Therapeutic Polymeric Nanoparticles Comprising Vinca Alkaloids and Methods of Making and Using Same
The present disclosure generally relates to therapeutic nanoparticles. Exemplary nanoparticles disclosed herein may include about 1 to about 20 weight percent of a vinca alkaloid; and about 50 to about 99 weight percent biocompatible polymer.
1 . A therapeutic nanoparticle comprising:
about 1 to about 20 weight percent of a vinca alkaloid; and
about 50 to about 99 weight percent biocompatible polymer, wherein the biocompatible polymer is selected from the group consisting of
a) a diblock poly(lactic) acid-poly(ethylene)glycol copolymer,
b) a diblock poly(lactic)-co-(glycolic) acid-poly(ethylene)glycol copolymer,
c) a combination of a) and a poly (lactic) acid homopolymer or poly(lactic)-co-(glycolic) acid; and
d) a combination of b) and a poly (lactic) acid homopolymer or poly(lactic)-co-(glycolic) acid.
2 . The therapeutic nanoparticle of claim 1 wherein said vinca alkaloid is vinorelbine or vincristine or a pharmaceutically acceptable salt thereof.
3 . The therapeutic nanoparticle of claim 1 or 2 , wherein the diameter of the therapeutic nanoparticle is about 70 to about 140 nm.
4 . The therapeutic nanoparticle of claims 1 - 3 , wherein the diameter is about 80 to about 130 nm.
5 . The therapeutic nanoparticle of any one of claims 1 - 4 , comprising about 9 to about 16 weight percent of a vinca alkaloid compound.
6 . The therapeutic nanoparticle of any one of claims 1 - 4 , comprising about 3 to about 9 weight percent of a vinca alkaloid compound.
7 . The therapeutic nanoparticle of any one of claims 1 - 6 , 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.
8 . The therapeutic nanoparticle of any one of claims 1 - 6 , wherein said diblock poly(lactic)-co-glycolic acid-poly(ethylene)glycol copolymer comprises poly(lactic acid)-co-glycolic 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.
9 . The therapeutic nanoparticle of any one of claims 1 - 8 , wherein the particle substantially immediately releases less than about 2% of the therapeutic agent when placed in a phosphate buffer solution at room temperature.
10 . The therapeutic nanoparticle of any one of claims 1 - 9 , wherein the particle substantially immediately releases less than about 7% of the therapeutic agent when placed in a phosphate buffer solution at room temperature.
11 . The therapeutic nanoparticle of any one of claims 1 - 10 , wherein the particle substantially immediately releases less than about 10% of the therapeutic agent when placed in a phosphate buffer solution at 37° C.
12 . The therapeutic nanoparticle of any one of claims 1 - 11 , wherein the biocompatible polymer is diblock poly(lactic) acid-poly(ethylene)glycol copolymer.
13 . The therapeutic nanoparticle of any one of claims 1 - 11 , wherein the therapeutic nanoparticle comprises about 40 to about 50 weight percent diblock poly(lactic)acid-poly(ethylene)glycol copolymer and about 40 to about 49 weight percent poly (lactic) acid homopolymer.
14 . The therapeutic nanoparticle of any one of claims 1 - 11 , wherein the poly(lactic)-co-poly (glycolic) acid portion of the diblock poly(lactic)-co-poly (glycolic) acid-poly(ethylene)glycol copolymer is about 50 mole percent glycolic acid and about 50 mole percent poly(lactic) acid.
15 . The therapeutic nanoparticle of any one of claims 1 - 14 , wherein the poly (lactic) acid homopolymer has a weight average molecular weight of about 8 to about 12 kDa.
16 . The therapeutic nanoparticle of any one of claims 1 - 14 , wherein the poly (lactic) acid homopolymer has a weight average molecular weight of about 10 kDa.
17 . The therapeutic nanoparticle of any one of claims 1 - 16 , wherein said diblock poly(lactic)-co-glycolic acid-poly(ethylene)glycol copolymer comprises poly(lactic acid)-co-glycolic 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.
18 . The therapeutic nanoparticle of any one of claims 1 - 16 , 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.
19 . The therapeutic nanoparticle of any one of claims 1 - 18 , wherein said therapeutic nanoparticle comprises about 10 weight percent to about 20 weight percent vinorelbine or a pharmaceutically acceptable salt thereof.
20 . The therapeutic nanoparticle of any one of claims 1 - 18 , wherein said therapeutic nanoparticle comprises about 3 weight percent to about 10 weight percent vincristine or a pharmaceutically acceptable salt thereof.
21 . The therapeutic nanoparticle of any one of claims 1 - 20 , further comprising about 0.2 to about 10 weight percent of a diblock poly(lactic)-co-poly (glycolic) acid-poly(ethylene)glycol copolymer covalently bound to a targeting ligand.
22 . A therapeutic nanoparticle comprising:
about 10 to about 20 weight percent of vinorelbine or vincristine, or a pharmaceutically acceptable salt thereof;
a diblock polymer chosen from: poly(lactic) acid-poly(ethylene)glycol copolymer or a poly(lactic)-co-poly (glycolic) acid-poly(ethylene)glycol copolymer.
23 . A therapeutic nanoparticle comprising:
about 2 to about 20 weight percent of vincristine or vinorelbine, or a pharmaceutically acceptable salt thereof;
a diblock polymer chosen from: poly(lactic) acid-poly(ethylene)glycol copolymer or a poly(lactic)-co-poly (glycolic) acid-poly(ethylene)glycol copolymer; and
optionally, a poly(lactic) acid homopolymer.
24 . The therapeutic nanoparticle of claim 22 or 23 , wherein the poly(lactic) acid homopolymer has a weight average molecular weight of about 10 kDa.
25 . The therapeutic nanoparticle of any of claims 22 - 24 , wherein the therapeutic nanoparticle comprises about 40 to about 45 weight percent diblock polymer and about 40 to about 45 weight percent homopolymer.
26 . The therapeutic nanoparticle of any one of claims 22 - 25 , wherein the particle substantially immediately releases less than about 4% of the therapeutic agent when placed in a phosphate buffer solution at room temperature.
27 . The therapeutic nanoparticle of any one of claims 22 - 26 , wherein the particle substantially immediately releases less than about 2% of the therapeutic agent when placed in a phosphate buffer solution at room temperature.
28 . The therapeutic nanoparticle of any one of claims 1 - 27 , further comprising cetyl alcohol.
29 . A pharmaceutically acceptable composition comprising a plurality of therapeutic nanoparticles of any of claims 1 - 28 ; and
a pharmaceutically acceptable excipient.
30 . The pharmaceutically acceptable composition of claim 29 , wherein the pharmaceutically acceptable excipient is a sugar.
31 . The pharmaceutically acceptable composition of 30, wherein the pharmaceutically acceptable excipient is sucrose.
32 . A method of treating prostate, breast, or non-small cell lung cancer, comprising administering to a patient in need thereof an effective amount of a composition comprising the therapeutic nanoparticle of any one of claims 1 - 28 .
33 . A plurality of therapeutic nanoparticles prepared by:
combining vinorelbine or vincristine or pharmaceutically acceptable salts thereof and a diblock poly(lactic)acid-polyethylene glycol or a diblock poly(lactic)acid-co-poly(glycolic)acid-polyethylene glycol polymer and optionally a homopolymer, with an organic solvent to form a first organic phase having about 10 to about 40% solids;
combining the first organic phase with a first aqueous solution to form a second phase;
emulsifying the second phase to form an emulsion phase;
quenching the emulsion phase to form a quenched phase;
adding a drug solubilizer to the quenched phase to form a solubilized phase of unencapsulated therapeutic agent; and
filtering the solubilized phase to recover the nanoparticles, thereby forming a slurry of therapeutic nanoparticles each having about 3 to about 20 weight percent of vinorelbine or vincristine.
34 . The plurality of therapeutic nanoparticles of claim 33 , wherein filtering comprises concentrating, diafiltering, and terminally filtering the solubilized phase.
35 . A controlled release therapeutic nanoparticle comprising:
about 10 to about 20 weight percent of a therapeutic agent selected from the group consisting of: vinorelbine or vincristine, or a pharmaceutically acceptable salt thereof;
a diblock polymer chosen from: poly(lactic) acid-poly(ethylene)glycol copolymer or a poly(lactic)-co-poly (glycolic) acid-poly(ethylene)glycol copolymer, wherein said therapeutic agent is released at a controlled release rate.
36 . The controlled release therapeutic nanoparticle of claim 35 , wherein said therapeutic agent is released over a period of at least 1 day or more when administered to a patient.