Classifications

• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
  • A61K47/30—Macromolecular organic or inorganic compounds, e.g. inorganic polyphosphates
  • A61K47/36—Polysaccharides; Derivatives thereof, e.g. gums, starch, alginate, dextrin, hyaluronic acid, chitosan, inulin, agar or pectin
• • 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
  • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
  • A61K31/47—Quinolines; Isoquinolines
  • A61K31/473—Quinolines; Isoquinolines ortho- or peri-condensed with carbocyclic ring systems, e.g. acridines, phenanthridines
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
  • A61K47/02—Inorganic compounds
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
  • A61K47/06—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
  • A61K47/26—Carbohydrates, e.g. sugar alcohols, amino sugars, nucleic acids, mono-, di- or oligo-saccharides; Derivatives thereof, e.g. polysorbates, sorbitan fatty acid esters or glycyrrhizin
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K9/00—Medicinal preparations characterised by special physical form
  • A61K9/0012—Galenical forms characterised by the site of application
  • A61K9/0019—Injectable compositions; Intramuscular, intravenous, arterial, subcutaneous administration; Compositions to be administered through the skin in an invasive manner
• • 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
  • A61K9/19—Particulate form, e.g. powders, Processes for size reducing of pure drugs or the resulting products, Pure drug nanoparticles lyophilised, i.e. freeze-dried, solutions or dispersions
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P35/00—Antineoplastic agents
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P35/00—Antineoplastic agents
  • A61P35/02—Antineoplastic agents specific for leukemia
• • 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

Definitions

• the present invention relates to injectable pharmaceutical compositions containing 6,9-bis[(2-aminoethyl)amino]benzo[g]isoquinoline-5,10-dione dimaleate (from now on also referred to as "BBR 2778") as active ingredient in the form of a lyophilised powder with a carrier selected from lactose and dextran, mixed with sodium chloride.
• BBR 2778 6,9-bis[(2-aminoethyl)amino]benzo[g]isoquinoline-5,10-dione dimaleate
• BBR 2778 is a novel anthracenedione derivative with anti-tumoral activity which acts as a DNA intercalating agent and topoisomerase II inhibitor. Pre-clinical studies demonstrate that its cardiotoxicity is lower than that of other known drugs belonging to the same class. BBR 2778 has proved more active than mitoxantrone against haematological tumours, especially ascitic L1210 leukaemia and YC-8 lymphoma, in a wide range of doses.
• BBR 2778 Clinical trials on the use of BBR 2778 in the treatment of non- Hodgkin's lymphoma are at an advanced stage.
• the formulation of BBR2778 in injectable liquid pharmaceutical compositions has proved problematic in terms of stability in solution using common solvents suitable for parenteral administration, especially intravenous administration.
• a lyophilised formulation to be reconstituted with a suitable solvent such as saline immediately before use has therefore been considered.
• a first aspect of the invention therefore provides injectable pharmaceutical compositions containing 6,9-bis[(2-aminoethyl)amino]benzo [g]isoquinoline-5,10-dione dimaleate (BBR 2778) as active ingredient in the form of a lyophilised powder with a carrier selected from lactose and dextran, mixed with sodium chloride, to be reconstituted with a solvent suitable for reconstituting the lyophilisate and suitable for parenteral administration, which solvent is preferably contained in a separate ampoule.
• BBR 2778 6,9-bis[(2-aminoethyl)amino]benzo [g]isoquinoline-5,10-dione dimaleate
• a further aspect of the invention relates to a process for the preparation of said compositions.
• the weight ratio between the carrier and sodium chloride is critical, and is typically between 1 :1 and 3: 1.
• the weight ratio between BBR 2778 and the carrier is preferably between 1 :2 and 1 :6.
• the particularly preferred carrier is lactose.
• the unit dose of BBR 2778 will usually be between 25 and 200 mg, and preferably between 50 and 100 mg.
• the unit dose currently being tested in clinical trials is 50 mg.
• the preferred compositions according to the invention will contain 100 to 200 mg of sodium chloride and 100 to 300 mg of lactose.
• compositions of the invention can also contain other excipients commonly used for parenteral formulations, such as antioxidants, buffers, local anaesthetics, salts, amino acids and the like.
• the vials or ampoules of sterile lyophilised powder will then be reconstituted at the time of use with sterile solvents constituted by sterile pyrogen-free water or sterile saline, in volumes of approx. 5 ml to 20 ml, depending on the active ingredient content.
• compositions of the invention are prepared by a process which comprises lyophilisation of an aqueous solution of BBR 2778, lactose or dextran and sodium chloride by means of: • a freezing stage at a temperature below at least -45°C for at least 3 hours;
• a primary drying stage consisting of increasing the temperature of the product to -35°C ⁇ 5°C in approx. 3 hours and maintaining said temperature for at least 40 hours;
• a secondary drying stage consisting of increasing the temperature of the product to +30°C ⁇ 5°C in 10 hours and maintaining said temperature for at least 8 hours.
• compositions according to the invention are stable at room temperature for at least 24 months.
• the lyophilised product is not subject to deliquescence, and maintains its appearance unchanged over time.
• a further advantage of the invention is the reduction in lyophilisation times and the consequent reduction in the cost of the process.
• lactose prepared by dissolving the various components in water for injection at 20-25°C, is distributed between type I glass vials under sterile conditions at the rate of 5 ml per vial, after sterile filtration.
• a lyophilisation stopper is placed on the mouth of the vials.
• the pre-stoppered vials are then loaded directly onto lyophilisation shelves and frozen at -45°C ⁇ 5°C for at least 3 hours.
• Primary drying is conducted by increasing the temperature of the shelves in the vacuum freeze-dryer from -45°C to -30°C ⁇ 3°C in 3 hours, and maintaining the temperature at -30°C for 40 hours.
• Secondary drying is performed by increasing the temperature of the shelves from -30°C to +30°C ⁇ 3°C in 10 hours and then maintaining said temperature of +30°C for a further 8 hours.
• the freeze-dryer is returned to atmospheric pressure with nitrogen filtered under sterile conditions, and the vials are stoppered by activating the stoppering device.
• the vials are unloaded in a sterile environment and crimped.
• the solution When reconstituted with 5 ml of water for injection, the solution has a pH of between 3.0 and 4.5.
• 60 mg/ml of dextran 40000 prepared by dissolving the various components in water for injection at 20-25°C, is distributed between type I glass vials under sterile conditions, at the rate of 5 ml per vial, after sterile filtration.
• a lyophilisation stopper is placed on the mouth of the vials.
• the pre-stoppered vials are then loaded onto trays, which are placed on the shelves of the freeze-dryer.
• the vials are then frozen in the lyophilisation chamber at -45°C ⁇ 5°C for at least 3 hours.
• Primary drying is conducted by increasing the temperature of the shelves in the vacuum freeze dryer from -45°C to 0°C ⁇ 2°C in 6 hours and maintaining the temperature at 0°C for 30 hours. The temperature of the product during primary drying is maintained at around -30°C.
• Secondary drying is performed by increasing the temperature of the shelves from 0°C to +30°C ⁇ 2°C in 3 hours and then maintaining said temperature of + 30°C for a further 8 hours.
• the freeze-dryer is returned to atmospheric pressure with nitrogen filtered under sterile conditions, and the vials are stoppered by activating the stoppering device.
• the vials are unloaded in a sterile environment and crimped.
• the solution When reconstituted with 5 ml of water for injection, the solution has a pH of between 3.0 and 4.5.

Landscapes

• Health & Medical Sciences (AREA)
• Chemical & Material Sciences (AREA)
• Life Sciences & Earth Sciences (AREA)
• Veterinary Medicine (AREA)
• Medicinal Chemistry (AREA)
• Pharmacology & Pharmacy (AREA)
• Animal Behavior & Ethology (AREA)
• General Health & Medical Sciences (AREA)
• Public Health (AREA)
• Epidemiology (AREA)
• Engineering & Computer Science (AREA)
• Chemical Kinetics & Catalysis (AREA)
• General Chemical & Material Sciences (AREA)
• Inorganic Chemistry (AREA)
• Bioinformatics & Cheminformatics (AREA)
• Organic Chemistry (AREA)
• Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
• Molecular Biology (AREA)
• Biochemistry (AREA)
• Oil, Petroleum & Natural Gas (AREA)
• Dermatology (AREA)
• Hematology (AREA)
• Oncology (AREA)
• Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
• Medicinal Preparation (AREA)
• Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)

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Related Child Applications (3)

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Citations (5)

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• 2002
  • 2002-05-16 IT IT2002MI001040A patent/ITMI20021040A1/it unknown
• 2003
  • 2003-05-09 WO PCT/EP2003/004871 patent/WO2003097101A1/en not_active Ceased
  • 2003-05-09 ES ES03729997T patent/ES2298521T3/es not_active Expired - Lifetime
  • 2003-05-09 JP JP2004505097A patent/JP4624780B2/ja not_active Expired - Lifetime
  • 2003-05-09 US US10/514,301 patent/US20060199831A1/en not_active Abandoned
  • 2003-05-09 EP EP03729997A patent/EP1503797B1/en not_active Expired - Lifetime
  • 2003-05-09 AT AT03729997T patent/ATE381944T1/de not_active IP Right Cessation
  • 2003-05-09 DE DE60318310T patent/DE60318310T2/de not_active Expired - Lifetime
  • 2003-05-09 CA CA2486001A patent/CA2486001C/en not_active Expired - Lifetime
  • 2003-05-09 MX MXPA04011348A patent/MXPA04011348A/es active IP Right Grant
  • 2003-05-09 AU AU2003240613A patent/AU2003240613A1/en not_active Abandoned
• 2010
  • 2010-12-10 US US12/964,861 patent/US9211262B2/en not_active Expired - Lifetime
• 2012
  • 2012-10-25 FR FR12C0064C patent/FR12C0064I2/fr active Active
• 2015
  • 2015-11-10 US US14/937,689 patent/US20160256557A1/en not_active Abandoned

Patent Citations (5)

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