Pharmaceutical dosage form for immediate release of an indolinone derivative

Abstract

The present invention relates to a pharmaceutical dosage form delivering an immediate release profile containing the active substance 3-Z-[1-(4-(N-((4-methyl-piperazin-1-yl)-methylcarbonyl)-N-methyl-amino)-anilino)-1-phenyl-methylene]-6-methoxycarbonyl-2-indolinone-monoethanesulphonate.

1 . Pharmaceutical dosage form comprising active substance 3-Z-[1-(4-(N-((4-methyl-piperazin-1-yl)-methylcarbonyl)-N-methyl-amino)-anilino)-1-phenyl-methylene]-6-methoxycarbonyl-2-indolinone-monoethanesulphonate and lecithin, which delivers an immediate release profile in which not less than 70% (Q65%) of the active substance is dissolved in 60 minutes in vitro under the following in vitro dissolution conditions according to European Pharmacopeia 6.2: Apparatus 2 (paddle), dissolution medium with 0.1 M HCl (pH 1) and stirring speed of 50 to 150 rpm, at a temperature of 37° C. 
     
     
         2 . Pharmaceutical dosage form according to  claim 1 , which delivers an immediate release profile in which not less than 75% (Q 70%) of the active substance is dissolved in 60 minutes in vitro 
     
     
         3 . Pharmaceutical dosage form according to  claim 1 , which delivers an immediate release profile in which not less than 85% (Q 80%) of the active substance is dissolved in 60 minutes in vitro. 
     
     
         4 . Pharmaceutical dosage form according to  claim 1 , which delivers an immediate release profile in which not less than 85% (Q 80%) of the active substance is dissolved in 45 minutes in vitro. 
     
     
         5 . Pharmaceutical dosage form according to  claim 1 , which delivers an immediate release profile in which not less than 85% (Q 80%) of the active substance is dissolved in 30 minutes in vitro. 
     
     
         6 . Pharmaceutical dosage form according to  claim 1 , which exhibits comparable in vitro dissolution profiles independent from a dosage strength of 5 to 1000 mg of the active substance. 
     
     
         7 . Pharmaceutical dosage comprising the active substance 3-Z-[1-(4-(N-((4-methyl-piperazin-1-yl)-methylcarbonyl)-N-methyl-amino)-anilino)-1-phenyl-methylene]-6-methoxycarbonyl-2-indolinone-monoethanesulphonate and lecithin, which delivers an immediate release profile in which the maximum concentration of the analyte/active substance in plasma at steady state (C max,ss ) increases in a dose-proportional manner. 
     
     
         8 . Pharmaceutical dosage comprising the active substance 3-Z-[1-(4-(N-((4-methyl-piperazin-1-yl)-methylcarbonyl)-N-methyl-amino)-anilino)-1-phenyl-methylene]-6-methoxycarbonyl-2-indolinone-monoethanesulphonate and lecithin, which delivers an immediate release profile in which the area under the plasma concentration-time curve of the analyte/active substance in plasma at steady state over a dosing interval τ (AUC τ,ss ) increases in a dose-proportional manner. 
     
     
         9 . Pharmaceutical dosage comprising the active substance 3-Z-[1-(4-(N-((4-methyl-piperazin-1-yl)-methylcarbonyl)-N-methyl-amino)-anilino)-1-phenyl-methylene]-6-methoxycarbonyl-2-indolinone-monoethanesulphonate and lecithin, which delivers an immediate release profile characterized in that it reaches a maximum plasma concentration in the blood of a human subject within less than between 0.75 and 6 hours. 
     
     
         10 . Pharmaceutical dosage comprising the active substance 3-Z-[1-(4-(N-((4-methyl-piperazin-1-yl)-methylcarbonyl)-N-methyl-amino)-anilino)-1-phenyl-methylene]-6-methoxycarbonyl-2-indolinone-monoethanesulphonate and lecithin, which delivers an immediate release profile wherein the maximum plasma concentration in the plasma of human subjects is at least within a range of 4 ng/ml and 32 ng/ml, with a geometric mean value of 14 ng/ml, if a dosage form comprising 150 mg (3 times 50 mg) of 3-Z-[1-(4-(N-((4-methyl-piperazin-1-yl)-methylcarbonyl)-N-methyl-amino)-anilino)-1-phenyl-methylene]-6-methoxycarbonyl-2-indolinone-monoethanesulphonate has been administered. 
     
     
         11 . Pharmaceutical dosage form according to  claim 1 , wherein it is an orally deliverable dosage form. 
     
     
         12 . Pharmaceutical dosage form according to  claim 1 , wherein it is in the form of a tablet, capsule, oral solution, elixir, emulsion, pellets, powder or granules. 
     
     
         13 . Pharmaceutical dosage form according to  claim 1 , which comprises a suspension of the active substance. 
     
     
         14 . Pharmaceutical dosage form according to  claim 13 , in which the suspension of the active substance is a viscous suspension of 3-Z-[1-(4-(N-((4-methyl-piperazin-1-yl)-methylcarbonyl)-N-methyl-amino)-anilino)-1-phenyl-methylene]-6-methoxycarbonyl-2-indolinone-monoethanesulphonate comprising a carrier and a thickener. 
     
     
         15 . Pharmaceutical dosage form according to  claim 1 , comprising the active substance in an amount of 0.01 to 90 wt.-% of the composition. 
     
     
         16 . Pharmaceutical dosage form according to  claim 1 , comprising dose-range values of between 5 to 1000 mg of the active substance. 
     
     
         17 . Pharmaceutical dosage form according to  claim 1  which is used in a body-weight-independent (BWI) dosing. 
     
     
         18 . Process for the treatment of a disease or condition selected from oncological diseases, immunologic diseases or pathological conditions involving an immunologic component, and fibrotic diseases, characterised in that an effective amount of a pharmaceutical dosage form according to  claim 1  is administered orally to a patient once or several times daily. 
     
     
         19 . Pharmaceutical dosage form comprising active substance 3-Z-[1-(4-(N-((4-methyl-piperazin-1-yl)-methylcarbonyl)-N-methyl-amino)-anilino)-1-phenyl-methylene]-6-methoxycarbonyl-2-indolinone-monoethanesulphonate and lecithin, which delivers an immediate release profile in which not less than 85% (Q80%) of the active substance is dissolved in 45 minutes in vitro under the following in vitro dissolution conditions according to European Pharmacopeia 6.2: Apparatus 2 (paddle), dissolution medium with 0.1 M HCl (pH 1) and stirring speed of 50 to 150 rpm, at a temperature of 37° C. 
     
     
         20 . The pharmaceutical composition of  claim 19 , wherein the 3-Z-[1-(4-(N-((4-methyl-piperazin-1-yl)-methylcarbonyl)-N-methyl-amino)-anilino)-1-phenyl-methylene]-6-methoxycarbonyl-2-indolinone-monoethanesulphonate is present in an amount of 120.40 mg. 
     
     
         21 . The pharmaceutical composition of  claim 19 , wherein the 3-Z-[1-(4-(N-((4-methyl-piperazin-1-yl)-methylcarbonyl)-N-methyl-amino)-anilino)-1-phenyl-methylene]-6-methoxycarbonyl-2-indolinone-monoethanesulphonate is present in an amount of 180.60 mg. 
     
     
         22 . Process for the treatment of a disease or condition selected from oncological diseases, immunologic diseases or pathological conditions involving an immunologic component, and fibrotic diseases, characterised in that an effective amount of a pharmaceutical dosage form according to  claim 19  is administered orally to a patient once or several times daily.