Drug loaded polymeric nanoparticles and methods of making and using same
View Patent ↗The present disclosure generally relates to nanoparticles having about 0.2 to about 35 weight percent of a therapeutic agent; and about 10 to about 99 weight percent of biocompatible polymer such as a diblock poly(lactic) acid-poly(ethylene)glycol. Other aspects of the invention include methods of making such nanoparticles.
1. A therapeutic nanoparticle having a hydrodynamic diameter of the therapeutic nanoparticle of about 70 to about 130 nm; comprising:
about 5 to about 30 weight percent of a therapeutic agent;
about 10 to about 99 weight percent of a diblock poly(lactic) acid-poly(ethylene)glycol copolymer, wherein said diblock poly(lactic) acid-poly(ethylene)glycol copolymer comprises poly(lactic acid) having a number average molecular weight of about 15 to about 20 kDa and poly(ethylene)glycol having a number average molecular weight of about 4 to about 6 kDa; and about 0.2 to about 10 weight percent of a polymer conjugate represented by: PLA-PEG-ligand; wherein the ligand is covalently bound to the PEG, and wherein PLA is poly(lactic)acid and PEG is poly(ethylene)glycol; and wherein the particle releases less than about 5% of the therapeutic agent over 1 hour when placed in a phosphate buffer solution at room temperature.
2. The therapeutic nanoparticle of claim 1 , wherein the therapeutic nanoparticle releases less than 10% of the therapeutic agent over about one minute when placed in a phosphate buffer solution at 37° C.
3. The therapeutic nanoparticle of claim 1 wherein said therapeutic agent is a taxane.
4. The therapeutic nanoparticle of claim 1 , wherein the hydrodynamic diameter is about 70 to about 120 nm.
5. The therapeutic nanoparticle of claim 1 , wherein the therapeutic nanoparticle substantially retains the therapeutic agent for at least 5 days at 25° C.
6. The therapeutic nanoparticle of claim 3 , comprising about 10 to about 20 weight percent of the taxane.
7. The therapeutic nanoparticle of claim 1 , comprising about 40 to about 90 weight percent diblock poly(lactic) acid-poly(ethylene)glycol copolymer.
8. The therapeutic nanoparticle of claim 1 , wherein the particle releases less than about 10% of the therapeutic agent over 24 hours when placed in a phosphate buffer solution at room temperature.
9. The therapeutic nanoparticle of claim 1 , wherein the ligand has molecular weight of about 100 g/mol to about 6000 g/mol.
10. The therapeutic nanoparticle of claim 8 , wherein the ligand has a molecular weight of about 100 g/mol to about 500 g/mol.
11. The therapeutic nanoparticle of claim 9 , wherein the ligand is represented by the formula:
12. The therapeutic nanoparticle of claim 11 , wherein the PLA-PEG-Ligand comprises a PLA having number average molecular weight of about 10 kDa to about 20 kDa and a PEG having a number average molecular weight of about 4 kDa to about 8 kDa.
13. The therapeutic nanoparticle of claim 1 , wherein the diblock poly(lactic) acid-poly(ethylene)glycol copolymer comprises poly(lactic acid) having a number average molecular weight of about 16 kDa.
14. The therapeutic nanoparticle of claim 13 , wherein said diblock poly(lactic) acid-poly(ethylene)glycol copolymer comprises poly(ethylene)glycol having a number average molecular weight of about 5 kDa.
15. The therapeutic nanoparticle of claim 6 , wherein said taxane is docetaxel.
16. A method of treating prostate or breast cancer comprising administering to a patient in need thereof an effective amount of the therapeutic nanoparticle of claim 15 .
17. A pharmaceutical composition comprising:
a plurality of polymeric nanoparticles each having a hydrodynamic diameter of about 60 nm to about 140 nm and comprising about 3 to about 40 weight percent of a chemotherapeutic agent; about 10 to about 99 weight percent of a diblock poly(lactic)acid-poly(ethylene)glycol copolymer comprising poly(lactic)acid having a number average molecular weight of about 15 to about 20 kDa and poly(ethylene)glycol having a number average molecular weight of about 4 to about 6 kDa, about 0.2 to about 10 weight percent of a polymer conjugate represented by: PLA-PEG-ligand; wherein the ligand is covalently bound to the PEG or covalently bound to the PEG through an alkylene linker, and wherein PLA is poly(lactic)acid and PEG is poly(ethylene)glycol and
a saccharide;
wherein said nanoparticles are stable for at least 3 days when held at 25° C. in said composition.
18. The pharmaceutical composition of claim 17 , wherein the saccharide is sucrose.
19. The pharmaceutical composition of claim 17 , wherein the chemotherapeutic agent is a taxane.
20. A method of treating prostate or breast cancer comprising administering to a patient in need thereof an effective amount of the composition of claim 19 .
21. A therapeutic nanoparticle having a hydrodynamic diameter of the therapeutic nanoparticle of about 70 to about 130 nm; comprising:
about 5 to about 30 weight percent of a therapeutic agent;
about 10 to about 99 weight percent of a diblock poly(lactic) acid-poly(ethylene)glycol copolymer, wherein said diblock poly(lactic) acid-poly(ethylene)glycol copolymer comprises poly(lactic acid) having a number average molecular weight of about 15 to about 20 kDa and poly(ethylene)glycol having a number average molecular weight of about 4 to about 6 kDa; and about 0.2 to about 10 weight percent of a polymer conjugate represented by: PLA-PEG-ligand; wherein the ligand is covalently bound to the PEG, and wherein PLA is poly(lactic)acid and PEG is poly(ethylene)glycol; and wherein the therapeutic nanoparticle substantially retains the therapeutic agent for at least 5 days at 25° C.
22. The therapeutic nanoparticle of claim 21 , wherein the diblock poly(lactic) acid-poly(ethylene)glycol copolymer comprises poly(lactic acid) having a number average molecular weight of about 16 kDa.
23. The therapeutic nanoparticle of claim 22 , wherein said diblock poly(lactic) acid-poly(ethylene)glycol copolymer comprises poly(ethylene)glycol having a number average molecular weight of about 5 kDa.
24. The therapeutic nanoparticle of claim 21 , comprising about 40 to about 90 weight percent diblock poly(lactic) acid-poly(ethylene)glycol copolymer.
25. A therapeutic nanoparticle having a hydrodynamic diameter of the therapeutic nanoparticle of about 70 to about 130 nm; comprising:
about 5 to about 30 weight percent of a therapeutic agent;
about 10 to about 99 weight percent of a diblock poly(lactic) acid-poly(ethylene)glycol copolymer, wherein said diblock poly(lactic) acid-poly(ethylene)glycol copolymer comprises poly(lactic acid) having a number average molecular weight of about 15 to about 20 kDa and poly(ethylene)glycol having a number average molecular weight of about 4 to about 6 kDa; and about 0.2 to about 10 weight percent of a polymer conjugate represented by: PLA-PEG-ligand; wherein the ligand is covalently bound to the PEG, and wherein PLA is poly(lactic)acid and PEG is poly(ethylene)glycol; and wherein the therapeutic nanoparticle releases less than 10% of the therapeutic agent over about one minute when placed in a phosphate buffer solution at 37° C.
26. The therapeutic nanoparticle of claim 25 , wherein the diblock poly(lactic) acid-poly(ethylene)glycol copolymer comprises poly(lactic acid) having a number average molecular weight of about 16 kDa.
27. The therapeutic nanoparticle of claim 26 , wherein said diblock poly(lactic) acid-poly(ethylene)glycol copolymer comprises poly(ethylene)glycol having a number average molecular weight of about 5 kDa.
28. The therapeutic nanoparticle of claim 25 , comprising about 40 to about 90 weight percent diblock poly(lactic) acid-poly(ethylene)glycol copolymer.