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 comprising:
about 5 to about 15 weight percent of a mTOR inhibitor; and
about 50 to about 99 weight percent biocompatible polymer, wherein the biocompatible polymer is 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 20 kDa and poly(ethylene)glycol having a number average molecular weight of about 4 to about 6 kDa, wherein the diameter of the therapeutic nanoparticle is about 70 to about 130 nm; and
wherein the particle releases less than about 10% of the mTOR inhibitor over about one minute when placed in a phosphate buffer solution at room temperature.
2. The therapeutic nanoparticle of claim 1 wherein said mTOR inhibitor is sirolimus, temsirolimus, or everolimus or a pharmaceutically acceptable salt thereof.
3. The therapeutic nanoparticle of claim 1 , wherein the diameter is about 80 to about 130 nm.
4. The therapeutic nanoparticle of claim 1 , wherein said diblock poly(lactic) acid-poly(ethylene)glycol copolymer comprises poly(lactic acid) having a number average molecular weight of about 16 kDa and poly(ethylene)glycol having a number average molecular weight of about 5 kDa.
5. A therapeutic nanoparticle comprising:
about 10 to about 20 weight percent of a therapeutic agent selected from the group consisting of sirolimus, temsirolimus, or everolimus; and
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 20 kDa and poly(ethylene)glycol having a number average molecular weight of about 4 to about 6 kDa, wherein the diameter of the therapeutic nanoparticle is about 70 to about 130 nm; and wherein the particle releases about 0.1 to about 20% therapeutic agent over about one hour when placed in an aqueous solution at 25° C.
6. The therapeutic nanoparticle of claim 5 , wherein the particle substantially immediately releases less than about 4% of the therapeutic agent when placed in a phosphate buffer solution at room temperature.
7. The therapeutic nanoparticle of claim 5 , wherein the particle substantially immediately releases less than about 2% of the therapeutic agent when placed in a phosphate buffer solution at room temperature.
8. The therapeutic nanoparticle of claim 1 , further comprising cetyl alcohol.
9. A method of treating dermal Kaposi's sarcoma, lymphomas, glioblastoma multiforme, mantle cell lymphoma, renal cell carcinoma, comprising administering to a patient in need thereof an effective amount of a composition comprising the therapeutic nanoparticle of claim 1 .
10. A method of ameliorating organ rejection after transplant in a patient in need thereof, comprising administering to the patient an effective amount of a composition comprising the therapeutic nanoparticle of claim 1 .
11. A method of treating, preventing or deterring restenosis in a patient in need thereof, comprising administering to the patient an effective amount of a composition comprising the therapeutic nanoparticle of claim 1 .
12. A method of treating or deterring neointimal hyperplasia in a patient in need thereof, comprising administering to the patient an effective amount of a composition comprising the therapeutic nanoparticle of claim 1 .
13. A method of treating autosomal dominant polycystic kidney disease, comprising administering to the patient an effective amount of a composition comprising the therapeutic nanoparticle of claim 1 .
14. A method of treating tuberous sclerosis complex, comprising administering to the patient an effective amount of a composition comprising the therapeutic nanoparticle of claim 1 .
15. The therapeutic nanoparticle of claim 1 , wherein the diameter of the nanoparticle is about 70 to about 120 nm.
16. The therapeutic nanoparticle of claim 1 , wherein the nanoparticle substantially immediately releases less than about 10% of the mTOR inhibitor over 30 minutes when placed in a phosphate buffer solution at 37° C.
17. The therapeutic nanoparticle of claim 1 , wherein the mTOR inhibitor is everolimus.
18. The therapeutic nanoparticle of claim 5 , wherein the therapeutic agent is everolimus.
19. A pharmaceutical composition comprising:
a plurality of nanoparticles each comprising about 4 to about 25 weight percent of a mTOR inhibitor, about 50 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 20 kDa and poly(ethylene)glycol having a number average molecular weight of about 4 to about 6 kDa, and having a diameter of about 70 to about 140 nm; and
a saccharide;
wherein said nanoparticles are stable for at least 3 days when held at 25° C.
20. The pharmaceutical composition of claim 19 , wherein said nanoparticles substantially retains the mTOR inhibitor for at least 5 days at 25° C.
21. The pharmaceutical composition of claim 19 , comprising sucrose.
22. The pharmaceutical composition of claim 19 , wherein said nanoparticles release less than about 10% mTOR inhibitor when placed in a phosphate buffer solution at 25° C. for 30 minutes.
23. The pharmaceutical composition of claim 19 , wherein the mTOR inhibitor is everolimus.
24. The pharmaceutical composition of claim 19 , wherein the poly(lactic) acid of the copolymer has a number average molecular weight of about 16 kDa and the poly(ethylene)glycol has a number average molecular weight of about 5 kDa.