Therapeutic polymeric nanoparticles with mTOR inhibitors and methods of making and using same
View Patent ↗The present disclosure generally relates to therapeutic nanoparticles. Exemplary nanoparticles disclosed herein may include about 1 to about 20 weight percent of a mTOR inhibitor; and about 70 to about 99 weight percent biocompatible polymer.
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 mTOR inhibitor;
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;
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
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.
2. The therapeutic nanoparticle of claim 1 wherein said mTOR inhibitor is selected from the group consisting of sirolimus, temsirolimus, and everolimus, and pharmaceutically acceptable salts thereof.
3. The therapeutic nanoparticle of claim 1 , wherein the hydrodynamic diameter is about 70 to about 120 nm.
4. The therapeutic nanoparticle of claim 1 , wherein the therapeutic nanoparticle substantially retains the therapeutic agent for at least 5 days at 25° C.
5. The therapeutic nanoparticle of claim 1 , comprising about 10 to about 20 weight percent of the mTOR inhibitor.
6. The therapeutic nanoparticle of claim 1 , comprising about 40 to about 90 weight percent diblock poly(lactic) acid-poly(ethylene)glycol copolymer.
7. The therapeutic nanoparticle of claim 1 , 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.
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 9 , wherein the ligand has a molecular weight of about 100 g/mol to about 500 g/mol.
11. The therapeutic nanoparticle of claim 10 , 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.
12. 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.
13. The therapeutic nanoparticle of claim 12 , wherein said diblock poly(lactic) acid-poly(ethylene)glycol copolymer comprises poly(ethylene)glycol having a number average molecular weight of about 5 kDa.
14. A method of treating lymphoma comprising administering to a patient in need thereof an effective amount of the therapeutic nanoparticle of claim 13 .
15. 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 mTOR inhibitor; 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.
16. The pharmaceutical composition of claim 15 , wherein the saccharide is sucrose.