Capsule pharmaceutical dosage form comprising a suspension formulation of an indolinone derivative

Abstract

The present invention relates to a suspension formulation 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, to a capsule pharmaceutical dosage form containing said suspension formulation, to a process for preparing said suspension formulation, to a process for preparing said capsule comprising said suspension formulation and to the packaging material for the finished capsule.

1 . Formulation of 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 which comprises a suspension of the active substance. 
     
     
         2 . Formulation according to  claim 1 , 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. 
     
     
         3 . Formulation according to  claim 2  in which the carrier is selected from acetylated monoglycerides, corn oil glycerides, ethyl oleate, glycerol mono/dioleate, glycerol monolinolate, glycerol, macrogolglycerol caprylocaprate, macrogolglycerol linoleate, medium chain partial glycerides, medium chain triglycerides, caprylic-capric triglycerides, caprylic/capric/linoleic triglycerides, caprylic/capric/succinic triglycerides, propylene glycol dicaprylate/dicaprate, oleic acid, liquid or semisolid low/intermediate viscous polyethylene glycols, polyoxyl castor oil, polyoxyl hydrogenated castor oil, propylene glycol monocaprylate, propylene glycol monolaurate, refined animal derived oil, refined soybean oil, refined vegetable oil, sorbitan monostearate, triacetin, and triethyl citrate, or mixtures thereof. 
     
     
         4 . Formulation according to  claim 2  in which the thickener is selected from semisolid highly viscous or solid polyethyleneglycols, oleogel forming excipients, lipophilic or amphiphilic excipients of high viscosity, and hard fats. 
     
     
         5 . Formulation according to  claim 2  in which the carrier is a lipid (lipophilic) carrier. 
     
     
         6 . Formulation according to  claim 2  which further comprises a glidant/solubilizing agent. 
     
     
         7 . Formulation according to  claim 6  in which the glidant/solubilizing agent is selected from lecithin. 
     
     
         8 . Formulation according to  claim 7 , comprising 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 in medium chain triglycerides, hard fat and lecithin. 
     
     
         9 . Formulation according to  claim 1 , which further comprises one or more macrogolglycerols and/or solubilizing agents. 
     
     
         10 . Formulation according to  claim 9 , wherein the macrogolglycerols are selected from macrogolglycerol hydroxystearate or macrogolglycerol ricinoleate. 
     
     
         11 . Capsule comprising a capsule shell and a capsule formulation, characterized in that the capsule formulation comprises the formulation in accordance with  claim 1 . 
     
     
         12 . Capsule according to  claim 11 , characterised in that the capsule is a soft gelatin capsule. 
     
     
         13 . Capsule according to  claim 11 , characterised in that the capsule shell comprises glycerol as plasticizing agent. 
     
     
         14 . Capsule according to  claim 11 , characterised in that the capsule is a hard gelatin or a hydroxypropylmethylcellulose (HPMC) capsule, a polyvinyl alcohol polymer capsule or a pullulan capsule, optionally with a sealing or banding. 
     
     
         15 . Process for the treatment and/or prevention 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 formulation according to any one of  claims 1  to  10  or capsule according to any one of  claims 11  to  14  is administered orally to a patient once or several times daily. 
     
     
         16 . Formulation according to any one of  claims 1  to  10  or capsule according to any one of  claims 11  to  14  for use in a dosage range of from 0.1 mg to 20 mg of active substance/kg body weight. 
     
     
         17 . One or more capsules according to any one of  claims 11  to  14  in a glass container or flexible/hard plastic container suitable for the packaging of capsules. 
     
     
         18 . One or more capsules according to any one of  claims 11  to  14  in a plastic blister, optionally with an over-packaging of aluminium, or aluminium blister suitable for the packaging of capsule.