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.

What is claimed is: 
     
         1 . A therapeutic nanoparticle 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 or pharmaceutically acceptable salt thereof. 
     
     
         2 . The therapeutic nanoparticle according to  claim 1  further comprising a pharmaceutically acceptable salt thereof and a polymer selected from diblock poly(lactic) acid-poly(ethylene)glycol copolymer, diblock poly(lactic acid-co-glycolic acid)-poly(ethylene)glycol copolymer, and combination thereof. 
     
     
         3 . The therapeutic nanoparticle according to  claim 2  further comprising a substantially hydrophobic acid, 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 hydrophobic acid. 
     
     
         4 . The therapeutic nanoparticle according to  claim 3  comprising about 0.2 to about 20 weight percent of a therapeutic agent, wherein the therapeutic agent is 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 a pharmaceutically acceptable salt thereof. 
     
     
         5 . The therapeutic nanoparticle according to  claim 3  comprising about 50 to about 99.75 weight percent of a polymer selected from diblock poly(lactic) acid-poly(ethylene)glycol copolymer or a diblock poly(lactic acid-co-glycolic acid)-poly(ethylene)glycol copolymer and combination, wherein the therapeutic nanoparticle comprises about 10 to about 30 weight percent poly(ethylene)glycol. 
     
     
         6 . The therapeutic nanoparticle according to  claim 3  comprising about 0.05 to about 30 weight percent of a substantially hydrophobic acid. 
     
     
         7 . The therapeutic nanoparticle according to  claim 3  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. 
 
     
     
         8 . The therapeutic nanoparticle according to  claim 3  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. 
 
     
     
         9 . The therapeutic nanoparticle according to  claim 3  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. 
 
     
     
         10 . The therapeutic nanoparticle according to  claim 3 , wherein the molar ratio of the substantially hydrophobic acid to the therapeutic agent ranges from about 0.25:1 to about 2:1. 
     
     
         11 . The therapeutic nanoparticle according to  claim 3 , wherein the molar ratio of the substantially hydrophobic acid to the therapeutic agent is about 0.25:1 to about 1:1. 
     
     
         12 . The therapeutic nanoparticle according to  claim 3 , wherein the substantially hydrophobic acid and the therapeutic agent form a hydrophobic ion pair in the therapeutic nanoparticle. 
     
     
         13 . The therapeutic nanoparticle according to  claim 3 , wherein the hydrophobic acid is a fatty acid. 
     
     
         14 . The therapeutic nanoparticle according to  claim 13 , 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. 
     
     
         15 . The therapeutic nanoparticle according to  claim 14 , wherein the fatty acid is oleic acid. 
     
     
         16 . The therapeutic nanoparticle according to  claim 3 , wherein the hydrophobic acid is a bile acid. 
     
     
         17 . The therapeutic nanoparticle of  claim 16 , 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. 
     
     
         18 . The therapeutic nanoparticle of  claim 17 , wherein the bile acid is cholic acid. 
     
     
         19 . The therapeutic nanoparticle according to  claim 3 , wherein the hydrophobic acid is selected from the group consisting of dioctyl sulfosuccinic acid, 1-hydroxy-2-naphthoic acid, dodecylsulfuric acid, naphthalene-1,5-disulfonic acid, naphthalene-2-sulfonic acid, pamoic acid, undecanoic acid, and combinations thereof. 
     
     
         20 . The therapeutic nanoparticle according to  claim 19 , wherein the hydrophobic acid is pamoic acid. 
     
     
         21 . The therapeutic nanoparticle according to  claim 3 , 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. 
     
     
         22 . The therapeutic nanoparticle according to  claim 21 , wherein the targeting ligand is covalently bound to the poly(ethylene)glycol. 
     
     
         23 . The therapeutic nanoparticle according to  claim 3 , wherein the substantially hydrophobic acid is a mixture of two or more substantially hydrophobic acids. 
     
     
         24 . The therapeutic nanoparticle of  claim 23 , wherein the two substantially hydrophobic acids are oleic acid and cholic acid. 
     
     
         25 . A therapeutic nanoparticle prepared by the process comprising the steps of:
 emulsification of a first organic phase comprising a first polymer, a therapeutic agent, and a substantially hydrophobic acid, thereby forming an emulsion phase;   quenching of the emulsion phase thereby forming a quenched phase; and   filtration of the quenched phase to recover the therapeutic nanoparticles, wherein the therapeutic agent is 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 a pharmaceutically acceptable salt thereof.   
     
     
         26 . The therapeutic nanoparticle according to  claim 3 , wherein a targeting ligand is additionally present and is PLA-PEG-GL, wherein GL has the following structure: 
       
         
           
           
               
               
           
         
       
     
     
         27 . The therapeutic nanoparticle according to  claim 3 , further comprising a solubilizer. 
     
     
         28 . A pharmaceutical composition comprising a therapeutic nanoparticle according to  claim 3  and a pharmaceutically acceptable excipient. 
     
     
         29 . The pharmaceutical composition of  claim 28  comprising a plurality of therapeutic nanoparticles. 
     
     
         30 . A method of treating cancer in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of a therapeutic nanoparticle according to  claim 3 . 
     
     
         31 . The method of  claim 30 , wherein the cancer is chronic myelogenous leukemia. 
     
     
         32 . The method of  claim 30 , wherein the cancer is selected from the group consisting of chronic myelomonocytic leukemia, hypereosinophilic syndrome, renal cell carcinoma, hepatocellular carcinoma, Philadelphia chromosome positive acute lymphoblastic leukemia, non-small cell lung cancer, pancreatic cancer, breast cancer, a solid tumor, head and neck cancer and mantle cell lymphoma. 
     
     
         33 . The method of  claim 32 , wherein the cancer is breast cancer. 
     
     
         34 . The method of  claim 30 , wherein the cancer is gastrointestinal stromal tumor. 
     
     
         35 . A method of treating cancer in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of a pharmaceutical composition according to  claim 28 . 
     
     
         36 . The method of  claim 35 , wherein the cancer is chronic myelogenous leukemia. 
     
     
         37 . The method of  claim 35 , wherein the cancer is gastrointestinal stromal tumor. 
     
     
         38 . The method of  claim 35 , wherein the cancer is selected from the group consisting of chronic myelomonocytic leukemia, hypereosinophilic syndrome, renal cell carcinoma, hepatocellular carcinoma, Philadelphia chromosome positive acute lymphoblastic leukemia, non-small cell lung cancer, pancreatic cancer, breast cancer, a solid tumor, head and neck cancer and mantle cell lymphoma. 
     
     
         39 . The method of  claim 38 , wherein the cancer is breast cancer. 
     
     
         40 . A process for preparing a therapeutic nanoparticle, comprising the steps of:
 combining a first organic phase with a first aqueous solution to form a second phase;   emulsifying the second phase to form an emulsion phase, wherein the emulsion phase comprises a first polymer, therapeutic agent, and a substantially hydrophobic acid;   quenching of the emulsion phase thereby forming a quenched phase; and   filtering the quenched phase to recover the therapeutic nanoparticles, wherein the therapeutic agent is 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 a pharmaceutically acceptable salt thereof.