contain the daily doses of both compounds, or may contain a fraction of the daily dose, such as one-third of the doses.
  • each dosage unit may contain the entire dose of one of the compounds, and a fraction of the dose of the other compound. In such case, the patient would daily take one of the combination dosage units, and one or more units containing only the other compound.
  • Granules are prepared either by blending or by wet granulation with a suitable granulating agent using conventional wet or dry massing processes. Tablets are prepared by compression of granules, using methods known to those skilled in the art. Powders and granules may be filled into sachets or tabletted.

Landscapes

  • Health & Medical Sciences (AREA)
  • Chemical & Material Sciences (AREA)
  • Medicinal Chemistry (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Animal Behavior & Ethology (AREA)
  • General Health & Medical Sciences (AREA)
  • Public Health (AREA)
  • Veterinary Medicine (AREA)
  • Epidemiology (AREA)
  • Child & Adolescent Psychology (AREA)
  • Engineering & Computer Science (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Diabetes (AREA)
  • Hematology (AREA)
  • Obesity (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • General Chemical & Material Sciences (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Organic Chemistry (AREA)
  • Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Medicinal Preparation (AREA)

Abstract

L'invention se rapporte à des formulations pharmaceutiques permettant de traiter l'obésité et les conditions associées. Plus particulièrement, cette invention se rapporte à des formulations pharmaceutiques contenant de la sibutramine et des analogues de cette dernière ainsi qu'un agent de lest.
EP00975935A 1999-11-06 2000-10-27 Formulation pharmaceutique Withdrawn EP1274412A1 (fr)

Applications Claiming Priority (3)

Application Number Priority Date Filing Date Title
GB9926251 1999-11-06
GBGB9926251.1A GB9926251D0 (en) 1999-11-06 1999-11-06 Pharmaceutical formulation
PCT/EP2000/010582 WO2001034140A1 (fr) 1999-11-06 2000-10-27 Formulation pharmaceutique

Publications (1)

Publication Number Publication Date
EP1274412A1 true EP1274412A1 (fr) 2003-01-15

Family

ID=10864032

Family Applications (1)

Application Number Title Priority Date Filing Date
EP00975935A Withdrawn EP1274412A1 (fr) 1999-11-06 2000-10-27 Formulation pharmaceutique

Country Status (7)

Country Link
EP (1) EP1274412A1 (fr)
JP (1) JP2003519622A (fr)
AR (1) AR029406A1 (fr)
AU (1) AU1388501A (fr)
CA (1) CA2390128A1 (fr)
GB (1) GB9926251D0 (fr)
WO (1) WO2001034140A1 (fr)

Families Citing this family (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2004096202A1 (fr) * 2003-04-28 2004-11-11 Cipla Limited Formulation pharmaceutique contenant un agent anti-obesite et un acidulant
KR100781882B1 (ko) * 2005-07-12 2007-12-05 주식회사유한양행 시부트라민을 함유하는 약제학적 조성물
KR100857724B1 (ko) 2006-06-30 2008-09-10 한올제약주식회사 용해도와 용출률이 향상된 시부트라민 함유 경구투여용 고체분산체
KR100886542B1 (ko) 2007-02-16 2009-03-02 주식회사 드림파마 시부트라민의 가용화 조성물 및 이의 제조방법

Family Cites Families (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
IE61928B1 (en) * 1988-11-29 1994-11-30 Boots Co Plc Treatment of obesity
US5459164A (en) * 1994-02-03 1995-10-17 Boots Pharmaceuticals, Inc. Medical treatment

Non-Patent Citations (1)

* Cited by examiner, † Cited by third party
Title
See references of WO0134140A1 *

Also Published As

Publication number Publication date
WO2001034140A1 (fr) 2001-05-17
JP2003519622A (ja) 2003-06-24
AR029406A1 (es) 2003-06-25
CA2390128A1 (fr) 2001-05-17
AU1388501A (en) 2001-06-06
GB9926251D0 (en) 2000-01-12

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