Method and Apparatus for Forming Multiple Emulsions

• US 20090131543A1
• Filed: 03/03/2006
• Published: 05/21/2009
• Est. Priority Date: 03/04/2005
• Status: Active Grant

• Current Assignee: President and Fellows of Harvard College (Harvard Corporation)
• Original Assignee: President and Fellows of Harvard College (Harvard Corporation)
• Inventors: Link, Darren Roy, Weitz, David A., Utada, Andrew S.
• Granted Patent: US 9,039,273 B2
• Time in Patent Office: Days
• US Class Current: 516/54
• CPC Class Codes: A61K 9/113 Multiple emulsions, e.g. oil-in-water-in-oil A61K9/0026 takes precedence
• CPC Class Codes: A61K 9/1273 Polymersomes; Liposomes with polymerisable or polymerised bilayer-forming substances polymers grafted or coated on phosphatidyl liposomes A61K9/1271, on non-phosphatidyl liposomes A61K9/1272
• CPC Class Codes: A61K 9/5089 Processes
• CPC Class Codes: B01F 2025/915 Reverse flow, i.e. flow changing substantially 180° in direction
• CPC Class Codes: B01F 23/41 Emulsifying
• CPC Class Codes: B01F 25/313 wherein additional components are introduced in the centre of the conduit
• CPC Class Codes: B01F 25/31324 arranged concentrically
• CPC Class Codes: B01F 33/30 Micromixers
• CPC Class Codes: B01F 33/3011 using a sheathing stream of a fluid surrounding a central stream of a different fluid, e.g. for reducing the cross-section of the central stream or to produce droplets from the central stream
• CPC Class Codes: B82Y 10/00 Nanotechnology for information processing, storage or transmission, e.g. quantum computing or single electron logic
• CPC Class Codes: B82Y 30/00 Nanotechnology for materials or surface science, e.g. nanocomposites
• CPC Class Codes: F15D 1/008 comprising fluid injection or suction means
• CPC Class Codes: Y10S 516/924 Significant dispersive or manipulative operation or step in making or stabilizing colloid system
• CPC Class Codes: Y10T 137/0391 Affecting flow by the addition of material or energy

Abstract

The present invention generally relates to multiple emulsions, and to methods and apparatuses for making multiple emulsions. A multiple emulsion generally describes larger droplets that contain one or more smaller droplets therein. The larger droplets may be suspended in a third fluid in some cases. These can be useful for encapsulating species such as pharmaceutical agents, cells, chemicals, or the like. In some cases, one or more of the droplets can change form, for instance, to become solidified to form a microcapsule, a liposome, a polymerosome, or a colloidosome. Multiple emulsions can be formed in one step in certain embodiments, with generally precise repeatability, and can be tailored to include one, two, three, or more inner droplets within a single outer droplet (which droplets may all be nested in some cases).

Claims

1. A method of making a multiple emulsion comprising:

forming a first droplet from a first fluid stream surrounded by a second fluid while the second fluid is surrounded by a third fluid, wherein the first fluid stream is expelled from an end defining an exit opening of a first conduit concentrically disposed in a second conduit into a third conduit including an end defining an entrance opening, wherein the third conduit is concentrically disposed in the second conduit and the entrance opening of the third conduit opposes the exit opening of the first conduit.

2. The method of claim 1, wherein the first fluid is miscible in the third fluid.

3. The method of claim 1, wherein the second fluid comprises a material selected from surfactants, prepolymers, polymers, lipids, copolymers and amphiphiles

4. The method of claim 3, wherein the copolymer is a diblock copolymer, a triblock copolymer and/or a random copolymer.

5. The method of claim 1, wherein the second fluid comprises two surfactants.

6. The method of claim 3, wherein the material is amphiphilic.

7. The method of claim 1, wherein the second fluid comprises a phase change fluid.

8. The method of claim 1, wherein the first and second fluids form a polymerosome or a liposome.

9. The method of claim 1, wherein the second fluid forms a droplet surrounding a single droplet of the first fluid.

10. The method of claim 9, wherein greater than 90% of the second fluid droplets formed contain a single first fluid droplet.

11. The method of claim 1, wherein the second fluid stream forms a droplet around the first droplet.

12. The method of claim 1, wherein the first fluid comprises a species selected from a cell and a drug.

13. The method of claim 9, wherein the standard deviation of the diameter of the second fluid droplets is less than 10%.

14. The method of claim 9, wherein the second fluid droplet is less than about 200 microns in diameter.

15. The method of claim 9, wherein the second fluid droplet is less than about 50 microns in diameter.

16. The method of claim 9, wherein the second fluid droplet is less than about 10 microns in diameter.

17. The method of claim 9, wherein the second fluid droplet is less than about 1 micron in diameter.

18. The method of claim 9, wherein the second fluid droplet is less than about 500 nm in diameter.

19. The method of claim 1, wherein the second fluid is essentially void of surfactants.

20. The method of claim 11, further comprising reducing the amount of the second fluid in the second fluid droplet.

21. The method of claim 20, wherein the second fluid is reduced through evaporation or diffusion.

22. The method of claim 21, further comprising bringing about a phase change in the second fluid.

23. The method of claim 1, comprising a plurality of inner droplets inside an outer droplet of the second fluid.

24. The method of claim 1, wherein the viscosity of the first fluid is substantially equal to the viscosity of the second fluid.

25. The method of claim 24, wherein the viscosity of the third fluid is substantially different from the viscosity of the first fluid.

26. A method comprising:

flowing a first fluid stream in a first direction;

flowing a second fluid stream in the same direction as the first fluid, the second stream circumscribing the first stream;

flowing a third fluid stream in a second direction that is substantially opposed to the first direction; and

altering the direction of flow of the third fluid stream to flow substantially parallel to the first direction.

27. The method of claim 26, wherein at least a portion of the third stream circumscribes a portion of the second stream.

28. The method of claim 26, wherein the fluid of the first stream is miscible in the fluid of the third stream.

29. An apparatus for forming droplets, the apparatus comprising:

a first conduit having a first diameter;

a second conduit including an end defining an exit opening, the second conduit concentrically disposed in the first conduit; and

a third conduit including an end defining an entrance opening, the third conduit concentrically disposed in the first conduit wherein the entrance opening opposes the exit opening of the second conduit.

30. The apparatus of claim 29, wherein the second and third conduits are disposed in different portions of the first conduit.

31. The apparatus of claim 29, wherein the exit opening of the second conduit is of smaller diameter than is the entrance opening of the third conduit.

32. The apparatus of claim 29, wherein the exit opening of the second conduit is tapered.

33. The apparatus of claim 29, wherein the first conduit is substantially polygonal in cross section and the second and third conduits are substantially circular in cross section.

34. The apparatus of claim 29, wherein the first conduit is substantially circular in cross section and the second and third conduits are substantially polygonal in cross section.

35. The apparatus of claim 29, wherein each of the three conduits is axially aligned.

36. The apparatus of claim 29, wherein at least one of the conduits has an average diameter of less than 1 mm.

37. The apparatus of claim 29, wherein at least one of the conduits comprises a glass capillary.

38. The apparatus of claim 29, wherein the interior diameter of the third conduit increases along a portion of the conduit starting from the entrance opening.

39. The apparatus of claim 29, wherein the interior of a portion of the third conduit adjacent to the entrance opening is constricted.

40. The apparatus of claim 29, the apparatus further comprising a fourth conduit including an end defining an exit opening, the fourth conduit concentrically disposed in the second conduit.

41-65. -65. (canceled)