Pharmaceutical compositions for the treatment of cancer and other diseases or disorders

Abstract

This invention provides novel pharmaceutical compositions of the compound of formula (I): or a pharmaceutically acceptable salt thereof, that are suitable for the bulk production of an oral pharmaceutical dosage form; processes for the production of said oral pharmaceutical dosage form; and the use of the pharmaceutical composition for the treatment of patients suffering from or subject to diseases, disorders, or conditions involving cell survival, proliferation and migration, including chronic inflammatory proliferative disorders, proliferative ocular disorders, benign proliferative disorders, and cancer.

1 . A pharmaceutical composition comprising a compound of formula (I): 
       
         
           
           
               
               
           
         
       
       or a pharmaceutically acceptable salt thereof, at least one solvent, at least one buffer, and optionally one or more pharmaceutically acceptable excipients independently selected from the group consisting of preservatives and surfactants. 
     
     
         2 . The pharmaceutical composition of  claim 1 , further comprising a taste-masking agent. 
     
     
         3 . The pharmaceutical composition of  claim 1 , wherein the pharmaceutical composition comprises, about 0.05% w/w to about 5% w/w of the compound of formula (I), or a pharmaceutically acceptable salt thereof, about 50% w/w to about 99.2% w/w of solvent, about 0.01% w/w to about 30% w/w of buffer, no more than about 5% w/w of preservative, and no more than about 5% of surfactant. 
     
     
         4 . The pharmaceutical composition of  claim 2 , wherein the pharmaceutical composition comprises, about 0.05% w/w to about 5% w/w of the compound of formula (I), or a pharmaceutically acceptable salt thereof, about 50% w/w to about 99% w/w of solvent, about 0.01% w/w to about 30% w/w of buffer, no more than about 60% w/w of taste-masking agent, no more than about 5% w/w of preservative, and no more than about 5% of surfactant. 
     
     
         5 . The pharmaceutical composition of  claim 2 , wherein the pharmaceutical composition comprises, about 0.10% w/w to about 2% w/w of the compound of formula (I), or a pharmaceutically acceptable salt thereof, about 65% w/w to about 99% w/w of solvent, about 0.20% w/w to about 3% w/w of buffer, and about 15% w/w to about 50% w/w of taste-masking agent. 
     
     
         6 . The pharmaceutical composition of  claim 1 , wherein the pharmaceutical composition comprises, about 0.44% w/w of the compound of formula (I), or a pharmaceutically acceptable salt thereof, about 99.14% w/w of solvent, and about 0.42% w/w of buffer. 
     
     
         7 . The pharmaceutical composition of any one of  claims 1  to  6 , wherein the pharmaceutical composition is a liquid oral pharmaceutical dosage form. 
     
     
         8 . The pharmaceutical composition of  claim 7 , wherein the dosage form is for pediatric dosing. 
     
     
         9 . The pharmaceutical composition of  claim 1  or  2 , wherein the salt of formula (I) is a sodium salt of formula (II): 
       
         
           
           
               
               
           
         
       
       or a crystalline form thereof. 
     
     
         10 . The pharmaceutical composition of  claim 9 , wherein the pharmaceutical composition comprises, about 0.47% w/w of the compound of formula (II), or a crystalline form thereof, about 77.36% w/w of solvent, about 21.75% w/w of taste-masking agent, and about 0.42% w/w of buffer. 
     
     
         11 . The pharmaceutical composition of  claim 1  or  2 , wherein the compound of formula (I) is present in an amount of about 0.05% w/w to about 5% w/w. 
     
     
         12 . The pharmaceutical composition of  claim 1  or  2 , wherein the compound of formula (I) is present in an amount of about 0.10% w/w to about 2% w/w. 
     
     
         13 . The pharmaceutical composition of  claim 1  or  2 , wherein the solvent is present in an amount of about 50% w/w to about 99% w/w. 
     
     
         14 . The pharmaceutical composition of  claim 1  or  2 , wherein the solvent is present in an amount of about 65% w/w to about 99% w/w. 
     
     
         15 . The pharmaceutical composition of  claim 1  or  2 , wherein the solvent is selected from the group consisting of propylene glycol, glycerin, PEG400, PEG3350, purified water, and mixtures thereof. 
     
     
         16 . The pharmaceutical composition of  claim 15 , wherein the solvent is a mixture of PEG400, propylene glycol, and purified water. 
     
     
         17 . The pharmaceutical composition of  claim 1  or  2 , wherein the buffer is present in an amount of about 0.01% w/w to about 30% w/w. 
     
     
         18 . The pharmaceutical composition of  claim 1  or  2 , wherein the buffer is present in an amount of about 0.20% w/w to about 3% w/w. 
     
     
         19 . The pharmaceutical composition of  claim 1  or  2 , wherein the buffer is selected from the group consisting of sodium bicarbonate, monosodium phosphate, disodium phosphate, monopotassium phosphate, dipotassium phosphate, potassium bicarbonate, sodium carbonate and potassium carbonate, and mixtures thereof. 
     
     
         20 . The pharmaceutical composition of  claim 19 , wherein the buffer is sodium bicarbonate. 
     
     
         21 . The pharmaceutical composition of  claim 1  or  2 , wherein the preservative, when present, is present in an amount of no more than about 5% w/w. 
     
     
         22 . The pharmaceutical composition of  claim 1  or  2 , wherein the preservative, when present, is selected from the group consisting of parabens and their sodium salts, sodium benzoate, and mixtures thereof. 
     
     
         23 . The pharmaceutical composition of  claim 22 , wherein the preservative is selected from the group consisting of methylparaben, propylparaben, and mixtures thereof. 
     
     
         24 . The pharmaceutical composition of  claim 1  or  2 , wherein the surfactant, when present, is present in an amount of no more than about 5% w/w. 
     
     
         25 . The pharmaceutical composition of  claim 1 , wherein the surfactant, when present, is selected from the group consisting of sodium lauryl sulfate, sodium dodecyl sulfate, polysorbates, poloxamers, glyceryl monooleate, and mixtures thereof. 
     
     
         26 . The pharmaceutical composition of  claim 25 , wherein the surfactant is sodium lauryl sulfate. 
     
     
         27 . The pharmaceutical composition of  claim 2 , wherein the taste-masking agent is present in an amount of about 5% w/w to about 60% w/w. 
     
     
         28 . The pharmaceutical composition of  claim 2 , wherein the taste-masking agent is selected from the group consisting of sorbitol, maltitol, sucrose, acesulfame potassium and mixtures thereof. 
     
     
         29 . The pharmaceutical composition of  claim 28 , wherein the taste-masking agent is sorbitol. 
     
     
         30 . A unit dose pharmaceutical composition comprising about 0.05 mg/mL to about 25 mg/mL of the compound of formula (I), or a pharmaceutically acceptable salt thereof. 
     
     
         31 . A process for bulk production of an oral liquid pharmaceutical dosage form of the compound of formula (I), or a pharmaceutically acceptable salt thereof, comprising the steps of:
 (a-1) dissolving the compound of formula (I), or a pharmaceutically acceptable salt thereof, into a mixture comprising at least one solvent, at least one buffer, and optionally one or more taste-masking agents;   (a-2) filtering the resulting solution from (a-1) through a suitably sized filter; and   (a-3) filling the filtered solution resulting from (a-2) into suitable bottles.   
     
     
         32 . The process of  claim 31 , comprising the steps of:
 (a-1) dissolving the compound of formula (I), or a pharmaceutically acceptable salt thereof, into a mixture comprising propylene glycol, purified water, PEG400, sorbitol, acesulfame potassium, and sodium bicarbonate;   (a-2) filtering the resulting solution from (a-1) through a suitably sized filter; and   (a-3) filling the filtered solution resulting from (a-2) into suitable bottles.   
     
     
         33 . The process of  claim 31 , comprising the steps of:
 (a-1) dissolving the compound of formula (II), or a crystalline form thereof, into a mixture comprising propylene glycol, water, PEG400, sorbitol, acesulfame potassium, and sodium bicarbonate;   (a-2) filtering the resulting solution from (a-1) through a suitably sized filter; and   (a-3) filling the filtered solution resulting from (a-2) into suitable bottles.   
     
     
         34 . A method for treating cancer, comprising the administration of a therapeutically effective amount of the pharmaceutical composition of  claim 1 . 
     
     
         35 . The method of  claim 34 , wherein the cancer is selected from the group consisting of colorectal cancer, ovarian cancer, breast cancer, gastric cancer, prostate cancer, pancreatic cancer, neuroblastoma, and ALL.