Therapeutic nanoparticles comprising a protonatable nitrogen 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;
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; wherein the nanoparticle has a hydrodynamic diameter of about 90 to about 140 nm.
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. The therapeutic nanoparticle of claim 1 , wherein the pK a of the basic therapeutic agent is at least about 1.0 pK a units greater than the pK a of the pamoic acid.
5. The therapeutic nanoparticle of claim 1 , wherein the pK a of the basic therapeutic agent is at least about 2.0 pK a units greater than the pK a of the pamoic acid.
6. The therapeutic nanoparticle of claim 1 , wherein the pK a of the basic therapeutic agent is at least about 4.0 pK a units greater than the pK a of the pamoic acid.
7. The therapeutic nanoparticle of claim 1 , wherein the pamoic acid and the basic therapeutic agent form a hydrophobic ion pair in the therapeutic nanoparticle.
8. The therapeutic nanoparticle of claim 1 , comprising about 4 to about 20 weight percent of the protonatable nitrogen-containing therapeutic agent.
9. The therapeutic nanoparticle of claim 1 , comprising about 10 to about 20 weight percent of the protonatable nitrogen-containing therapeutic agent.
10. The therapeutic nanoparticle of claim 1 , further comprising about 0.2 to about 30 weight percent poly(lactic) acid-co-poly(glycolic) acid-poly(ethylene)glycol copolymer functionalized with a targeting ligand.
11. A therapeutic nanoparticle comprising:
a hydrophobic ion-pair comprising pamoic acid and a therapeutic agent having at least one ionizable amine moiety; 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; wherein the hydrodynamic diameter of about 90 to about 140 nm.
12. The therapeutic nanoparticle of claim 11 , wherein the difference between the pKa of the basic therapeutic agent and the pamoic acid is at least about 1.0 pKa units.
13. The therapeutic nanoparticle of claim 11 , wherein the difference between the pKa of the basic therapeutic agent and the pamoic acid is at least about 2.0 pKa units.
14. The therapeutic nanoparticle of claim 11 , wherein the difference between the pKa of the basic therapeutic agent and the pamoic acid is at least about 4.0 pKa units.
15. The therapeutic nanoparticle of claim 11 , comprising about 4 to about 20 weight percent of the protonatable nitrogen-containing therapeutic agent.
16. The therapeutic nanoparticle of claim 11 , comprising about 10 to about 20 weight percent of the protonatable nitrogen-containing therapeutic agent.
17. The therapeutic nanoparticle of claim 11 , wherein the hydrodynamic diameter is about 90 to about 120 nm.
18. The therapeutic nanoparticle of claim 11 , further comprising about 0.2 to about 30 weight percent poly(lactic) acid-co-poly(glycolic) acid-poly(ethylene)glycol copolymer functionalized with a targeting ligand.