EP2448575A2 - Composition pharmaceutique présentant une solubilité et une stabilité accrues - Google Patents

Composition pharmaceutique présentant une solubilité et une stabilité accrues

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Publication number
EP2448575A2
EP2448575A2 EP10742615A EP10742615A EP2448575A2 EP 2448575 A2 EP2448575 A2 EP 2448575A2 EP 10742615 A EP10742615 A EP 10742615A EP 10742615 A EP10742615 A EP 10742615A EP 2448575 A2 EP2448575 A2 EP 2448575A2
Authority
EP
European Patent Office
Prior art keywords
pharmaceutical composition
weight
telmisartan
range
hctz
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Withdrawn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
EP10742615A
Other languages
German (de)
English (en)
Inventor
Bilgic Mahmut
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.)
Bilgic Mahmut
Original Assignee
Individual
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 Individual filed Critical Individual
Publication of EP2448575A2 publication Critical patent/EP2448575A2/fr
Withdrawn legal-status Critical Current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
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
    • A61K31/4164—1,3-Diazoles
    • A61K31/4184—1,3-Diazoles condensed with carbocyclic rings, e.g. benzimidazoles
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/54—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with at least one nitrogen and one sulfur as the ring hetero atoms, e.g. sulthiame
    • A61K31/549—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with at least one nitrogen and one sulfur as the ring hetero atoms, e.g. sulthiame having two or more nitrogen atoms in the same ring, e.g. hydrochlorothiazide
    • 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

Definitions

  • the present invention relates to pharmaceutical compositions having problems of solubility and stability and the medical use and the preparation method of these compositions.
  • the present invention provides a combination which is effective in the treatment of essential hypertension.
  • This effect provided by a combination in accordance with the invention is named as “desired effect” during the patent.
  • Defined combination comprises telmisartan as an antihypertensive agent and hydrochlorothiazide (HCTZ) as a thiazide derivative diuretic.
  • HCTZ hydrochlorothiazide
  • Hypertension can be classified as essential (primer) or secondary hypertension. Hypertension which is not related to any known medical reason is named as essential hypertension; the elevation of blood pressure caused by another reason as renal desease and tumors is named as secondary hypertension.
  • TPR total peripheric resistance
  • renin-angiotensin system Due to the high activity of renin-angiotensin system, the involvement of sodium and water, the formation of vasoconstriction and the formation of hypertension related to the increase of blood volume.
  • Hypertension is a serious disease and without treatment, consequences can reach to life- threatening sizes. Hypertension without treatment is an important risk factor for the disease as cerebrovascular accident (paralysis), miocard infarct (heart attack), hypertensive cardiomiopathie (congestive heart failure), cardiac dilatation, heartbeat disorder, atherosclerosis which can cause ischemic heart disease, coronary arterial disease, arterial aneurism, hypertensive retinopathy (retina damage), hypertensive nephropathy (chronical kidney failure), hypertensive encephalopathy (confusion, headache, convulsion), bleeding in brain blood vessel and thrombosis.
  • cerebrovascular accident paralysis
  • miocard infarct hemocard infarct
  • hypertensive cardiomiopathie congestive heart failure
  • cardiac dilatation heartbeat disorder
  • atherosclerosis which can cause ischemic heart disease, coronary arterial disease, arterial aneurism, hypertensive retinopathy (retina damage), hypertensive
  • the best method suitably proved in the treatment of essential hypertension is the inhibition of the renin-angiotensin system.
  • Drugs used for this reason are angiotensin II receptor antagonists such as telmisartan.
  • Another drug group proved to being effective to control hypertension is diuretics which increase the activity of angiotensin II receptor antagonists.
  • telmisartan Chemical name of telmisartan is 4'-[(l,4'-dimethyl-2'-propyl [2,6'-bi-lH-benzimidazole]-r- yl)methyl]-[l,r-bifenyl]-2-carboxylic acid. (Formula 1).
  • Telmisartan is firstly described in the patent numbered EP502314 Bl (In patent family, patents numbered EP0552765 Bl, US5591762 A, US5594003 A, US5602127 A and US5614519 A are included). In the patent, processes for preparing telmisartan, pharmaceutical compositions comprising telmisartan and angiotensin antagonist activity of telmisartan are also situated.
  • Telmisartan is a strong, long acting and non-peptide angiotensin II receptor antagonist and it is used in the treatment of hypertension.
  • Angiotensin II is synthesized from angiotensin I with a reaction catalyzed by angiotensin converting enzyme (ACE).
  • Angiotensin II has effects as vasoconstriction, excitation of aldosterone synthesis and secretion, cardiac excitation and the enhancement of sodium back absorption from kidney tubulus.
  • Telmisartan inhibits effects of angiotensin II by selectively blocking binding to ATI receptor in many tissues as vascular smooth muscle and adrenal gland. For this reason, mechanism of action of telmisartan is independent from routes wherein synthesis of angiotensin II occurs.
  • AT2 receptors are found in many tissues. However, it is not known that AT2 receptor is related to cardiovascular homeostasy. The ATI receptor affinity of telmisartan is more than its AT2 receptor affinity.
  • HCTZ is a thiazide derivative diuretic with a chemical name of 6-chloro-3, 4-dihydro-2H- 1,2,4- benzothiadiazine-7-sulfonamide 1,1 -dioxide, (formula II)
  • HCTZ has been firstly described in the patent numbered US3025292.
  • HCTZ is a thiazide derivative diuretic which is used in the treatment of edema and hypertension.
  • Thiazide derivative diuretic increases elimination of sodium, chloro and water by inhibing the passage of sodium from kidney tubulus.
  • the diuretic effect of HCTZ indirectly decreases the plasma volume with the elevations of plasma renin activity, aldosterone secretion and lost of urinary potassium and with the decreases of serum potassium level.
  • the connection of renin- aldosterone comes through angiotensin II.
  • diuretics with angiotensin II receptor antagonist is tend to reverse potassium lost caused by diuretics.
  • Antihypertensive mechanism of action of thiazide has not been well understood. Generally, they don't influence blood pressure. Firstly, they lower blood pressure by decreasing cardiac flow rate and plasma and extracellular fluid volume. With the treatment continued a couple of weeks, hypotensive effect continues, despite lower plasma volume has been getting slowly normal. The reason for this is the decrease of peripheral vascular resistance and probably, the decrease of the susceptibility of smooth muscle cells to noradrenaline. The diuresis starts 2 hours after taking orally HCTZ, reach to maximum level approximately in 4 hours and finish in between 6-12 hours.
  • an aspect of the invention is to combine telmisartan and HCTZ in a pharmaceutical form like tablet by providing a formulation in accordance with the invention comprising a pharmaceutically acceptable, non-toxic and therapeutically effective amount of these two agents.
  • Telmisartan is an active agent exposing polymorphism.
  • the polymorphs of telmisartan are also faced to solubility problems.
  • Polymorph B of telmisartan is described in patent application numbered WO0043370 Al which is characterized with an endothermic pick seen at 183 ⁇ 2 0 C after DSC analysis .In the application, it is described that polymorph B is turned to polymorph A under temperature and moisture effect. Solubility of said two polymorphs is low.
  • particle size reduction One of the known techniques applied to address the solubility problem of poorly soluble drugs such as telmisartan is particle size reduction. Because the dissolution rate of a particulate solid depends on the surface area and the surface area increases as the particle size reduces, reducing particle size may increase dissolution rate.
  • particle size reduction may not always effective at increasing the dissolution rate of a drug. Because, many hydrophobic drugs have a strong tendency to agglomerate while being transformed into larger particles during the dosage form manufacturing process depending on an overall decrease in effective surface area. Another technique applied to increase the surface area is nanoparticulate technology. But, there are some barriers faced during the processes for obtaining nanoparticles such as technical and mechanical limitation of breaking the drug particles into the size of nano particles and the stabilization of these small drug particles in the dosage form.
  • composition to increase solubility of telmisartan wherein the composition comprises,
  • the amount of water soluble diluents in the pharmaceutical composition is less than 25% by weight of the pharmaceutical composition.
  • compositions proposed in the above patents and patent applications head to the use of surfactant and emulsifier to remedy the solubility problem.
  • crystalline telmisartan sodium salt characterized with a melting point of 245 ⁇ 5°C and that preparation process of crystalline telmisartan sodium salt obtained by acid addition salts formed with hydrochloric acid, hydrobromic acid, toluensulphonic acid and methanesulfonic acid; are described.
  • WO2006050921 A2 crystalline and amorphous form of alkaline and alkaline earth salts (sodium, potassium, magnesium and calcium) of telmisartan are described.
  • telmisartan salts (ammonium, choline, ters-butyl amine, arginin, meglumin, ethanolamine, piperazine, diethylamine, sulphuric acid, maleic acid, tartaric acid, citric acid, fumaric acid, oxalic acid, benzenesulphonic acid, naphthalene-2-sulphonic acid, tris-(hydroxymethyl)amine) and/or its polymorphs (telmisartan potassium) and its preparation processes are described.
  • telmisartan salts and their polymorphs are described in consideration of exhibiting higher solubility than free form.
  • any proof is submitted about that these salts really provide a pharmaceutical composition with high solubility and stability, and a formulation is not proposed for most of them.
  • HCTZ is a substance which is easily soluble in aqueous solutions.
  • it is incompatible with basic agents.
  • incompatibility problem with substances of composition also arises.
  • basic agents increasing solubility and stability of telmisartan contact with HCTZ, they cause incompatibility.
  • stability problem arises in tablets.
  • EP 1467712 Bl Another method described in the patent numbered EP 1467712 Bl, is to produce separate film coated tablet in the size and shape which can be filled in capsule for telmisartan and HCTZ. However, division of doses to form small tablets causes the decrease of dissolution rate.
  • bilayer pharmaceutical tablet formulation comprising telmisartan and HCTZ and its production method are described.
  • bilayer tablet production should be prepared by taking into consideration of stability caused by release properties, solubility and incompatibility, it is a complicated application.
  • telmisartan the incompatibility between substances forming composition comprising telmisartan and HCTZ and thereby the stability problem.
  • present invention presents a novel composition and an incomplex production method to provide targeted therapeutic efficiency of telmisartan which have solubility problem and which can be stable in only basic medium and targeted therapeutic activity of HCTZ which is incompatible with basic agents needed to formulate telmisartan.
  • pharmaceutical composition of this invention proposes to the solubility problem of telmisartan without the need of using surfactant and emulsifier.
  • telmisartan ammonium salt which has a solubility higher than free acid without the need of another process as different from above patent and patent applications described in the prior art.
  • Another embodimentof the invention is formulating active ingredients separately to overcome incompatibility and thereby stability problem and adding tromethamine as stabilizing agent to the formulation.
  • Obtained composition is a composition having improved solubility and stability properties and is effective in the treatment of hypertension.
  • the present invention relates to a process for preparation of pharmaceutical composition
  • a process for preparation of pharmaceutical composition comprising a therapeutically effective amount of telmisartan and a therapeutically effective amount of HCTZ for use in the manufacture of a medicament for the treatment of essential hypertension, characterized in that telmisartan and HCTZ are preformulated in a series of manufacturing process steps and that ammonia is used during the preparation of composition.
  • the manufacturing process which provides a formulation so as to obtain the desirable effect is as follows: a granulation solution is obtained by adding and dissolving telmisartan, tromethamine and optionally at least one pharmaceutically acceptable excipient, preferably a binder in the solution of ammonia mixed with a suitable pure solvent or solvent mixture, preferably water; granulation is made by spraying granulation solution on a pharmaceutically acceptable diluent;
  • first mixture is obtained by drying obtained granules at 50°C to have maximum 2% of moisture and sieving;
  • secondary mixture is obtained by mixing and sieving HCTZ with at least one pharmaceutically acceptable excipient selected from at least one diluent, dispenser and glidant; both mixtures are mixed to obtain a homogeneous tablet;
  • final mixture is optionally treated with at least one pharmaceutically acceptable excipient, preferably a lubricant and is made to ready for the pressing;
  • tablets are coated.
  • the present invention is directed to obtain a combination of HCTZ and telmisartan which provides the desired effect, depending on the synergically increasing antihypertensive effect of HCTZ and angiotensin II receptor antagonists.
  • telmisartan and incompatibility
  • stability problem between substances forming the composition comprising HCTZ and telmisartan are faced during the studies as defined above, the An in-complex method should be generated to overcome the solubility problem of telmisartan and the incompatibility problem between substances forming the composition and on the other hand, therapeutically effective amount of active agents and suitable amount of excipients should be found to provide the desired effect of the combination of telmisartan and HCTZ.
  • composition comprising telmisartan and HCTZ preformulated in a series of manufacturing process steps and the use of ammonia during its preparation provides optimum activity for the treatment of essential hypertension.
  • composition comprising telmisartan and HCTZ in certain ratios, a sufficient amount of ammonia, andtromethamine and optionally at least one pharmaceutically acceptable excipient selected from substances as diluent, binder, disintegrant, lubricant and glidant provides optimum efficiency for the treatment of essential hypertension.
  • the solubility problem of telmisartan is solved with a composition wherein the content of the composition is established according to the solubility properties of the substance and with an incomplex production method.
  • the incompatibility problem between HCTZ and basic substances which are necessary to formulate telmisartan is solved with an incomplex production method wherein active ingredients are formulated separately.
  • the pharmaceutical composition comprises telmisartan as active ingredient is in the form of free acid.
  • telmisartan contacts with ammonia which is added to composition for increasing solubility and ensuring stability, telmisartan ammonium salt is obtained spontaneously. Therefore, there is no need for further process to obtain telmisartan ammonium salt.
  • Tromethamine adding to the pharmaceutical composition is also increasing the stability of composition.
  • a granulation solution is obtained by adding telmisartan, tromethamine as a stabilizing agent and optionally at least one pharmaceutically acceptable excipient, preferably a binder, in the solution of ammonia mixed with a suitable pure solvent or solvent mixture, preferably water. Then, granulation is made by spraying this granulation solution on a pharmaceutically acceptable diluent. Obtained granules are dried at 50°C to have maximum 2% of moisture and sieved. Granules obtained with this method exhibit 80% solubility in the dissolution medium in first 20 minutes.
  • HCTZ is mixed and sieved with at least one pharmaceutically acceptable excipient selected from at least one diluent, disintegrant and glidant.
  • the final mixture which is generated by combining obtained mixtures is made ready for tablet press by treating optionally at least one pharmaceutically acceptable excipient, preferably a lubricant.
  • - Tablets are optionally coated with film coating.
  • telmisartan in the range of 0.1-40% by weight
  • HCTZ in the range of 0.1-20% by weight
  • ammonia in the range till 10% by weight
  • tromethamine in the range of 0.1-20% by weight
  • Pharmaceutically acceptable diluents can be selected from lactose, microcrystalline, cellulose, starch, pre-gelatinized starch, modified starch, calcium phosphate (dibasic and/or tribasic), calcium sulphate trihydrate, calcium sulphate dihydrate, calcium carbonate, caoline, lactilol, powder cellulose, dextrose, dextrates, dextrin, sucrose, maltose, fructose, mannitol, sorbitol and xylitol.
  • sorbitol or mannitol are preferably used in the secondary mixture of HCTZ; in the secondary mixture of HCTZ, lactose and/or microcrystalline cellulose are preferably used.
  • diluent is present preferably in the range of 0-95% by weight and more preferably 5-85% by weight.
  • Pharmaceutically acceptable binders are selected from starches (as potatoes starch, corn starch, wheat starch), sugars as sucrose, glucose, dextrose, lactose, maltodextrine, natural and synthetic gums (as acacia), gelatin, cellulose derivative (as microcrystalline cellulose, HPC, HEC, HPMC, carboxymethylcellulose, methylcellulose, ethylcellylose), polyvinylpyrrolidone, polyethylene, glycol, wax, calcium carbonate, calcium phosphate, alcohols (as sorbitol, xilitol, mannitol) and water.
  • polyvinylpyrrolidone (povidone) is used.
  • binder is present preferably in the range of 0-10% by weight, more preferably 0.1-5% by weight.
  • Pharmaceutically acceptable disintegrants are selected from starch (corn starch, potatoes starch) sodium starch glycolate, pre-gelatinized starch, cellulose derivative (as croscarmellose sodium or microcrystalline cellulose), polyvinylpyrrolidone, crospovidone, alginic acid, sodium alginate, clays (as xanthane gum or veegum), ion-exchange resins, food acids and effervescent systems based on alkali carbonate compounds.
  • a starch derivative is used.
  • disintegrantr is present preferably in the range of 0-10% by weight, more preferably 0.1-5% by weight.
  • lubricants are selected from metallic stearate (as magnesium stearate, calcium stearate, aluminum stearate), fatty acid esters (as sodium stearyl fumarate), fatty acids (as stearic acids), fatty alcohols, glyceryl behenate, mineral oil, paraffines, hydrogenated vegetable oils, leucine, polyethylene glycols, metallic lauryl sulfates (as sodium lauryl sulfate, magnesium lauryl sulfate), sodium chloride, sodium benzoate, sodium acetate and talc.
  • magnesium stearate is used.
  • lubricant is present preferably in the range of 0-10% by weight, more preferably 0.1-5% by weight.
  • glidants are selected from silicon dioxide, magnesium trisilicate, powdered cellulose, starch, talc, calcium phosphate tribasic, stearates metallic, metallic lauryl sulfates and calcium silicate.
  • silicon dioxide is used.
  • glidant is present in the range of less than 1% by weight.

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  • Health & Medical Sciences (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Animal Behavior & Ethology (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Epidemiology (AREA)
  • Medicinal Chemistry (AREA)
  • Chemical & Material Sciences (AREA)
  • General Health & Medical Sciences (AREA)
  • Public Health (AREA)
  • Veterinary Medicine (AREA)
  • Biophysics (AREA)
  • Molecular Biology (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)

Abstract

La présente invention concerne des compositions pharmaceutiques permettant de résoudre les problèmes de solubilité et de stabilité, le procédé de préparation de ces compositions ainsi que leur usage médical.
EP10742615A 2009-07-02 2010-06-25 Composition pharmaceutique présentant une solubilité et une stabilité accrues Withdrawn EP2448575A2 (fr)

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
TR200905145 2009-07-02
PCT/TR2010/000126 WO2011002425A2 (fr) 2009-07-02 2010-06-25 Composition pharmaceutique présentant une solubilité et une stabilité accrues

Publications (1)

Publication Number Publication Date
EP2448575A2 true EP2448575A2 (fr) 2012-05-09

Family

ID=43012669

Family Applications (1)

Application Number Title Priority Date Filing Date
EP10742615A Withdrawn EP2448575A2 (fr) 2009-07-02 2010-06-25 Composition pharmaceutique présentant une solubilité et une stabilité accrues

Country Status (2)

Country Link
EP (1) EP2448575A2 (fr)
WO (1) WO2011002425A2 (fr)

Family Cites Families (16)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US3025292A (en) 1962-03-13 Reduction of i
US5594003A (en) 1991-02-06 1997-01-14 Dr. Karl Thomae Gmbh Tetrahydroimidazo[1,2-a]pyridin-2-yl-(benzimidazol-1-yl)-methyl-biphenyls useful as angiotensin-II antagonists
SI9210098B (sl) 1991-02-06 2000-06-30 Dr. Karl Thomae Benzimidazoli, zdravila, ki te spojine vsebujejo, in postopek za njihovo pripravo
DE4225756A1 (de) 1992-01-22 1994-03-10 Thomae Gmbh Dr K Benzimidazole, diese Verbindungen enthaltende Arzneimittel und Verfahren zu ihrer Herstellung
US5614519A (en) 1991-02-06 1997-03-25 Karl Thomae Gmbh (1-(2,3 or 4-N-morpholinoalkyl)-imidazol-4-yl)-benizimidazol-1-yl-methyl]-biphenyls useful as angiotensin-II antagonists
US5602127A (en) 1991-02-06 1997-02-11 Karl Thomae Gmbh (Alkanesultam-1-yl)-benzimidazol-1-yl)-1yl)-methyl-biphenyls useful as angiotensin-II antagonists
DE19901921C2 (de) 1999-01-19 2001-01-04 Boehringer Ingelheim Pharma Polymorphe von Telmisartan, Verfahren zu deren Herstellung und deren Verwendung zur Herstellung eines Arzneimittels
DE10153737A1 (de) 2001-10-31 2003-05-28 Boehringer Ingelheim Pharma Kristallines Natriumsalz des Telmisartans, Verfahren zu dessen Herstellung und dessen Verwendung zur Herstellung eines Arzneimittels
IL162754A0 (en) 2002-01-16 2005-11-20 Boehringer Ingelheim Pharma Bilayer pharmaceutical tablet comprising telmisartane and a diuretic and preparation thereof
DE10244681A1 (de) 2002-09-24 2004-04-08 Boehringer Ingelheim International Gmbh Neue feste Telmisartan enthaltende pharmazeutische Formulierungen und deren Herstellung
DE10319450A1 (de) * 2003-04-30 2004-11-18 Boehringer Ingelheim Pharma Gmbh & Co. Kg Pharmazeutische Formulierung des Telmisartan Natriumsalzes
US20090012140A1 (en) 2004-11-11 2009-01-08 Lek Pharmaceuticals D.D Preparation of Telmisartan Salts with Improved Solubility
AU2005315855A1 (en) * 2004-12-17 2006-06-22 Boehringer Ingelheim International Gmbh Combination therapy comprising telmisartan and hydrochlorothiazide
US20070116759A1 (en) 2005-11-22 2007-05-24 Gershon Kolatkar Pharmaceutical compositions of telmisartan
SI22297A (sl) 2006-06-23 2007-12-31 Krka, Tovarna Zdravil, D.D., Novo Mesto Priprava soli telmisartana
US20090142398A1 (en) * 2007-11-21 2009-06-04 Pharmascience Inc. Novel pharmaceutical compositions comprising a disintegration matrix

Non-Patent Citations (1)

* Cited by examiner, † Cited by third party
Title
See references of WO2011002425A2 *

Also Published As

Publication number Publication date
WO2011002425A2 (fr) 2011-01-06
WO2011002425A3 (fr) 2011-03-03

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