WO2003092726A1 - Combinaison d'insuline et d'un derive de thiazolidinedione et utilisation de celle-ci pour traiter le diabete - Google Patents

Combinaison d'insuline et d'un derive de thiazolidinedione et utilisation de celle-ci pour traiter le diabete Download PDF

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Publication number
WO2003092726A1
WO2003092726A1 PCT/EP2003/003406 EP0303406W WO03092726A1 WO 2003092726 A1 WO2003092726 A1 WO 2003092726A1 EP 0303406 W EP0303406 W EP 0303406W WO 03092726 A1 WO03092726 A1 WO 03092726A1
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Prior art keywords
insulin
thiazolidine
dione
compound
formula
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PCT/EP2003/003406
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English (en)
Inventor
Gérard Moinet
Gérard Botton
Didier Mesangeau
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Merck Patent Gmbh
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Priority to AU2003226768A priority Critical patent/AU2003226768A1/en
Publication of WO2003092726A1 publication Critical patent/WO2003092726A1/fr

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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K38/00—Medicinal preparations containing peptides
    • A61K38/16—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof
    • A61K38/17—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from animals; from humans
    • A61K38/22—Hormones
    • A61K38/28—Insulins
    • 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
    • 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
    • A61P3/08—Drugs for disorders of the metabolism for glucose homeostasis
    • A61P3/10—Drugs for disorders of the metabolism for glucose homeostasis for hyperglycaemia, e.g. antidiabetics

Definitions

  • the present invention relates to a combination of at least one derivative of 5-phenoxyalkyl-2,4-thiazolidinedione type as described, for example, in WO 97/47612 and insulin.
  • the invention also relates to the use of a combination of a 5-phenoxy- alkyl-2,4-thiazolidinedione and insulin for the preparation of medicaments for reducing hyperglycaemia, more particularly the hyperglycaemia of non-insu- lin-dependent diabetes.
  • EP 207 581 These compounds are activators of the peroxisome proliferator-activated receptor ⁇ (PPAR ⁇ ).
  • Insulin is known as an agent for treating type I diabetes (or insulin- dependent diabetes). Insulin is also used as a hypoglycaemiant agent in the treatment of non-insulin-dependent diabetes (NIDDM).
  • NIDDM non-insulin-dependent diabetes
  • Diabetes is a chronic disease with many pathological manifestations. It is accompanied by disorders of lipid and sugar metabolism and circulatory disorders.
  • insulin resistance syndrome (syndrome X) is characterised especially by a reduction in the action of insulin (Presse Medicale, 26, No. 14, (1997), 671-677) and is involved in a great many pathological conditions, such as diabetes and more particularly non-insulin-dependent diabetes, dyslipidaemia, obesity, arterial hypertension and also certain macrovascular complications, for instance atherosclerosis, and microvascular complications, for instance retinopathies, nephropathies and neuropathies.
  • one aim of the present invention is to propose a pharmaceutical combination for significantly improving glucose metabolism.
  • a further aim of the invention is to propose a pharmaceutical combination that is suitable for treating diabetes by displaying considerable action on the metabolic syndrome of insulin resistance.
  • an aim of the invention is to propose a combination that is particularly suitable for diabetics in the various stages of the disease.
  • insulin and at least one compound of the formula (I) are administered simultaneously or sequentially, in the form of separate pharmaceutical compositions, one comprising insulin in a pharmaceutically acceptable vehicle, the other comprising the compound of the formula (I) in a pharmaceutically acceptable vehicle.
  • insulin and at least one compound of the formula (I) are combined in the same pharmaceutical composition.
  • the term “pharmaceutical combi- nation” refers to one or other of these aspects.
  • Such a combination is particularly suitable for treating diabetes, more particularly non-insulin-dependent diabetes. It is particularly suitable for reducing the hyperglycaemia of non-insulin-dependent diabetes.
  • insulin resistance syndrome is also suitable for treating at least one of the pathologies associated with insulin resistance syndrome, more particularly chosen from dyslipidae- mia, obesity, arterial hypertension, macrovascular complications, for instance atherosclerosis, and microvascular complications, for instance retinopathies, nephropathies and neuropathies.
  • These treatments may be performed preventively and/or curatively.
  • A represents a saturated or unsaturated, linear or branched hydrocarbon-based group containing from 2 to 16 carbon atoms
  • D represents a homo-carbon-based or hetero-carbon-based, mono-, bi- or tricyclic aromatic structure possibly including one or more hetero atoms
  • X represents a substituent of the aromatic structure, chosen from hydrogen, an alkyl group containing from 1 to 6 carbon atoms, an alkoxy group containing from 1 to 6 carbon atoms, an alkoxyalkyl group, in which the alkoxy and alkyl groups are defined as above, an aryl group, defined as an aromatic ring structure comprising one or two rings optionally including one or two hetero atoms in the ring, such as, for example, a phenyl or an ⁇ - or ⁇ -naphthyl, an arylalkyl group, in which the alkyl group is defined as above and the aryl group is defined as above and optionally comprises one or more substituents, an arylalkylaryl group, in which the arylalkyl and aryl fractions are defined as above, a halogen, a tri
  • D preferably represents a phenyl or naphthyl radical.
  • alkyl groups containing from 1 to 6 carbon atoms that may especially be mentioned are the methyl, ethyl, propyl, isopropyl, butyl, iso- butyl, tert-butyl, pentyl and hexyl radicals.
  • alkoxy groups con- taining from 1 to 6 carbon atoms that may especially be mentioned are the methoxy, ethoxy, propoxy, isopropoxy, butoxy and isobutoxy radicals.
  • halogen groups that may especially be mentioned are fluorine, chlorine, bromine and iodine.
  • the A chain is a linear or branched hydrocarbon-based chain contain- ing from 2 to 16 carbon atoms, that is saturated or contains one or more ethylenic groups, optionally substituted by at least one hydroxyl radical or with a phenyl radical.
  • linear alkyl radicals that may especially be mentioned include the divalent ethyl, propyl, butyl, pentyl, hexyl, octyl, nonyl, decyl, dodecyl and hexadecyl radicals.
  • branched alkyl chains that may especially be mentioned are the divalent 2-ethylhexyl, 2-methylbutyl, 2- methylpentyl, 1 -methylhexyl and 3-methylheptyl radicals.
  • monohydroxyalkyl chains that are preferred are radicals containing 2 or 3 carbon atoms, such as 2-hydroxyethyl, 2-hydroxypropyl or 3-hydroxypropyl.
  • polyhydroxyalkyl chains that are preferred are radicals containing 3 to 6 carbon atoms and 2 to 5 hydroxyl radicals, such as 2,3- dihydroxypropyl, 2,3,4-trihydroxybutyl or 2,3,4,5-tetrahydroxypentyl or a pentaerythritol residue.
  • the present invention also relates to the tautomeric forms of the compounds of the general formula (I), to the enantiomers, diastereoisomers and epimers of these compounds, and also to the solvates thereof.
  • ketone functions borne by the thiazolidine ring can enolise and give rise to mono-enols.
  • the thiazolidinedione derivatives may be salified and be in the form of basic salts.
  • Examples of basic salts of the compounds of the general formula (I) include pharmacologically acceptable salts, such as sodium salts, potassium salts, magnesium salts, calcium salts, amine salts and other salts of the same type (aluminium, iron, bismuth, etc.).
  • pharmacologically acceptable salts such as sodium salts, potassium salts, magnesium salts, calcium salts, amine salts and other salts of the same type (aluminium, iron, bismuth, etc.).
  • the amine salts that are not pharmacologically acceptable may serve as a means of identification, purification or resolution.
  • Insulin is a hypoglycaemiant hormone of polypeptide nature, which may be obtained according to many known methods. These methods may more particularly be chemical, semi-synthetic, biological (especially by simple extraction of human or animal insulin) or biogenetic (by expression of recombinant insulin).
  • insulin includes insulin analogues that have structural differences with human insulin, these structural differences not significantly modifying, however, their biological activity compared with human or animal insulin.
  • insulins that may especially be mentioned include Insuman®
  • the invention thus relates to a pharmaceutical composition
  • a pharmaceutical composition compris- ing, as active principles, (i) insulin and (ii) at least one compound of the formula (I) with one or more pharmaceutically acceptable excipients.
  • excipient and “pharmaceutically acceptable vehicle” mean any solvent, dispersing medium, absorption retardants, etc. that do not produce a side reaction, for example an allergic reaction, in humans or animals.
  • composition contains therapeutically effective amount of the various active principles.
  • the ratios of the respective amounts of insulin and of compound of the formula (I) thus vary in consequence.
  • Another embodiment of the invention includes the essentially simulta- neous administration of separate compositions, on the one hand comprising the compound of the formula (I), and on the other hand insulin.
  • the administration may also be performed sequentially, using separate compositions, on the one hand comprising the compound of the formula (I), and on the other hand insulin.
  • the compound of the formula (I) and the insulin may thus be administered individually in a pharmaceutically acceptable form, including for the compound of the formula (I) its pharmaceutically acceptable derivatives, such as its pharmaceutically acceptable salts or its solvates.
  • the dosage naturally depends on the active agent under consideration, the mode of administration, the therapeutic indication and the age and condition of the patient.
  • the unit dose of insulin preferably comprises from 10 to 400 IU (international units) of insulin (the does depending especially on the insulin under consideration and the condition of the patient).
  • the unit dose of the compound of the formula (I) comprises from 12.5 to 200 mg of this compound (the dose depending especially on the active agents under consideration).
  • the daily dosage ranges between 0.1 and 1 IU and preferably between 0.5 and 1.0 IU per kg of body weight of insulin and between 25 and 200 mg of compound of the formula (I) for an adult.
  • the pharmaceutical compositions of the invention may be formulated so as to be administered to the patient via a single route (for example by injection) or via different routes (for example orally for the compound of the formula (I) and by injection for insulin).
  • compositions of the invention comprising the active principle(s) is (are) in the form of injectable solutions and suspensions packaged in vials or bottles for slow infusion.
  • the injection may especially be performed subcutaneously, intramuscularly or intravenously.
  • composition comprising insulin is preferably intended for par- enteral administration, more particularly by injection.
  • the insulin and the compound of the formula (I) may also be administered by inhalation.
  • the efficacy of inhalation of insulin is discussed especially in the article by Skyler et al., Lancet, 2001 , 357(9253) : 331-5.
  • the compositions of the invention are in the form of gel capsules, effervescent tablets, coated or uncoated tablets, sachets, sugar-coated tablets, drinkable vials or solutions, micro- granules or sustained-release forms.
  • the forms for oral administration are prepared by mixing the active substance with various types of excipients or of vehicles, such as fillers, disintegration (or crumbling) agents, binders, dyes, flavour enhancers and the like, followed by shaping the mixture.
  • the dye can be any dye permitted for pharmaceutical use.
  • flavour enhancers include cocoa powder, mint, borneol and cinnamon powder.
  • binders examples include polyvinylpyrrolidone, hydroxypropylmethylcellulose, alginic acid, carbomer, carboxymethyl- cellulose, dextrin, ethylcellulose, starch, sodium alginate, polymethacrylate, maltodextrin, liquid glucose, magnesium aluminium silicate, hydroxyethyl- cellulose, hydroxypropylcellulose, ethylcellulose, methylcellulose and guar gum.
  • alginic acid sodium carboxymethylcellulose, colloidal silicon dioxide, croscarmellose sodium, crospovidone, guar gum, mag- nesium aluminium silicate, methylcellulose, microcrystalline cellulose, cellulose powder, pregelatinised starch, sodium alginate or sodium starch glyco- late as disintegration agent.
  • the fillers are, for example, cellulose, lactose, calcium hydrogen phosphate and microcrystalline cellulose.
  • the tablets can be obtained in a conventional manner by compressing granules in the presence of one or more lubricants. Suitable lubricants are calcium stearate, glyceryl monostearate, glyceryl palmitostearate, hydrogen- ated castor oil, hydrogenated plant oil, light mineral oil, magnesium stearate, polyethylene glycol, sodium benzoate, sodium lauryl sulfate, stearyl sodium fumarate, stearic acid, talc and zinc stearate. These tablets can then be coated using polymers in solution or suspension, such as hydroxypropyl- methylcellulose or ethylcellulose.
  • the granules used to do this are prepared, for example, by using the wet granulation process starting with a mixture of the active principles with one or more excipients such as a binder, a crumbling agent (or disintegration agent) and a filler.
  • excipients such as a binder, a crumbling agent (or disintegration agent) and a filler.
  • the mixture of the active principles with a suitable filler is incorporated into empty gelatin capsules optionally in the presence of a lubricant such as magnesium stearate, stearic acid, talc or zinc stearate.
  • a suitable filler for example lactose
  • a lubricant such as magnesium stearate, stearic acid, talc or zinc stearate.
  • Gel capsules or soft capsules are prepared by dissolving the active principles in a suitable solvent (for example polyethylene glycol), followed by incorporation into soft capsules.
  • a suitable solvent for example polyethylene glycol
  • the forms for parenteral administration are obtained in a conventional manner by mixing the active principle(s) with buffers, stabilisers, preserving agents, solubilising agents, tonicity agents and suspension agents. In accordance with the known techniques, these mixtures are subsequently sterilised and then packaged in the form of intravenous injections.
  • buffer a person skilled in the art can use buffers based on organophosphate salts.
  • suspension agents include methylcellulose, hydroxy- ethylcellulose, hydroxypropylcellulose, acacia and sodium carboxymethyl- cellulose.
  • solubilising agents include castor oil solidified with poly- oxyethylene, polysorbate 80, nicotinamide or macrogol.
  • stabilisers that are useful according to the invention are sodium sulfite and sodium metasulfite, while mention may be made of sodium p-hydroxybenzoate, sorbic acid, cresol and chlorocresol as preserving agents.
  • the active principles are dissolved or suspended in a suitable vehicle with a dispersant, a humectant, a suspension agent (for example polyvinylpyrrolidone), a pre- serving agent (such as methylparaben or propylparaben), a flavour enhancer or a dye.
  • the active principle(s) is (are) mixed in a manner that is known per se with a suitable base constituent, such as polyethylene glycol or semisynthetic glycerides.
  • the active principles are combined with suitable diluents, suitable stabilisers, agents that promote the sustained release of the active substances or any other type of additive for the formation of a central core which is then coated with a suitable polymer (for example a water-soluble resin or a water-insoluble resin).
  • suitable diluents for example a water-soluble resin or a water-insoluble resin.
  • microcapsules thus obtained are then optionally formulated in suitable dosage units.
  • the present invention also relates to the use of a combination of insu- lin and of a compound of the formula (I) for the preparation of a pharmaceutical composition for treating diabetes.
  • the invention relates to the use of insulin in combination with the said compound of the formula (I) for the preparation of medicaments whose combination is intended to reduce the hyperglycaemia of non-insulin-dependent diabetes.
  • the invention relates to the use of insulin in combination with the said compound of the formula (I) for the preparation of a medicinal combination for treating at least one pathology associated with insulin resistance syndrome, such as, especially, dyslipi- daemia, obesity, arterial hypertension, and microvascular and macrovascular complications, for instance atherosclerosis, retinopathies, nephropathies and neuropathies.
  • the invention is directed more particularly towards the use as defined above, in which insulin and the compound of the formula (I) are in forms suitable for simultaneous administration.
  • the invention is also directed towards the use as defined above, in which insulin and the compound of the formula (I) are in forms suitable for sequential administration.
  • the invention furthermore relates to a pharmaceutical kit for treating diabetes, comprising:
  • a pharmaceutical composition comprising insu- lin in a pharmaceutically acceptable vehicle
  • a pharmaceutical composition comprising a compound of the formula (I) in a pharmaceutically acceptable vehicle.
  • the invention also relates to a method for treating diabetes, whether insulin-dependent or non-insulin-dependent, more particularly non-insulin- dependent diabetes, in a mammal, comprising the simultaneous or sequential administration of insulin and of at least one compound of the formula (I) to the said mammal.
  • the invention also relates to a method for treating diabetes, whether insulin-dependent or non-insulin-dependent, more particularly non-insulin- dependent diabetes, in a mammal, comprising the administration of a composition comprising insulin and at least one compound of the formula (I) to the said mammal.
  • a tablet having the composition below is prepared:
  • a tablet having the composition below is prepared:
  • a tablet having the composition below is prepared:
  • a tablet having the composition below is prepared:
  • a tablet having the composition below is prepared:
  • Wistar rats Male or female Wistar rats (from the company Iffa Credo) are ren- dered diabetic by intraperitoneal administration of streptozotocin.
  • the rats are selected on the basis of a hyperglycaemia (350 mg/dl).
  • the infused-leg technique used is that described by Ruderman et al. (Biochem. J. 124 : 639-651 ,1971).
  • the leg is infused at a rate of 5 ml/minute with a Krebs-Ringer solution containing 8 mM of glucose.
  • the infusion system is non-recirculatory.
  • the glucose uptake is defined by the difference between the concentration of the infusate entering and leaving, multiplied by the infusion flow rate. Normalisation to grams of tissue is performed on the basis of a weight of muscle mass of the leg equal to 6.5% of the body weight of the animal.
  • the effects of insulin are determined at various concentrations: 0-30- 62.5-125 and 500 ⁇ U/ml/minute. Each concentration is infused for 60 minutes, after a "washing" infusion with nutritional fluid for 45 minutes.
  • results are expressed by analysis of the area under the curve (AUC) of the glucose uptake. Each value, after the start of the infusion, corresponds to the difference between the measured value and the baseline value before infusion.
  • the measuring times to calculate the AUC are 0 - 10 - 20 - 30 - 40 - 50 and 60 minutes. Results: The results are collated in Table 1 below. Insulin induces a dose-dependent increase in muscular glucose uptake.
  • compound A makes it possible either to reduce the doses of insulin often associated with oral antidiabetic treatment, or to improve the control of the carbohydrate metabolism of non-insulin-dependent diabetic patients treated with insulin.
  • Table 1 AUC means the area under the curve of the kinetics of muscular glucose uptake, expressed as delta vs. the baseline value of the glucose uptake in ⁇ mol/g.h.
  • Compound A an oral antidiabetic drug without PPAR activity, was studied in diabetic STZ rats (55 mg/kg) with low level of insulin.
  • the main characteristics of this model were strong hyperglycaemia (> 450 mg/dl), low level of insulinaemia and absence of insulin release in response to glucose.
  • Rats were screened for baseline glucose levels 2 days after STZ injection. The animals with glucose levels below 450 mg dl were excluded from this study. Prior to treatment, blood was collected at day -10 and day -2 from the tail vein of each conscious animal to monitor the change in hyperglycaemia. In diabetic rats with insulin treatments, insulin implants were inserted sub- cutaneously in anaesthetised rats, with a trocard. One full and one half-size implant were implanted into each diabetic rat. These implants were inserted 2 days after STZ injection, immediately after glycaemia level determination. Compound A (100 mg/kg/day) was administered 10 days after induction of diabetes to 2 groups of rats, one without and one with insulin implants (3 lU/day).
  • Blood samples for glucose, insulin and HbA1c (only at 28 days) determination were collected from the tail vein in heparinised tubes at days -12, -10 , 3 , 14 and 28 after STZ injection.
  • the plasma glucose determined in the fed condition decreased: 466.19 ⁇ 39.9 vs 584.10 ⁇ 47.83 mg/dl.
  • HbA1c marker of evolution of hyperglycaemia over time decreased significantly: 6.11 ⁇ 0.36 vs 9.52 vs ⁇ 0.71 % in the control diabetic group P ⁇ 0.004. Comparatively, the HbA1 c in the normal group was 3.29 ⁇ 0.07 %. (Table 1)
  • Compound A in this insulin-deficient diabetic rat model, significantly improved the glucose metabolism and decreased the hyperglycaemia.
  • hbA1 C expressed in % and plasma glucose expressed in mg/dl
  • each diabetic rat received, 2 days after administration of STZ, a subcutaneous implant impregnated with bovine insulin (Linplant).
  • HbA1c decreased significantly with Insulin + compound A combination: 3.017 ⁇ 0.031 vs 5.48 ⁇ 0.36 % P ⁇ 0.0001 in diabetic group (Table 3).
  • Table 3 Effects of compound A on HbA1c (%) in diabetic rats after administration of insulin implant Insulin in combination with treatment with compound A allows the gly- caemia to be normalised.
  • Compound A improves glucose utilisation, as shown by the large decrease in the HbA1C level.
  • the combination of compound A with insulin induces a strong potentiation of the effects of insulin. It is possible to conceive that treatment with compound A will enable a reduction in the doses of insulin in type 1 or type 2 diabetic patients.

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  • Health & Medical Sciences (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Diabetes (AREA)
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Abstract

L'invention concerne une combinaison d'un dérivé du type 5-phénoxyalkyl-2,4-thiazolidinedione et d'insuline, ces composantes étant administrées simultanément ou de façon séquentielle, pour le traitement du diabète.
PCT/EP2003/003406 2002-04-30 2003-04-02 Combinaison d'insuline et d'un derive de thiazolidinedione et utilisation de celle-ci pour traiter le diabete WO2003092726A1 (fr)

Priority Applications (1)

Application Number Priority Date Filing Date Title
AU2003226768A AU2003226768A1 (en) 2002-04-30 2003-04-02 Combination of insulin and a thiazolidinedione derivative, and use thereof for treating diabetes

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
FR0205466A FR2838968A1 (fr) 2002-04-30 2002-04-30 Association d'insuline et d'un derive de thiazolidinedione et son utilisation pour traiter le diabete
FR02/05466 2002-04-30

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WO2003092726A1 true WO2003092726A1 (fr) 2003-11-13

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AU (1) AU2003226768A1 (fr)
FR (1) FR2838968A1 (fr)
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Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO1997005875A2 (fr) * 1995-08-10 1997-02-20 Warner-Lambert Company Procede permettant de reduire la quantite d'insuline exogene administree a un patient souffrant de diabete sucre non-insulinodependant
WO1997047612A1 (fr) * 1996-06-07 1997-12-18 Merck Patent Gmbh Nouveaux derives de thiazolidine-2,4-dione substitues, leurs procedes d'obtention et les compositions pharmaceutiques en renfermant
WO1998057634A1 (fr) * 1997-06-18 1998-12-23 Smithkline Beecham Plc Traitement du diabete a l'aide de thiazolidinedione et de metformine
WO2001017513A2 (fr) * 1999-09-03 2001-03-15 Takeda Chemical Industries, Ltd. Composition pharmaceutique

Patent Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO1997005875A2 (fr) * 1995-08-10 1997-02-20 Warner-Lambert Company Procede permettant de reduire la quantite d'insuline exogene administree a un patient souffrant de diabete sucre non-insulinodependant
WO1997047612A1 (fr) * 1996-06-07 1997-12-18 Merck Patent Gmbh Nouveaux derives de thiazolidine-2,4-dione substitues, leurs procedes d'obtention et les compositions pharmaceutiques en renfermant
WO1998057634A1 (fr) * 1997-06-18 1998-12-23 Smithkline Beecham Plc Traitement du diabete a l'aide de thiazolidinedione et de metformine
WO2001017513A2 (fr) * 1999-09-03 2001-03-15 Takeda Chemical Industries, Ltd. Composition pharmaceutique

Non-Patent Citations (1)

* Cited by examiner, † Cited by third party
Title
SKYLER J S: "Insulin therapy in type II diabetes: Who needs it, how much of it, and for how long?", POSTGRADUATE MEDICINE, MCGRAW-HILL, MINNEAPOLIS, US, vol. 101, no. 2, 1 February 1997 (1997-02-01), pages 85 - 90,92-94,, XP002080749, ISSN: 0032-5481 *

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AU2003226768A1 (en) 2003-11-17
FR2838968A1 (fr) 2003-10-31

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