Therapeutic nanoparticles comprising a therapeutic agent and methods of making and using the same

Abstract

The present disclosure generally relates to nanoparticles comprising a substantially hydrophobic acid and a therapeutic agent (1-(4-{[4-(dimethylamino)piperidin-1-yl]carbonyl}phenyl)-3-[4-(4,6-dimorpholin-4-yl-1,3,5-triazin-2-yl)phenyl]urea), or pharmaceutically acceptable salts thereof, and a polymer. Other aspects include methods of making and using such nanoparticles.

1 - 73 . (canceled) 
     
     
         74 . A therapeutic nanoparticle comprising:
 a therapeutic agent selected from the group consisting of 1-(4-{[4-(dimethylamino)piperidin-1-yl]carbonyl}phenyl)-3-[4-(4,6-dimorpholin-4-yl-1,3,5-triazin-2-yl)phenyl]urea and pharmaceutically acceptable salt thereof;   a polymer selected from the group consisting of diblock poly(lactic) acid-poly(ethylene)glycol (PLA-PEG) copolymer, diblock poly(lactic acid-co-glycolic acid)-poly(ethylene)glycol (PLGA-PEG) copolymer, and combinations thereof; and   a substantially hydrophobic acid selected from the group consisting of dioctyl sulfosuccinic acid, 1-hydroxy-2-naphthoic acid, dodecyl sulfuric acid, naphthalene-1,5-disulfonic acid, naphthalene-2-sulfonic acid, pamoic acid, undecanoic acid, and combinations thereof;   wherein the substantially hydrophobic acid and the therapeutic agent form a hydrophobic ion pair that is encapsulated in the therapeutic nanoparticle; and   wherein the hydrophobic ion pair is dispersed throughout a polymeric matrix comprising the polymer.   
     
     
         75 . The therapeutic nanoparticle according to  claim 74 , wherein the pK a  of the protonated therapeutic agent is at least about 1.0 pK a  units greater than the pK a  of the substantially hydrophobic acid. 
     
     
         76 . The therapeutic nanoparticle according to  claim 74  comprising about 0.2 to about 20 weight percent of the therapeutic agent. 
     
     
         77 . The therapeutic nanoparticle according to  claim 74  comprising about 50 to about 99.75 weight percent of the polymer, and wherein the therapeutic nanoparticle comprises about 10 to about 30 weight percent poly(ethylene)glycol. 
     
     
         78 . The therapeutic nanoparticle according to  claim 74  comprising about 0.05 to about 30 weight percent of the substantially hydrophobic acid. 
     
     
         79 . The therapeutic nanoparticle according to  claim 74  comprising:
 1-(4-{[4-(dimethylamino)piperidin-1-yl]carbonyl}phenyl)-3-[4-(4,6-dimorpholin-4-yl-1,3,5-triazin-2-yl)phenyl]urea; 
 and PLA-PEG (in a 16:5 molar ratio) in a weight ratio of about 1:7 1-(4-{[4-(dimethylamino)piperidin-1-yl]carbonyl}phenyl)-3-[4-(4,6-dimorpholin-4-yl-1,3,5-triazin-2-yl)phenyl]urea:PLA-PEG. 
 
     
     
         80 . The therapeutic nanoparticle according to  claim 74  comprising:
 1-(4-{[4-(dimethylamino)piperidin-1-yl]carbonyl}phenyl)-3-[4-(4,6-dimorpholin-4-yl-1,3,5-triazin-2-yl)phenyl]urea; 
 and PLA-PEG (in a 16:5 molar ratio) in a weight ratio of about 1:5 1-(4-{[4-(dimethylamino)piperidin-1-yl]carbonyl}phenyl)-3-[4-(4,6-dimorpholin-4-yl-1,3,5-triazin-2-yl)phenyl]urea:PLA-PEG. 
 
     
     
         81 . The therapeutic nanoparticle according to  claim 74  comprising:
 1-(4-{[4-(dimethylamino)piperidin-1-yl]carbonyl}phenyl)-3-[4-(4,6-dimorpholin-4-yl-1,3,5-triazin-2-yl)phenyl]urea; 
 and PLA-PEG (in a 16:5 molar ratio) in a weight ratio of about 1:14 1-(4-{[4-(dimethylamino)piperidin-1-yl]carbonyl}phenyl)-3-[4-(4,6-dimorpholin-4-yl-1,3,5-triazin-2-yl)phenyl]urea:PLA-PEG. 
 
     
     
         82 . The therapeutic nanoparticle according to  claim 74 , wherein the molar ratio of the substantially hydrophobic acid to the therapeutic agent ranges from about 0.25:1 to about 2:1. 
     
     
         83 . The therapeutic nanoparticle according to  claim 74 , wherein the molar ratio of the substantially hydrophobic acid to the therapeutic agent is about 0.25:1 to about 1:1. 
     
     
         84 . The therapeutic nanoparticle according to  claim 74 , wherein the hydrophobic acid is a fatty acid. 
     
     
         85 . The therapeutic nanoparticle according to  claim 84 , wherein the fatty acid is an omega-9 fatty acid selected from the group consisting of: oleic acid, eicosenoic acid, mead acid, erucic acid, nervonic acid, and combinations thereof. 
     
     
         86 . The therapeutic nanoparticle according to  claim 85 , wherein the fatty acid is oleic acid. 
     
     
         87 . The therapeutic nanoparticle according to  claim 74 , wherein the hydrophobic acid is a bile acid. 
     
     
         88 . The therapeutic nanoparticle of  claim 87 , wherein the bile acid is selected from the group consisting of chenodeoxycholic acid, ursodeoxycholic acid, deoxycholic acid, hycholic acid, beta-muricholic acid, cholic acid, lithocholic acid, an amino acid-conjugated bile acid, and combinations thereof. 
     
     
         89 . The therapeutic nanoparticle of  claim 88 , wherein the bile acid is cholic acid. 
     
     
         90 . The therapeutic nanoparticle according to  claim 74 , wherein the hydrophobic acid is selected from the group consisting of dioctyl sulfosuccinic acid, l-hydroxy-2-naphthoic acid, dodecyl sulfuric acid, naphthalene-1,5-disulfonic acid, naphthalene-2-sulfonic acid, pamoic acid, undecanoic acid, and combinations thereof. 
     
     
         91 . The therapeutic nanoparticle according to  claim 74 , wherein the hydrophobic acid is pamoic acid. 
     
     
         92 . The therapeutic nanoparticle according to  claim 74 , further comprising about 0.2 to about 30 weight percent poly(lactic) acid-poly(ethylene)glycol or poly(lactic) acid-co-poly(glycolic) acid-poly(ethylene)glycol copolymer functionalized with a targeting ligand. 
     
     
         93 . The therapeutic nanoparticle according to  claim 92 , wherein the targeting ligand is covalently bound to the poly(ethylene)glycol. 
     
     
         94 . The therapeutic nanoparticle according to  claim 74 , wherein the substantially hydrophobic acid is a mixture of two or more substantially hydrophobic acids. 
     
     
         95 . The therapeutic nanoparticle of  claim 94 , wherein the two substantially hydrophobic acids are oleic acid and cholic acid. 
     
     
         96 . The therapeutic nanoparticle according to  claim 74 , wherein PLA-PEG-GL is additionally present and wherein targeting ligand GL has the following structure: 
       
         
           
           
               
               
           
         
       
     
     
         97 . The therapeutic nanoparticle according to  claim 74 , further comprising a solubilizer. 
     
     
         98 . A pharmaceutical composition comprising a therapeutic nanoparticle according to  claim 74  and a pharmaceutically acceptable excipient. 
     
     
         99 . The pharmaceutical composition of  claim 98  comprising a plurality of therapeutic nanoparticles.