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 0.2 to about 20 weight percent of a basic therapeutic agent having a protonatable nitrogen, wherein the basic therapeutic agent is a tyrosine kinase inhibitor selected from the group consisting of sunitinib, imatinib, nilotinib, dasatinib, bosutinib, ponatinib, bafetinib, and pharmaceutically acceptable salts thereof;
pamoic acid, wherein the molar ratio of the pamoic acid to the basic therapeutic agent is about 0.25:1 to about 2:1; and
about 50 to about 99.75 weight percent of a diblock poly(lactic) acid-poly(ethylene)glycol copolymer or a diblock poly(lactic acid-co-glycolic 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 , wherein the molar ratio of the pamoic acid to the basic therapeutic agent is about 0.5:1 to about 1.5:1.
3. The therapeutic nanoparticle of claim 1 , wherein the molar ratio of the pamoic acid to the basic therapeutic agent is about 0.75:1 to about 1.25:1.
4. A therapeutic nanoparticle comprising:
a hydrophobic ion-pair comprising pamoic acid and a therapeutic agent having at least one ionizable amine moiety, wherein the therapeutic agent is a tyrosine kinase inhibitor selected from the group consisting of sunitinib, imatinib, nilotinib, dasatinib, bosutinib, ponatinib, bafetinib, and pharmaceutically acceptable salts thereof; and
about 50 to about 99.75 weight percent of a diblock poly(lactic) acid-poly(ethylene)glycol copolymer, 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.
5. The therapeutic nanoparticle of claim 4 , comprising about 0.05 to about 30 weight percent of the pamoic acid.
6. The therapeutic nanoparticle of claim 4 , wherein the pamoic acid and the therapeutic agent form a hydrophobic ion pair in the therapeutic nanoparticle.
7. The therapeutic nanoparticle of claim 4 , comprising about 2 to about 20 weight percent of the therapeutic agent.
8. The therapeutic nanoparticle of claim 4 , comprising about 10 to about 20 weight percent of the therapeutic agent.
9. The therapeutic nanoparticle of claim 4 , wherein the hydrodynamic diameter of the therapeutic nanoparticle is about 60 to about 150 nm.
10. The therapeutic nanoparticle of claim 4 , wherein the therapeutic agent is selected from the group consisting of dasatinib and pharmaceutically acceptable salts thereof.
11. The therapeutic nanoparticle of claim 9 , wherein the hydrodynamic diameter is about 90 to about 120 nm.
12. The therapeutic nanoparticle of claim 5 , wherein the therapeutic nanoparticle substantially immediately releases less than about 30% of the therapeutic agent when placed in a phosphate buffer solution at 37° C.
13. The therapeutic nanoparticle of claim 5 , wherein the poly(lactic) acid-poly(ethylene)glycol copolymer has a poly(lactic) acid number average molecular weight fraction of about 0.6 to about 0.8.
14. The therapeutic nanoparticle of claim 5 , wherein the therapeutic nanoparticle comprises about 10 to about 25 weight percent poly(ethylene)glycol.