Injectable pharmaceutical compositions of an anthracenedione derivative with anti-tumoral activity

an anthracenedione derivative and anti-tumoral technology, applied in the direction of drug compositions, biocides, organic non-active ingredients, etc., can solve the problems of chloride requiring the use of long lyophilisation cycles, unpredictability problems, and unstable formulation of bbr2778 in injectable liquid pharmaceutical compositions, so as to reduce the cost of the process and reduce the lyophilisation time

Inactive Publication Date: 2006-09-07
CELL THERAPUETICS INC
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Benefits of technology

[0024] A farther advantage of the invention is the reduction in lyophilisation times and the consequent reduction in the cost of the process.
[0025] The following examples illustrate the invention in greater detail.

Problems solved by technology

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.
Here again, however, unforeseeable problems arose, partly due to the low solubility of BBR 2778 in water and the need to use sodium chloride solutions in concentrations ranging from 0.9 to 4%, in which the drug is progressively more soluble.
However, the presence of sodium chloride requires the use of long lyophilisation cycles due to the low glass transition temperature observed.
Unsatisfactory results were also obtained with the use of other conventional lyophilisation carriers such as urea, glycine, ammonium chloride and TRIS in the presence and absence of sodium chloride, and by lyophilisation of BBR 2778 in the absence of excipients.

Method used

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Examples

Experimental program
Comparison scheme
Effect test

example 1

[0026] Preparation of vials containing lyophilised BBR 2778 in the presence of lactose and sodium chloride.

[0027] A solution containing 10 mg / ml of BBR 2778, 20 mg / ml of NaCl and 60 mg / ml of 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.

[0028] The pre-stoppered vials are then loaded directly onto lyophilisation shelves and frozen at −45° C.±5° C. for at least 3 hours.

[0029] 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.

[0030] 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...

example 2

[0033] Preparation of vials containing lyophilised BBR 2778 in the presence of dextran and sodium chloride.

[0034] A solution containing 10 mg / ml of BBR 2778, 20 mg / ml of NaCl and 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.

[0035] 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.

[0036] 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.

[0037] Secondary drying is pe...

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Abstract

Injectable pharmaceutical compositions containing 6,9-bis[(2-aminoethyl)amino]benzo[g]isoquinoline-5,10-dione dimalcate as active ingredient in the form of a lyophilised powder with a carrier selected from lactose and dextran, mixed with sodium chloride.

Description

[0001] 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. PRIOR ART [0002] 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. [0003] Clinical trials on the use of BBR 2778 in the treatment of non-Hodgkin's lymphoma are at an advanced stage. [0004] The formulation of BBR2778 in injectable liquid pharmaceutical compositions has pr...

Claims

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Application Information

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Patent Type & Authority Applications(United States)
IPC IPC(8): A61K31/473A61K9/00A61K9/19A61K47/02A61K47/26A61K47/36A61P35/00A61P35/02A61P43/00
CPCA61K9/0019A61K9/19A61K47/02A61K47/26A61K47/36A61P35/00A61P35/02A61P43/00A61K31/473
Inventor BERNAREGGI, ALBERTOLIVI, VALERIA
Owner CELL THERAPUETICS INC
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