Drug loaded polymeric nanoparticles and methods of making and using same
View Patent ↗The present disclosure generally relates to methods of making 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.
1. A method of preparing a plurality of therapeutic nanoparticles, comprising:
combining a therapeutic agent, a first polymer bound to a ligand, and a second polymer, with an organic solvent to form a first organic phase having about 5 to about 50% 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;
filtering the solubilized phase using a tangential flow filtration system; and
sterile filtering the solubilized phase to recover the therapeutic nanoparticles, thereby forming a slurry of therapeutic nanoparticles having a diameter of about 80 nm to about 150 nm.
2. The method of claim 1 , wherein emulsifying the second phase comprises:
emulsifying the second phase to form a coarse emulsion, and
emulsifying the coarse emulsion to form a fine emulsion phase.
3. The method of claim 2 , wherein the organic solvent comprises a solvent chosen from: ethyl acetate, benzyl alcohol, methylene chloride, chloroform, toluene, methyl ethyl ketone, dimethyl formamide, dimethyl sulfoxide, acetone, acetonitrile, acetic acid, Tween 80 and Span 80, and combinations of two or more thereof.
4. The method of claim 2 , wherein the first aqueous solution comprises a reagent chosen from: sodium cholate, ethyl acetate, benzyl alcohol or combinations thereof.
5. The method of claim 2 , wherein emulsifying the second phase comprises using a rotor stator homogenizer, probe sonicator, stir bar, or high pressure homogenizer.
6. The method of claim 2 , wherein emulsifying the coarse emulsion comprises using a high pressure homogenizer.
7. The method of claim 6 , wherein emulsifying the coarse emulsion comprises about 2 to about 3 passes through the homogenizer.
8. The method of claim 7 , wherein the homogenizer feed pressure is about 2000 to about 8000 psi per interaction chamber.
9. The method of claim 6 , wherein the homogenizer comprises multiple interaction chambers.
10. The method of claim 1 , wherein quenching is performed at about 0° C. to about 5° C.
11. The method of claim 1 , wherein the quench: emulsion ratio is about 8:1 to about 5:1.
12. The method of claim 1 , wherein filtering using a tangential flow filtration system comprises filtering at a first temperature of about 0° C. to about 5° C.
13. The method of claim 12 , wherein filtering using a tangential flow filtration system further comprises filtering at a second temperature of about 20° C. to about 30° C.
14. The method of claim 13 , wherein filtering using a tangential flow filtration system comprises processing about 1 to about 6 diavolumes at about 0° C. to about 5° C. and processing at least one diavolume at about 20° C. to about 30° C.
15. The method of claim 14 , wherein the second polymer is a PLA-PEG, and the first polymer is a PLA-PEG-Ligand, wherein the ligand is covalently bound to the PEG.
16. The method of claim 1 , wherein the ligand has a molecular weight of about 100 g/mol to about 500 g/mol.
17. The method of claim 15 , wherein the ligand is represented by the formula:
18. The method of claim 1 , wherein the therapeutic agent is a taxane.