Pharmaceutical dosage form for immediate release of an indolinone derivative

Patent metadata

Field	Value
Publication number	US-2017239191-A1
Application number	US-201715590487-A
Country	US
Kind code	A1
Filing date	May 9, 2017
Priority date	Jun 6, 2008
Publication date	Aug 24, 2017
Grant date	—

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.

First claim

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.

Assignees

• Boehringer Ingelheim Int

Inventors

• Messerschmid Roman
• Lach Peter
• Sokoliess Torsten
• Stopfer Peter
• Trommeshauser Dirk

Classifications

• C07D403/06

  linked by a carbon chain containing only aliphatic carbon atoms · CPC title

• A61K9/5078 Primary

  with drug-free core · CPC title

• A61K31/661

  Phosphorus acids or esters thereof not having P—C bonds, e.g. fosfosal, dichlorvos, malathion {or mevinphos} · CPC title

• C07D401/06

  linked by a carbon chain containing only aliphatic carbon atoms · CPC title

• C07F9/572

  Five-membered rings · CPC title