Process for preparing therapeutic nanoparticles
View Patent ↗The present disclosure generally relates to a process for preparing therapeutic nanoparticles, where the process includes combining a therapeutic agent with an organic acid. The therapeutic nanoparticles may have, for example, improved drug loading and/or drug release properties.
1. A method of preparing a plurality of therapeutic nanoparticles, comprising:
combining a therapeutic agent, a first polymer, and an organic acid with an organic solvent to form a first organic phase having about 1 to about 50% solids, wherein the organic acid has a pK a of less than about 3.5 at 25° C., and wherein the therapeutic agent has a solubility in a first solution consisting of the therapeutic agent, the organic solvent, and the organic acid that is at least 5 times higher as compared to a second solution consisting of the therapeutic agent and the organic solvent;
combining the first organic phase with a first aqueous solution to form the plurality of therapeutic nanoparticles; and
recovering the therapeutic nanoparticles by filtration,
wherein the organic solvent comprises a solvent selected from the group consisting of ethyl acetate, benzyl alcohol, methylene chloride, chloroform, toluene, methyl ethyl ketone, dimethyl formamide, dimethyl sulfoxide, acetone, acetonitrile, acetic acid, polysorbate 80, sorbitan monostearate 80, and combinations of two or more thereof;
wherein the organic acid comprises an acid selected from the group consisting of formic acid, oxalic acid, malonic acid, maleic acid, malic acid, tartaric acid, citric acid, gluconic acid, aspartic acid, glutaminic acid, fumaric acid, itaconic acid, a halogenated carboxylic acid, triflic acid, methanesulfonic acid, benzenesulfonic acid, p-toluenesulfonic acid, and combinations thereof; and
wherein the therapeutic agent is an anticancer agent.
2. The method of claim 1 , wherein the therapeutic nanoparticles comprise about 1 to about 10 weight percent of the therapeutic agent.
3. The method of claim 1 , wherein the method is a first method and the therapeutic nanoparticles have a therapeutic agent loading at least about 2 times higher as compared to therapeutic nanoparticles prepared by a second method, wherein the second method is identical to the first method except that the second method does not include the organic acid.
4. The method of claim 3 , wherein the therapeutic nanoparticles have a therapeutic agent loading at least about 5 times higher.
5. The method of claim 1 , wherein the concentration of the organic acid is between about 1 to about 10 weight percent.
6. The method of claim 1 , wherein the organic acid is a halogenated carboxylic acid.
7. The method of claim 1 , wherein the therapeutic nanoparticles substantially immediately release less than about 5% of the therapeutic agent when placed in a phosphate buffer solution at 37° C.
8. The method of claim 1 , wherein the therapeutic nanoparticles release about 0.01 to about 25% of the therapeutic agent over about 1 hour when placed in a phosphate buffer solution at 37° C.
9. The method of claim 1 , wherein the therapeutic nanoparticles release about 10 to about 45% of the therapeutic agent over about 4 hours when placed in a phosphate buffer solution at 37° C.
10. The method of claim 1 , wherein the therapeutic nanoparticles have a diameter of about 60 nm to about 150 nm.
11. The method of claim 1 , wherein combining the first organic phase with the first aqueous solution comprises emulsifying a second phase, formed from combining the first organic phase with the first aqueous solution, to form an emulsion phase.
12. The method of claim 11 , further comprising quenching the emulsion phase to form a quenched phase.
13. The method of claim 12 , further comprising adding a drug solubilizer to the quenched phase to form a solubilized phase of unencapsulated therapeutic agent.
14. The method of claim 11 , 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.
15. The method of claim 12 , wherein quenching is performed at about 0° C. to about 5° C.
16. The method of claim 12 , wherein the quench:emulsion ratio is about 2:1 to about 40:1.
17. The method of claim 13 , wherein the drug solubilizer is selected from the group consisting of polysorbate 80, polysorbate 20, polyvinyl pyrrolidone, cyclodextran, sodium dodecyl sulfate, sodium cholate, diethylnitrosamine, sodium acetate, urea, glycerin, propylene glycol, glycofurol, poly(ethylene)glycol, bris polyoxyethylene glycol dodecyl ether, sodium benzoate, and sodium salicylate.
18. The method of claim 1 , wherein filtration comprises filtering at a first temperature of about 0° C. to about 5° C.
19. The method of claim 18 , further comprising filtering at a second temperature of about 20° C. to about 30° C.
20. The method of claim 13 , further comprising purifying the solubilized phase before the filtration to substantially remove the organic solvent, unencapsulated therapeutic agent, and/or drug solubilizer.
21. The method of claim 1 , wherein filtration comprises sterile filtration.
22. The method of claim 21 , wherein the sterile filtration comprises filtering the therapeutic nanoparticles using a filtration train at a controlled rate.
23. The method of claim 1 , wherein the first polymer is a diblock poly(lactic) acid-poly(ethylene)glycol copolymer.
24. The method of claim 1 , wherein the organic acid is triflouroacetic acid.