Therapeutic Nanoparticles Comprising a Therapeutic Agent and Methods of Making and Using Same
The present disclosure generally relates to nanoparticles comprising a substantially hydrophobic acid, a basic therapeutic agent having a protonatable nitrogen, and a polymer. Other aspects include methods of making and using such nanoparticles.
1 . A therapeutic nanoparticle comprising:
about 0.05 to about 30 weight percent of a substantially hydrophobic acid;
about 0.2 to about 15 weight percent of a kinase inhibitor having a protonatable nitrogen;
wherein the pKa of the protonated kinase inhibitor is about 2.0 pKa units to about 10.0 pKa units greater than the pKa of the hydrophobic acid, as determined at 25° C.; and
about 50 to about 99.75 weight percent of a diblock poly(lactic) acid-poly(ethylene)glycol copolymer, wherein the therapeutic nanoparticle comprises about 10 to about 30 weight percent poly(ethylene)glycol.
2 . The therapeutic nanoparticle of claim 1 , comprising about 2 to about 5 weight percent of the kinase inhibitor.
3 . The therapeutic nanoparticle of claim 1 , wherein the substantially hydrophobic acid has a log P of about 2 to about 7.
4 . The therapeutic nanoparticle of claim 1 , wherein the substantially hydrophobic acid has a pKa about −1.0 to about 5.0 at 25° C.
5 . The therapeutic nanoparticle of claim 1 , wherein the substantially hydrophobic acid has a pKa about 2.0 to about 5.0 at 25° C.
6 . The therapeutic nanoparticle of claim 1 , wherein the hydrophobic acid is a fatty acid.
7 . The therapeutic nanoparticle of claim 1 , wherein the hydrodynamic diameter of the therapeutic nanoparticle is about 60 to about 150 nm.
8 . The therapeutic nanoparticle of claim 1 , comprising about 2 to about 15 weight percent of the kinase inhibitor.
9 . The therapeutic nanoparticle of claim 1 , comprising about 4 to about 10 weight percent of kinase inhibitor agent.
10 . The therapeutic nanoparticle of claim 1 , wherein the kinase inhibitor is a tyrosine kinase inhibitor selected from the group consisting of sunitinib, imatinib, nilotinib, dasatinib, bosutinib, ponatinib, bafetinib, and pharmaceutically acceptable salts thereof.
11 . The therapeutic nanoparticle of claim 1 , wherein the poly(lactic) acid-poly(ethylene)glycol copolymer has a poly(lactic) acid number average molecular weight fraction of about 0.75 to about 0.85.
12 . The therapeutic nanoparticle of claim 1 , wherein the poly(lactic) acid-poly(ethylene)glycol copolymer has a number average molecular weight of about 15 kDa to about 20 kDa poly(lactic acid) and a number average molecular weight of about 4 kDa to about 6 kDa poly(ethylene)glycol.