THERAPEUTIC NANOPARTICLES COMPRISING A THERAPEUTIC AGENT AND METHODS OF MAKING AND USING THE SAME
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 . 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.