Methods of processing compositions containing microparticles
A method for processing multi-phasic dispersions is provided. The method comprises providing a multi-phasic dispersion including dispersed and continuous phases, providing one or more non-solvents comprising an aqueous solution containing at least one multivalent cation, exposing the multi-phasic dispersion to the non-solvent to form a suspension containing one or more liquid phases and the solid microparticles, and removing at least a portion of the resulting one or more liquid phases while retaining at least the microparticles, thereby removing at least a portion of the non-volatile material from the microparticles.
1. A method of processing microparticles comprising:
providing a composition comprising a plurality of solid microparticles and at least one non-volatile material;
providing a non-solvent comprising an aqueous solution containing at least one free multivalent cation;
exposing the composition to the non-solvent to form a mixture containing one or more liquid phases and the solid microparticles; and
removing at least a portion of the one or more liquid phases while retaining at least the microparticles, thereby removing at least a portion of the non-volatile material from the composition,
wherein the non-volatile material is more soluble in the non-solvent than are the microparticles,
wherein the non-volatile material comprises a non-ionic aqueous-soluble polymer or a non-ionic aqueous-miscible polymer,
wherein the solid microparticles comprise at least one bioactive macromolecule that is an antibody,
wherein the activity of the bioactive macromolecule remains substantially the same before and after the exposing and removing steps, and
wherein the solid microparticles have a diameter of less than 1 mm.
2. The method of claim 1 , wherein the non-volatile material is soluble in the non-solvent.
3. The method of claim 1 , wherein the solid microparticles are substantially insoluble in the non-solvent.
4. The method of claim 3 , wherein the solid microparticles have less than 20 weight percent (wt. %) solubility in the non-solvent.
5. The method of claim 1 , wherein the solid microparticles have less than 20 wt. % solubility in the non-solvent and are more soluble in an aqueous solution that is the same as the non-solvent but is free of the free multivalent cation.
6. The method of claim 1 , wherein exposing and/or removing steps comprise centrifugal washing, diafiltration, filtration, dialysis, electrophoresis, or a combination thereof.
7. The method of claim 1 , wherein the non-solvent is free of chelating agents to the multivalent cation.
8. The method of claim 1 , wherein the multivalent cation is selected from the group consisting of Ba 2+ , Ca 2+ , Co 2+ , Cr 2+ , Cu 2+ , Fe 2+ , Mg 2+ , Mn 2+ , Sr 2+ , Zn 2+ , Al 3+ , Fe 3+ , and combinations thereof.
9. The method of claim 1 , wherein the multivalent cation is present in the non-solvent at a concentration of 0.01 mM to 50 mM.
10. The method of claim 1 , wherein the multivalent cation is present in the non-solvent at a concentration of 0.2 mM to 2 mM.
11. The method of claim 1 , wherein the non-solvent further comprises one or more non-chelating anions selected from the group consisting of acetate, ascorbate, aspartate, bicarbonate, carbonate, chloride, formate, salicylate, succinate, sulfate, and combinations of two or more thereof.
12. The method of claim 1 , wherein the bioactive macromolecule is selected from polycolonal antibodies and monoclonal antibodies.
13. The method of claim 1 , wherein the solid microparticles comprise the bioactive macromolecule at least on an outer surface of the solid microparticle.
14. The method of claim 1 , wherein the non-volatile material is selected from the group consisting of nonionic polyethers, nonionic copolyethers, nonionic polyesters, nonionic copolyesters, nonionic polyether-polyester copolymers, starch, cellulose, guar gum, nonionic starch ethers, nonionic cellulose ethers, nonionic guar ethers, nonionic starch esters, nonionic cellulose esters, nonionic starch etheresters, nonionic cellulose etheresters, nonionic vinyl polymers, ionic salts thereof, and combinations thereof.
15. The method of claim 1 , wherein the microparticles comprise a carrier macromolecule.
16. The method of claim 1 , wherein the microparticles are amorphous, spherical, or both.
17. The method of claim 1 , wherein exposing comprises combining the non-solvent and the composition to form a mixture having a single aqueous liquid phase.
18. The method of claim 1 , further comprising isolating the microparticles.
19. The method of claim 18 , further comprising drying the isolated microparticles into a powder.
20. The method according to claim 19 , wherein drying comprises lyophilizing the microparticles.
21. The method according to claim 1 , wherein the composition is a multi-phasic dispersion comprising dispersed and continuous phases, the dispersion comprising the solid microparticles and at least one of a non-volatile material and a solvent.
22. The method according to claim 1 , wherein the multivalent cation comprises Zn 2+ .