US20080233188A1 - Stable Pharmaceutical Compositions Comprising a Pyrimidine - Sulfamide - Google Patents

Stable Pharmaceutical Compositions Comprising a Pyrimidine - Sulfamide Download PDF

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Publication number
US20080233188A1
US20080233188A1 US12/066,448 US6644806A US2008233188A1 US 20080233188 A1 US20080233188 A1 US 20080233188A1 US 6644806 A US6644806 A US 6644806A US 2008233188 A1 US2008233188 A1 US 2008233188A1
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Prior art keywords
pharmaceutical composition
formula
weight based
sodium
compound
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Abandoned
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US12/066,448
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English (en)
Inventor
Charles Tokunbo Adesuyi
Lovelace Holman
Olivier Lambert
Bruce Hamilton Lithgow
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Actelion Pharmaceuticals Ltd
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Actelion Pharmaceuticals Ltd
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Application filed by Actelion Pharmaceuticals Ltd filed Critical Actelion Pharmaceuticals Ltd
Assigned to ACTELION PHARMACEUTICALS LTD. reassignment ACTELION PHARMACEUTICALS LTD. ASSIGNMENT OF ASSIGNORS INTEREST (SEE DOCUMENT FOR DETAILS). Assignors: ADESUYI, CHARLES TOKUNBO, HOLMAN, LOVELACE, LAMBERT, OLIVIER, LITHGOW, BRUCE HAMILTON
Publication of US20080233188A1 publication Critical patent/US20080233188A1/en
Priority to US12/388,142 priority Critical patent/US8367685B2/en
Priority to US13/736,699 priority patent/US9265762B2/en
Priority to US15/002,255 priority patent/US10117870B2/en
Priority to US15/900,586 priority patent/US10946015B2/en
Abandoned legal-status Critical Current

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    • 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
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
    • A61K31/506—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim not condensed and containing further heterocyclic rings
    • 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
    • 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
    • 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
    • A61K9/2059—Starch, including chemically or physically modified derivatives; Amylose; Amylopectin; Dextrin
    • 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
    • A61K9/2072—Pills, tablets, discs, rods characterised by shape, structure or size; Tablets with holes, special break lines or identification marks; Partially coated tablets; Disintegrating flat shaped forms
    • A61K9/2077—Tablets comprising drug-containing microparticles in a substantial amount of supporting matrix; Multiparticulate tablets
    • 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
    • A61K9/28—Dragees; Coated pills or tablets, e.g. with film or compression coating
    • A61K9/2806—Coating materials
    • A61K9/2833—Organic macromolecular compounds
    • A61K9/284—Organic macromolecular compounds obtained by reactions only involving carbon-to-carbon unsaturated bonds, e.g. polyvinyl pyrrolidone
    • A61K9/2846—Poly(meth)acrylates
    • 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
    • A61K9/28—Dragees; Coated pills or tablets, e.g. with film or compression coating
    • A61K9/2806—Coating materials
    • A61K9/2833—Organic macromolecular compounds
    • A61K9/286—Polysaccharides, e.g. gums; Cyclodextrin
    • A61K9/2866—Cellulose; Cellulose derivatives, e.g. hydroxypropyl methylcellulose
    • 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
    • A61K9/48—Preparations in capsules, e.g. of gelatin, of chocolate
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P11/00—Drugs for disorders of the respiratory system
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00—Drugs for disorders of the cardiovascular system
    • A61P9/10—Drugs for disorders of the cardiovascular system for treating ischaemic or atherosclerotic diseases, e.g. antianginal drugs, coronary vasodilators, drugs for myocardial infarction, retinopathy, cerebrovascula insufficiency, renal arteriosclerosis
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00—Drugs for disorders of the cardiovascular system
    • A61P9/12—Antihypertensives

Definitions

  • the present invention relates to stable pharmaceutical compositions comprising propylsulfamic acid [5-(4-bromo-phenyl)-6-[2-(5-bromo-pyrimidin-2-yloxy)-ethoxy]-pyrimidin-4-yl]-amide or pharmaceutically acceptable salts, solvates, hydrates or morphological forms thereof, said compound being hereinafter referred to as compound of formula I.
  • Compound of formula I has the following formula:
  • Compound of formula I is an endothelin receptor inhibitor and useful as endothelin receptors antagonist. Compound of formula I and the preparation thereof is disclosed in WO 02/053557.
  • any reference to compound of formula I is to be understood as referring also to pharmaceutically acceptable salts or solvates, including hydrates, of compound of formula I, as well as morphological forms thereof, if not indicated otherwise and where appropriate and expedient.
  • the present compound of formula I is currently being evaluated in clinical trials, thus a stable formulation had to be developed.
  • the present invention therefore relates to stable pharmaceutical compositions comprising the compound propylsulfamic acid [5-(4-bromo-phenyl)-6-[2-(5-bromo-pyrimidin-2-yloxy)-ethoxy]-pyrimidin-4-yl]-amide, or pharmaceutically acceptable salts, solvates, hydrates or morphological forms thereof.
  • a stable pharmaceutical composition according to this invention will comprise:
  • the pharmaceutical composition will be in the form of a tablet.
  • the pharmaceutical composition will be in the form of a capsule.
  • Stable pharmaceutical compositions according to this invention will preferably be such that the filler is selected from one or more of the following: lactose, maize starch, pregelatinized starch, dibasic calcium phosphate dihydrate (CaHPO 4 .2H 2 O), microcrystalline cellulose, maltodextrin and mannitol;
  • the disintegrant is selected from one or more of the following: croscarmellose sodium, sodium starch glycolate, calcium carboxymethylcellulose, sodium carboxymethylcellulose, cross-linked polyvinylpyrrolidone, polyvinylpyrrolidone, alginic acid, sodium alginate, pregelatinized starch, guar gum, clays and ion exchange resins;
  • the surfactant is selected from the following: sodium lauryl sulphate, polysorbates, polyethylene polyoxypropylene polymers, polyoxylethylene stearates, dioctyl sodium sulfosuccinate, polyoxyethylene sorbitan fatty acid
  • a stable pharmaceutical composition according to this invention can comprise:
  • a stable pharmaceutical composition according to this invention can comprise:
  • a stable pharmaceutical composition according to this invention can comprise:
  • a pharmaceutical composition according to this invention can notably comprise:
  • the surfactant is a polysorbate.
  • the lubricant is magnesium stearate.
  • the stable pharmaceutical composition of this invention may also contain a glidant.
  • the present invention therefore further provides stable pharmaceutical compositions, comprising:
  • Fillers according to the invention include but are not restricted to one or more of the following: lactose, maize starch, pregelatinized starch, dibasic calcium phosphate dihydrate (CaHPO 4 .2H 2 O), microcrystalline cellulose, maltodextrin and mannitol.
  • lactose with microcrystalline cellulose lactose with maize starch, pregelatinized starch with microcrystalline cellulose, or dibasic calcium phosphate dihydrate with microcrystalline cellulose are used.
  • lactose monohydrate e.g. Pharmatose® 200 Mesh
  • microcrystalline cellulose e.g. Avicel® PH101
  • Disintegrants include but are not restricted to one or more of the following: croscarmellose sodium, sodium starch glycolate, calcium carboxymethylcellulose (CMC-Ca), sodium carboxymethylcellulose CMC-Na, cross-linked polyvinylpyrrolidone (e.g. Crospovidone (PVP XL; Polyplasdone, commercially available from the ISP company or Kollidon® XL from BASF)), polyvinylpyrrolidone (PVP), alginic acid, sodium alginate, pregelatinized starch, guar gum, clays and ion exchange resins.
  • PVP cross-linked polyvinylpyrrolidone
  • alginic acid sodium alginate
  • pregelatinized starch guar gum
  • clays and ion exchange resins e.g., Amberlite XL
  • sodium starch glycolate is used as disintegrant, or a combination of sodium starch glycolate and PVP.
  • Surfactant according to the invention include but are not restricted to one or more of the following: sodium lauryl sulphate, polysorbates (commercially available as Tween®), polyethylene polyoxypropylene polymers (Pluronic F65), polyoxylethylene stearates (MYRJ), dioctyl sodium sulfosuccinate, polyoxyethylene sorbitan fatty acid esters (commercial available from Nikko Chemicals), polyoxyethylene C 1-4 -alkyl ethers, sucrose monoesters and lanolin esters and ethers.
  • sodium lauryl sulphate is used as surfactant.
  • a polysorbate included in a composition according to the present invention will have a mean polymerisation degree of from 20 to 100 monomer units (preferably about 80), and may for example be polysorbate 80.
  • the polysorbate should be vegetable-derived.
  • Glidants according to the invention include but are not restricted to one or more of the following: silica; colloidal silicon dioxide, e.g. colloidal silica anhydrous (e.g. Aerosil® 200), magnesium trisilicate, powdered cellulose, starch and talc.
  • colloidal silicone dioxide is used.
  • Lubricants according to the invention include but are not restricted to one or more of the following: Mg-, Al- or Ca-stearate, stearic acid, sodium stearyl fumarate, talc, sodium benzoate, a glyceryl mono fatty acid, e.g. having a molecular weight of from 200 to 800 Daltons (e.g. glyceryl monostearate (e.g. from Danisco, UK)), glyceryl dibehenate (e.g. CompritolAT0888TM, Gattefossé France), glyceryl palmito-stearic ester (e.g.
  • PrecirolTM Gattefossé France
  • polyethylene glycol PEG, BASF
  • hydrogenated cotton seed oil Lubitab, Edward Mendell Co Inc.
  • castor seed oil Cutina H R, Henkel
  • sucrose esters Surfhope S E, Mitsubishi-Kagaku Foods Co.
  • magnesium stearate is used.
  • any given excipient may serve more than one function e.g. as filler, disintegrant, surfactant, glidant, and/or lubricant.
  • the stable pharmaceutical composition of this invention may also contain tartaric acid.
  • Lactose as available from commercial suppliers is used for the present invention, preferably Lactose-monohydrate (such as Pharmatose® 200M from DMV International) is used for the present invention.
  • Lactose-monohydrate such as Pharmatose® 200M from DMV International
  • Maize starch as available from commercial suppliers is used for the present invention, preferably maize starch from Roquette.
  • Pregelatinised starch as available from commercial suppliers is used for the present invention, preferably Starch 1500 (from Colorcon).
  • Dibasic calcium phosphate dihydrate as available from commercial suppliers is used for the present invention, preferably dibasic calcium phosphate dihydrate in an unmilled form, such as Calipharm A or A-Tab.
  • Microcrystalline cellulose as available from commercial suppliers is used for the present invention, preferably Avicel PH101 from FMC international.
  • Polyvinylpyrrolidone as available from commercial suppliers is used for the present invention, preferably polyvinylpyrrolidone from BASF.
  • Sodium starch glycolate as available from commercial suppliers is used for the present invention, preferably sodium starch glycolate from Roquette.
  • Sodium lauryl sulphate as available from commercial suppliers is used for the present invention, preferably sodium lauryl sulphate from Ellis & Everard.
  • Colloidal silicon dioxide as available from commercial suppliers is used for the present invention, preferably Aerosil from Degussa AG.
  • Magnesium stearate as available from commercial suppliers is used for the present invention, preferably Magnesium stearate from Peter Greven.
  • C 1-4 -alkyl alone or in combination with other groups, means a straight-chain or branched-chain alkyl group with 1 to 4 carbon atoms.
  • straight-chain and branched C 1 -C 4 alkyl groups are methyl, ethyl, propyl, isopropyl, butyl, sec-butyl, isobutyl, tert-butyl.
  • X refers in the current application to an interval extending from X minus 10% of X to X plus 10% of X, and preferably to an interval extending from X minus 5% of X to X plus 5% of X.
  • salts encompasses either salts with inorganic acids or organic acids like hydrochloric or hydrobromic acid, sulfuric acid, phosphoric acid, citric acid, formic acid, acetic acid, maleic acid, tartaric acid, benzoic acid, methanesulfonic acid, p-toluenesulfonic acid, and the like that are non toxic to living organisms or in case the compound of formula (I) is acidic in nature with an inorganic base like an alkali or earth alkali base, e.g. sodium hydroxide, potassium hydroxide, calcium hydroxide and the like.
  • inorganic acids or organic acids like hydrochloric or hydrobromic acid, sulfuric acid, phosphoric acid, citric acid, formic acid, acetic acid, maleic acid, tartaric acid, benzoic acid, methanesulfonic acid, p-toluenesulfonic acid, and the like that are non toxic to living organisms or in case the compound of formula (I) is
  • ww % refers to a percentage by weight compared to the total weight of the composition considered.
  • a filler which is selected from one or more of the following: lactose, maize starch, pregelatinized starch, dibasic calcium phosphate dihydrate (CaHPO 4 .2H 2 O) and microcrystalline cellulose, maltodextrin and mannitol; a disintegrant which is selected from one or more of the following: croscarmellose sodium, sodium starch glycolate, CMC-Ca, CMC-Na, cross-linked PVP, PVP, alginic acid, sodium alginate, pregelatinized starch, guar gum, clays and ion exchange resins; a surfactant which is selected from the following: sodium lauryl sulphate, polysorbates, polyethylene polyoxypropylene polymers, polyoxylethylene stearates and dioctyl sodium sulfosuccinate, polyoxyethylene sorbitan fatty acid esters, polyoxyethylene C 1-4 -alkyl ethers, sucrose monoesters and lan
  • the pharmaceutical composition comprise
  • the pharmaceutical composition comprise
  • compositions or pharmaceutically acceptable salts, solvates, hydrates or morphological forms thereof, according to the invention may be used as a medicament.
  • compositions or pharmaceutically acceptable salts, solvates, hydrates or morphological forms thereof, according to the invention may be used for the preparation of a medicament, for use in the treatment of pulmonary arterial hypertension (PAH).
  • PAH pulmonary arterial hypertension
  • the amount of compound of formula I, or pharmaceutically acceptable salts, solvates, hydrates or morphological forms thereof may be a total amount of up to 90% in weight based on the total weight of the pharmaceutical composition.
  • the amount of compound of formula I, or pharmaceutically acceptable salts, solvates, hydrates or morphological forms thereof may be a total amount of up to 50% in weight based on the total weight of the pharmaceutical composition. More preferably, the amount of compound of formula I, or pharmaceutically acceptable salts, solvates, hydrates or morphological forms thereof, will be from 1 to 50%, notably from 5 to 30% and in particular from 10 to 20% in weight based on the total weight of the pharmaceutical composition.
  • the amount of filler may vary within a range of 10 to 95%, in particular 30 to 85% and more particularly 30 to 50% in weight based on the total weight of the pharmaceutical composition.
  • the amount of disintegrant may vary from 1 to 20%, preferably from 2 to 10% (e.g. from 3 to 8%) and notably from 2 to 5% in weight based on the total weight of the pharmaceutical composition.
  • the composition may contain 2 to 4% (e.g. 3%) disintegrant in weight based on the total weight of the pharmaceutical composition.
  • the amount of surfactant may vary from 0.01 to 7%, preferably from 0.1 to 3% and in particular from 0.1 to 1% in weight based on the total weight of the pharmaceutical composition.
  • the amount of glidant, when present in composition may vary within ranges of from 0.1 to 5%, in particular 0.1 to 2.5%, especially 0.5 to 1.0% in weight based on the total weight of the pharmaceutical composition.
  • the amount of lubricant may vary from 0.05 to 10%, preferably from 0.05 to 7%, most preferably from 0.1 to 3.0% and notably between 0.1 and 1% in weight based on the total weight of the pharmaceutical composition.
  • the amount of tartaric acid, when present in the composition may vary from 0.1 to 10%, preferably from 1 to 10%, and most preferably from 4 to 6% in weight based on the total weight of the pharmaceutical composition.
  • the total weight percent of the pharmaceutical composition is 100.
  • a pharmaceutical composition according to the invention is considered “stable”, if during a certain period of time 70%, preferably 80% and most preferably 95% of the initial content of compound of formula I, or pharmaceutically acceptable salt, solvate, hydrate or morphological form thereof, is maintained over said period of time.
  • the stability of the pharmaceutical composition may be tested in conventional manner, e.g. by measurement of compound of formula I and its degradation products, dissolution, friability, disintegration time, appearance and/or microscopy, e.g. after storage at 25° C. and 60% relative humidity, and/or storage at 40° C. and 75% relative humidity for defined periods of time.
  • the solid compositions of this invention will be stable for at least 6 or 12 months when kept at a temperature of 5 to 50° C. More preferably, they will be stable for at least 6 or 12 months when kept at a temperature of 15 to 45 C. Most preferred, they will be stable for at least 6 or 12 months when kept at a temperature of 25 to 40° C.
  • the pharmaceutical compositions are stable over a certain period of time such as 1 year, and preferably 2 years. More preferably, the pharmaceutical compositions are stable for 3 years.
  • the pharmaceutical composition may be formulated as capsule and tablet.
  • a batch size of 1625 g (6500 capsules) of 1 mg dosage strength may be prepared as follows:
  • the intragranular materials were pre-mixed in a high shear mixer e.g. a Diosna, (6 L bowl) for 5 minutes. About 731-893 g of water at a rate of 65 g/minute was added to the intra-granular materials whilst mixing until suitable granules were formed. The intra-granular materials were further mixed for 2 minutes. They were then dried in a fluid bed dryer with an inlet air temperature of 60° C. until the loss on drying of the granules were 6-9% w/w. The granules were then passed through a co-mill fitted with a 813 ⁇ m screen.
  • a high shear mixer e.g. a Diosna, (6 L bowl) for 5 minutes. About 731-893 g of water at a rate of 65 g/minute was added to the intra-granular materials whilst mixing until suitable granules were formed. The intra-granular materials were further mixed for 2 minutes. They were then dried in a fluid bed
  • magnesium stearate All the extra-granular materials except magnesium stearate were passed through a 1000 ⁇ m screen and were mixed with the granules for 25 minutes at 25 rpm in a 10 L Pharmatech double cone shell mixer. The magnesium stearate was screened through a 500 ⁇ m sieve and added to the rest of the powder mixture in the mixer and mixed for a further 3 minutes.
  • the powder was then filled in a size “0”, white-opaque hard gelatine capsules.
  • one or more lubricants may be sprayed on the material contacting surfaces of pressing tools, e.g. punches and/or dies, of the tabletting machine before compression.
  • the capsules may vary in size e.g. size 1 to “00”.
  • tablets may also be produced.
  • the tablets may vary in shape and be, for example, round, oval, oblong, cylindrical, clover-shaped or any other suitable shape.
  • the tablets obtained are clover shaped or round.
  • the edges of the tablets may be beveled or rounded.
  • the tablets are clover shaped with beveled edges.
  • the tablets according to the invention may be scored or engraved.
  • the tablet according to the invention may also be clover-shaped, quadrisected with beveled edges. It may have a diameter ranging between 5 and 15 mm (for example a diameter of 5 to 8 mm such as a diameter of 6 mm), notably a diameter ranging between 8 and 15 mm, and in particular a diameter ranging between 9 and 11 mm. Its thickness (before coating, if a coating pellicle is applied on the tablet) is ranging from 2.5 to 4.5 mm, preferably between 2.9 and 3.9 mm.
  • the capsules and tablets of the invention may be colored and/or marked so as to impart an individual appearance and to make them instantly recognizable.
  • the use of dyes can serve to enhance the appearance as well as to identify the tablets.
  • Dyes suitable for use in pharmacy typically include carotinoids, iron oxides or chlorophyll.
  • the tablets of the invention may be marked using an imprint code.
  • the capsules and tablets of the present invention are useful for the treatment of PAH and exhibit a good pharmacokinetic profile.
  • Procedures which may be used may be conventional or known in the art or based on such procedures e.g. those described in L. Lachman et al., The Theory and Practice of Industrial Pharmacy, 3rd Ed., 1986; H. Sucker et al., Pharmazeutician Technologie, Thieme, 1991; Hagers Handbuch der pharmazeutician für für Science, 13th Ed., (Mack Publ., Co., 1970) or later editions.
  • the drying step can notably be carried out using a fluid bed dryer.
  • the preparation process according to the present invention can be carried out according to the following process flow chart:
  • Two variants of this process may be carried out, one involving wet granulation (i.e. the process as shown in the flow chart above wherein some water is added to the intra-granular materials, said water being removed by the drying step), and the other involving direct compression (i.e. the process as shown in the flow chart above less the drying step, said drying step being superfluous since no water is added to the intra-granular materials).
  • the tablets obtained by the preparation process set out previously are coated by a protective pellicle.
  • Said protective pellicle will notably prevent direct contact of the tablet with moisture; they may also ease imprints in the tablet.
  • the amount of coating material by weight will be from 2 to 8%, preferably from 3 to 7% and more preferably from 4 to 6% of the weight of the tablet before its coating.
  • the coating material making said protective pellicle will include a low water vapour permeability polymer (such as a polyvinyl alcohol (e.g. Opadry® AMB) or dimethylaminoethyl methacrylate (e.g. EUDRAGIT® E PO)).
  • the coating material can further include a plasticizing agent (e.g. propylene glycol, triacetyne, dibutyl phthalate or dibutyl sebacate), a surfactant (e.g. sodium lauryl sulphate or a polysorbate such as Tween) and/or a lubricant/glidant (e.g. stearic acid, magnesium or calcium stearate or talc).
  • the coating material can also include a pigment (e.g. iron(II) oxide, iron(III) oxide or titanium oxide) to give the tablet a coloured aspect.
  • compositions of Examples 16-33 were prepared by following a wet granulation process summarized by the following flow chart:
  • the coating solution for the Opadry® AMB coated tablets was obtained by preparing a 20% w/w dispersion of the Opadry® AMB (a fine white powder) in purified water in a stainless steel vessel at room temperature. The dispersion was stirred using a Heidolph stirrer equipped with a stainless steel paddle for 45 minutes before use and throughout the coating process. The coating pan was allowed to equilibrate to the set point temperature (60° C.) prior to charging with tablets. The tablets were equilibrated in the drying pan for 10 minutes prior to coating. The same temperature and airflow was used for the heating, coating and drying phases.
  • the airflow in the coating pan was not measured at the time of coating but has subsequently been measured and was found to be approximately 250 m 3 per hour.
  • the film coating took between 110 and 120 minutes to complete (coating was stopped when 1460 g of the solution had been sprayed).
  • the tablets were dried for 10 min in the pan after coating.
  • the coating trail was performed in a Lödige LHC 25.
  • the spray gun type was an airborne spray gun Schlick 970/7-1 S75 with a nozzle diameter of 1.2 mm.
  • As delivery system for the spraying suspension a Verder CD 70 peristaltic pump and a silicone tube with 2 mm internal diameter were used.
  • the coating suspension for the EUDRAGIT® E PO coated tablets was obtained as follows. Water was given in a container, the relevant quantity of sodium lauryl sulphate was added and the mixture was homogenised for 5 min using an ULTRA Turrax. Afterwards the relevant quantity of stearic acid was added in small portions and homogenised for 5-10 min. After this homogenisation period, EUDRAGIT® E PO was added slowly in small portions and homogenised for 30 min. Then the relevant quantity of magnesium stearate was prepared as 15% suspension in water by means of an ULTRA Turrax and homogenised. The magnesium stearate suspension was given to the EUDRAGIT® E PO solution. The final coating suspension was stirred continuously with conventional propeller stirrer during the process.
  • Example 3 Compound of formula I 0.08 0.08 Pharmatose DCL11 68.62 — Starch 1500 — 93.62 Avicel PH101 25.00 — Sodium starch glycolate 4.00 4.00 Sodium lauryl sulphate 1.00 1.00 Aerosil 200 0.30 0.30 Magnesium stearate 1.00 1.00 100 100
  • Compound of formula I Capsules 10 mg Typical Percentage Batch Material Formula Unit Dose Quantity (Chemical name) Function (% w/w) (mg) (g) Intra-granular Compound of formula I Active 4.00 10.00 30.00 Pregelatinized maize starch, Diluent 69.70 174.25 522.75 EP/BP/NF Microcrystalline cellulose, EP Diluent/disintegrant 10.00 25.00 75.00 Sodium starch glycolate, EP Disintegrant 2.00 5.00 15.00 Sodium lauryl sulphate, EP/NF Surfactant 1.00 2.50 7.50 Extra-granular Microcrystalline cellulose, EP Diluent/disintegrant 10.00 25.00 75.00 Sodium starch glycolate, EP Disintegrant 2.00 5.00 15.00 Colloidal silicone dioxide, Glidant 0.30 0.75 2.25 EP/NF Magnesium stearate, EP/BP Lubricant 1.00 2.50 7.50 Total 100.000 250.00 750.00
  • Compound of formula I Capsules 100 mg Typical Percentage Batch Material Formula Unit Dose Quantity (Chemical name) Function (% w/w) (mg) (g) Intra-granular Compound of formula I Active 40.00 100.00 300.00 Pregelatinized maize starch, Diluent 33.70 84.25 252.75 EP/BP/NF Microcrystalline cellulose, EP Diluent/disintegrant 10.00 25.00 75.00 Sodium starch glycolate, EP Disintegrant 2.00 5.00 15.00 Sodium lauryl sulphate, EP/NF Surfactant 1.00 2.50 7.50 Extra-granular Microcrystalline cellulose, EP Diluent/disintegrant 10.00 25.00 75.00 Sodium starch glycolate, EP Disintegrant 2.00 5.00 15.00 Colloidal silicone dioxide, Glidant 0.30 0.75 2.25 EP/NF Magnesium stearate, EP/BP Lubricant 1.00 2.50 7.50 Total 100.000 250.00 100.000
  • Example 17 70 mg tablets containing 10 mg of compound of formula I made as in Example 17 above (having a diameter of 5 mm and a height of 3.1 mm) were coated using the general tablet coating methodology with EUDRAGIT® E PO mentioned above.
  • the uncoated tablet batch size was 500 g.
  • EUDRAGIT® E PO sodium lauryl sulphate, stearic acid, magnesium stearate and water were used:
  • EUDRAGIT ® E PO (g) 26.3 Sodium lauryl sulphate (g) 2.6 Stearic acid (g) 3.9 Magnesium stearate (g) 9.2 Water 238.4
  • Example 28 70 mg tablets containing 0.3 mg of compound of formula I made as in Example 28 above (having a diameter of 5 mm and a height of 2.9 mm) were coated using the general tablet coating methodology with EUDRAGIT® E PO mentioned above.
  • the uncoated tablet batch size was 600 g.
  • EUDRAGIT® E PO sodium lauryl sulphate, stearic acid and magnesium stearate were used:
  • EUDRAGIT ® E PO 92.0 Sodium lauryl sulphate (g) 9.2 Stearic acid (g) 13.8 Magnesium stearate (g) 32.2 Water 834.3
  • Stationary phase EC 250/3 Nucleodur C18 gravity 3 ⁇ m (cat. No. 7600820.30) Column: 250 mm ⁇ 3.00 mm 3 ⁇ m (Macherey-Nagel) Mobile phase: Isocratic Injected volume: 10 ⁇ l Column temperature: 25° C. Auto sampler temperature: 25° C. Flow rate: 0.5 ml/min Pressure: 149 bar Detection wavelength: 260 nm Chromatogram time: 10 min Mobile phase: Mix well 850 ml acetonitrile, 150 ml water and 5 ml trifluoroacetic acid. Degas before use.
  • 10 l of the dissolution medium are prepared as follows: 79.85 g of NaH 2 PO 4 .2H 2 O, 69.55 g of Na 2 HPO 4 and 5 g of Tween 80 are diluted with water to a total volume of 10 l.
  • a reference standard solution of compound of formula I is prepared in duplicate.
  • One of the reference standard solutions will be used as the working reference standard solution, and the other standard solution will be used as a control reference standard solution.
  • a reference standard solution of compound of formula I is obtained as follows:
  • the dissolution sample solution is prepared as follows:
  • dissolution medium 900 ml of dissolution medium are transferred into each vessel of the dissolution apparatus.
  • the dissolution medium is allowed to equilibrate for at least 30 min in the dissolution batch at 37° C. ⁇ 0.5° C.
  • a 10 mg tablet of compound of formula I is dropped into each vessel.
  • 12 ml of the sample solution are withdrawn from each vessel at 5, 10, 15, 30, 45 and 60 min. No medium replacement is required.
  • the sample solution is filtered without delay through a Gelman 1 ⁇ m glass fibre acrodisk syringe filter into an HPLC vial and cooled to room temperature.
  • the working reference standard solution is re-injected to ensure that the system drift is within the limit (2.0%).
  • compositions of Examples 16-20 when tested using the protocol explained, show the dissolution profile shown in FIG. 1 (wherein the percentage dissolution (Y-axis) is represented in function of the time in min (X-axis)).

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Cited By (11)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US20090318459A1 (en) * 2006-08-29 2009-12-24 Actelion Pharmaceuticals Ltd. Therapeutic Compositions Comprising a Specific Endothelin Receptor Antagonist and a PDE5 Inhibitor
US20100311774A1 (en) * 2008-02-20 2010-12-09 Martine Clozel Combination Comprising Paclitaxel for Treating Ovarian Cancer
US20110136818A1 (en) * 2008-08-13 2011-06-09 Martine Clozel Therapeutic compositions containing macitentan
US8324232B2 (en) 2007-08-17 2012-12-04 Actelion Pharmaceuticals Ltd. 4-pyrimidinesulfamide derivative
US20130236438A1 (en) * 2010-11-12 2013-09-12 Scharper Therapeutics S.R.L. Composition for Treating Phonatory and Olfactory Apparatus Disorders
US9265762B2 (en) 2005-09-12 2016-02-23 Actelion Pharmaceuticals Ltd. Stable pharmaceutical compositions comprising a pyrimidine-sulfamide
US20160074398A1 (en) * 2013-04-22 2016-03-17 Sandoz Ag Pharmaceutical composition containing crystalline macitentan
CN114096239A (zh) * 2019-07-05 2022-02-25 社会医疗技术员技术股份公司 压缩的马西替坦组合物、方法及其用途
US11464777B2 (en) 2018-12-21 2022-10-11 Actelion Pharmaceuticals Ltd Pharmaceutical composition for the treatment of pulmonary arterial hypertension
US11612600B2 (en) 2019-01-25 2023-03-28 Actelion Pharmaceuticals Ltd Pharmaceutical composition comprising macitentan for the treatment of chronic thromboembolic pulmonary hypertension
US12208101B2 (en) 2014-07-25 2025-01-28 Novartis Ag Tablet formulation of 2-fluoro-n-methyl-4-[7-(quinolin-6-ylmethyl)imidazo[1,2-b][1,2,4]triazin-2-yl]benzamide

Families Citing this family (16)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
TWI399223B (zh) * 2006-09-15 2013-06-21 Daiichi Sankyo Co Ltd 奧美沙坦酯及氨氯地平之固體劑型
JP2013501791A (ja) 2009-08-10 2013-01-17 ボード・オブ・リージエンツ，ザ・ユニバーシテイ・オブ・テキサス・システム エンドセリン受容体の阻害剤による星状細胞−腫瘍細胞の処置
WO2011074961A1 (en) 2009-12-18 2011-06-23 Frieslandcampina Nederland Holding B.V. Co-processed tablet excipient composition its preparation and use
AU2012213036A1 (en) 2011-02-04 2013-09-19 Actelion Pharmaceuticals Ltd Combinations comprising macitentan for the treatment of glioblastoma multiforme
PL3007695T3 (pl) 2013-06-13 2024-07-01 Akebia Therapeutics, Inc. Kompozycje i sposoby leczenia niedokrwistości
CN105693624B (zh) * 2013-06-14 2018-05-18 杭州普晒医药科技有限公司 马西替坦晶体及其制备方法、其药物组合物和用途
US20170158645A1 (en) * 2014-07-15 2017-06-08 Olon S.P.A. Amorphous form and new crystalline forms of macitentan
CN105388244B (zh) * 2015-12-10 2017-03-08 合肥久诺医药科技有限公司 一种马西替坦有关物质的高效液相色谱分析方法
WO2018153925A1 (en) 2017-02-22 2018-08-30 Amneal Pharmaceuticals Company Gmbh Stable pharmaceutical compositions comprising macitentan
CN118480033A (zh) 2019-05-22 2024-08-13 无锡智康弘义生物科技有限公司 一种嘧啶磺酰胺类化合物的晶型及其制备方法
ES2994089T3 (en) 2019-11-29 2025-01-17 Actelion Pharmaceuticals Ltd Initial triple combination therapy with macitentan, tadalafil, and selexipag for treating pulmonary arterial hypertension
WO2022238375A1 (en) 2021-05-11 2022-11-17 Actelion Pharmaceuticals Ltd Methods of treating pulmonary hypertension
TW202317119A (zh) * 2021-06-11 2023-05-01 瑞士商艾克泰聯製藥有限公司 用於口服投予之分散錠
JP2024530727A (ja) 2021-08-25 2024-08-23 ビーエーエスエフ ソシエタス・ヨーロピア 直接打錠補助組成物
WO2023038600A1 (en) * 2021-09-07 2023-03-16 Sanovel Ilac Sanayi Ve Ticaret Anonim Sirketi A capsule formulation comprising macitentan
EP4154873A1 (en) 2021-09-22 2023-03-29 Sanovel Ilac Sanayi Ve Ticaret A.S. The tablet comprising macitentan

Family Cites Families (35)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US5945098A (en) 1990-02-01 1999-08-31 Baxter International Inc. Stable intravenously-administrable immune globulin preparation
JPH04103525A (ja) 1990-08-22 1992-04-06 Sanwa Kagaku Kenkyusho Co Ltd 難水溶性薬物の持続性製剤化方法
RU2086544C1 (ru) 1991-06-13 1997-08-10 Хоффманн-Ля Рош АГ Бензолсульфонамидные производные пиримидина или их соли, фармацевтическая композиция для лечения заболеваний, связанных с активностью эндотелина
ES2154650T3 (es) 1992-10-02 2001-04-16 Genetics Inst Composicion que comprende una formulacion con factor de coagulacion viii, procedimiento para su preparacion y uso de un tensioactivo como estabilizador.
US5811120A (en) 1994-03-02 1998-09-22 Eli Lilly And Company Solid orally administerable raloxifene hydrochloride pharmaceutical formulation
TW442301B (en) 1995-06-07 2001-06-23 Sanofi Synthelabo Pharmaceutical compositions containing irbesartan
ES2156305T3 (es) 1995-12-20 2001-06-16 Yamanouchi Pharma Co Ltd Derivados de ariletenosulfonamida y composiciones de farmacos que los contienen.
JPH103525A (ja) 1996-06-14 1998-01-06 Dainippon Printing Co Ltd Ｉｃカード、命令コード格納方法及び命令コード実行方法
AR017426A1 (es) 1997-12-08 2001-09-05 Smithkline Beecham Corp Sal de monoargininilo del acido (e)-3-[1-n-butil-5-[2-(2-carboxifenil)metoxi-4-clorofenil]-1h-pirazol-4-il]-2-[(5-metoxi-2,3-dihidrobenzofuran-6-il)metil]-prop-2-enoico, composicion farmaceutica que la contiene, su uso para la manufactura de un medicamento y procedimiento para su preparacion
JP2002505269A (ja) 1998-03-06 2002-02-19 エウランド インターナショナル ソシエタ ペル アチオニ 急速崩壊錠剤
US20010014352A1 (en) * 1998-05-27 2001-08-16 Udit Batra Compressed tablet formulation
US20040062803A1 (en) * 1999-12-22 2004-04-01 Hedden David B. Sustained-release formulation of a cyclooxygenase-2 inhibitor
PL197782B1 (pl) * 1999-12-31 2008-04-30 Encysive Pharmaceuticals Inc Sulfonoamidy, środek farmaceutyczny i zastosowanie sulfonoamidów
GB0001621D0 (en) 2000-01-26 2000-03-15 Astrazeneca Ab Pharmaceutical compositions
JP2001335469A (ja) 2000-05-26 2001-12-04 Lion Corp 固体製剤の製造方法
MXPA02012795A (es) 2000-06-28 2004-07-30 Teva Pharma Carvedilol.
EP1364643A4 (en) 2000-12-01 2009-07-15 Kyowa Hakko Kogyo Kk COMPOSITION WITH IMPROVED SOLUBILITY OR ORAL ABSORBIBILITY
NZ526336A (en) 2000-12-07 2004-11-26 Cv Therapeutics Inc Substituted 1, 3,5-triazines and pyrimidines as ABCA-1 elevating compounds against coronary artery disease or atherosclerosis
NZ525614A (en) * 2000-12-18 2005-03-24 Actelion Pharmaceuticals Ltd Novel sulfamides and their use as endothelin receptor antagonists
FR2819720B1 (fr) 2001-01-22 2004-03-12 Fournier Lab Sa Nouveaux comprimes de fenofibrate
JP3930290B2 (ja) 2001-09-12 2007-06-13 富士フイルム株式会社 熱現像感光材料及びそれを用いた熱現像方法
KR20030041577A (ko) 2001-11-20 2003-05-27 디디에스텍주식회사 난용성 약물과 치환된 시클로덱스트린을 함유하는고체분산체 및 이를 함유하는 약제학적 조성물
MXPA04006608A (es) * 2002-01-07 2004-10-04 Pharmacia Corp Tratamiento de dolor, inflamacion y trastornos relacionados con inflamacion con una combinacion de inhibidor selectivo de ciclooxigenasa-2 y aspirina.
CN1652782A (zh) 2002-02-11 2005-08-10 美国辉瑞有限公司 用作pde4抑制剂的烟酰胺衍生物
CN1326569C (zh) * 2002-02-26 2007-07-18 阿斯特拉曾尼卡有限公司 含有水溶性纤维素衍生物的iressa药物制剂
GB0204771D0 (en) 2002-02-28 2002-04-17 Phoqus Ltd Fast disintegrating tablets
EP1591120A4 (en) 2003-01-28 2009-06-10 Takeda Chemical Industries Ltd RECEPTOR AGONISTS
MXPA05009098A (es) 2003-02-25 2005-11-17 Lilly Co Eli Clorhidrato de 1- (4-(2 -piperidiniletoxifenoxi) -2-(4-metansulfonilfenil) -6-hidroxinaftaleno cristalino no solvatado.
KR20070015506A (ko) 2003-12-10 2007-02-05 액티브 바이오틱스 인코포레이티드 리파마이신 유사체 및 그의 용도
US7094081B1 (en) 2005-03-24 2006-08-22 Delphi Technologies, Inc. Electrical connector assembly
AU2006290309B2 (en) 2005-09-12 2012-04-05 Actelion Pharmaceuticals Ltd. Stable pharmaceutical composition comprising a pyrimidine-sulfamide
AR062501A1 (es) 2006-08-29 2008-11-12 Actelion Pharmaceuticals Ltd Composiciones terapeuticas
TWI441639B (zh) 2008-02-20 2014-06-21 Actelion Pharmaceuticals Ltd 用於治療卵巢癌之包含紫杉醇之組合
US8809334B2 (en) 2008-08-13 2014-08-19 Actelion Pharmaceuticals Ltd. Therapeutic compositions containing macitentan
AU2012213036A1 (en) 2011-02-04 2013-09-19 Actelion Pharmaceuticals Ltd Combinations comprising macitentan for the treatment of glioblastoma multiforme

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US10117870B2 (en) 2005-09-12 2018-11-06 Actelion Pharmaceuticals Ltd. Stable pharmaceutical compositions comprising a pyrimidine-sulfamide
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US10946015B2 (en) 2005-09-12 2021-03-16 Actelion Pharmaceuticals Ltd Stable pharmaceutical compositions comprising a pyrimidine-sulfamide
US8268847B2 (en) 2006-08-29 2012-09-18 Actelion Pharmaceuticals, Ltd. Therapeutic compositions comprising a specific endothelin receptor antagonist and a PDE5 inhibitor
US20090318459A1 (en) * 2006-08-29 2009-12-24 Actelion Pharmaceuticals Ltd. Therapeutic Compositions Comprising a Specific Endothelin Receptor Antagonist and a PDE5 Inhibitor
US8324232B2 (en) 2007-08-17 2012-12-04 Actelion Pharmaceuticals Ltd. 4-pyrimidinesulfamide derivative
US8541433B2 (en) 2008-02-20 2013-09-24 Actelion Pharmaceuticals, Ltd. Combination comprising macitentan and paclitaxel for treating multi-drug resistant ovarian cancer
US20100311774A1 (en) * 2008-02-20 2010-12-09 Martine Clozel Combination Comprising Paclitaxel for Treating Ovarian Cancer
US8809334B2 (en) 2008-08-13 2014-08-19 Actelion Pharmaceuticals Ltd. Therapeutic compositions containing macitentan
US9173881B2 (en) 2008-08-13 2015-11-03 Actelion Pharmaceuticals Ltd. Therapeutic compositions containing macitentan
US9597331B2 (en) 2008-08-13 2017-03-21 Actelion Pharmaceuticals Ltd. Therapeutic compositions containing macitentan
US20110136818A1 (en) * 2008-08-13 2011-06-09 Martine Clozel Therapeutic compositions containing macitentan
US20130236438A1 (en) * 2010-11-12 2013-09-12 Scharper Therapeutics S.R.L. Composition for Treating Phonatory and Olfactory Apparatus Disorders
US20160074398A1 (en) * 2013-04-22 2016-03-17 Sandoz Ag Pharmaceutical composition containing crystalline macitentan
US9730932B2 (en) * 2013-04-22 2017-08-15 Sandoz Ag Pharmaceutical composition containing crystalline macitentan
US12208101B2 (en) 2014-07-25 2025-01-28 Novartis Ag Tablet formulation of 2-fluoro-n-methyl-4-[7-(quinolin-6-ylmethyl)imidazo[1,2-b][1,2,4]triazin-2-yl]benzamide
US11464777B2 (en) 2018-12-21 2022-10-11 Actelion Pharmaceuticals Ltd Pharmaceutical composition for the treatment of pulmonary arterial hypertension
US11612600B2 (en) 2019-01-25 2023-03-28 Actelion Pharmaceuticals Ltd Pharmaceutical composition comprising macitentan for the treatment of chronic thromboembolic pulmonary hypertension
CN114096239A (zh) * 2019-07-05 2022-02-25 社会医疗技术员技术股份公司 压缩的马西替坦组合物、方法及其用途

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SI1928409T1 (sl) 2012-12-31
ZA200802947B (en) 2009-12-30
KR20080055897A (ko) 2008-06-19
US8367685B2 (en) 2013-02-05
HRP20120957T1 (hr) 2012-12-31
RU2424805C2 (ru) 2011-07-27
PT1928409E (pt) 2012-11-27
BRPI0615898A2 (pt) 2011-05-31
CA2621273A1 (en) 2007-03-22
JP5054061B2 (ja) 2012-10-24
JP2009519893A (ja) 2009-05-21
JP2009235073A (ja) 2009-10-15
WO2007031933A3 (en) 2007-10-18
KR101313395B1 (ko) 2013-10-02
WO2007031933A2 (en) 2007-03-22
US11648249B2 (en) 2023-05-16
TW200803860A (en) 2008-01-16
US20130190336A1 (en) 2013-07-25
AU2006290309A1 (en) 2007-03-22
JP4955685B2 (ja) 2012-06-20
CN101262847B (zh) 2010-11-24
US20210186966A1 (en) 2021-06-24
EP1928409B1 (en) 2012-09-12
DK1928409T3 (da) 2012-11-05
US9265762B2 (en) 2016-02-23
CA2621273C (en) 2014-07-29
ES2393117T3 (es) 2012-12-18
CY1113395T1 (el) 2016-06-22

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