Methods and compositions for encapsulating active agents

• US 20040096515A1
• Filed: 12/08/2003
• Published: 05/20/2004
• Est. Priority Date: 12/07/2001
• Status: Abandoned Application

• Current Assignee: President and Fellows of Harvard College (Harvard Corporation)
• Original Assignee: President and Fellows of Harvard College (Harvard Corporation)
• Inventors: Dinsmore, Anthony D., Weitz, David A., Bausch, Andreas R., Hsu, Ming F., Nikolaides, Michael
• Application Number:
  US10/433,753
• Publication Number:
  US 20040096515A1
• Time in Patent Office: Days
• US Class Current: 424/490
• CPC Class Codes: A61K 9/5026 obtained by reactions only involving carbon-to-carbon unsaturated bonds, e.g. polyvinyl pyrrolidone, poly(meth)acrylates
• CPC Class Codes: A61K 9/5089 Processes
• CPC Class Codes: B01J 13/02 Making microcapsules or microballoons for medical preparations A61K9/50

Abstract

Methods for making self-assembled, selectively permeable elastic microscopie structures, referred to herein as colloidosomes, that have controlled pore-size, porosity and advantageous mechanical properties are described. In one form of the invention, a method of forming colloidosomes includes providing particles formed from a biocompatible material in a first solvent and forming an emulsion by adding a first fluid to the first solvent wherein the emulsion is defined by droplets of the first fluid surrounded by the first solvent. The method includes coating the surface of droplet with the particles and the stabilizing the particles on the surface of droplet. The colloidosomes produced typically have a yield strength of at least about 20 Pascals. In certain forms of the invention, the particles are spherical and are formed of a biocompatible polymer. Colloidosomes formed according to the methods described herein are also provided. In one form, a colloidosome includes a shell formed of biocompatible, substantially spherical particles wherein each of the particles are linked to neighboring particles. The shell defines an inner chamber sized for housing a desired active agent and has a plurality of pores extending therethrough. The colloidosomes are structurally stable, typically having a yield strength of at least about 20 Pascals. Colloidal suspension and methods of encapsulating a desired active agent are also described.

Claims

1. A method of forming colloidosomes, comprising:

(a) providing particles formed from a biocompatible material in a first solvent;

(b) forming an emulsion by adding a first fluid to said first solvent, said emulsion defined by droplets of said first fluid surrounded by said first solvent;

(c) coating the surface of said droplets with said particles; and

(d) stabilizing said particles on said surface of said droplet to form colloidosomes having a yield strength of at least about 20 Pascals.

2. The method of claim 1, wherein said first solvent is an aqueous solvent and said first fluid is an organic solvent.

3. The method of claim 1, wherein said first solvent is an organic solvent and said first fluid is an aqueous solvent.

4. The method of claim 1, wherein said first solvent is an organic solvent or an aqueous solvent and said first fluid is a gas.

5. The method of claim 1, wherein said particles are substantially spherical.

6. The method of claim 1, wherein said biocompatible material is a polymer.

7. The method of claim 6, wherein said polymer is hydrophobic.

8. The method of claim 7, wherein said hydrophobic polymer is polymethylmethacrylate.

9. The method of claim 7, wherein said hydrophobic polymer is polystyrene.

10. The method of claim 7, wherein said hydrophobic polymer is selected from the group consisting of polystyrene, polymethylmethacrylate, polyalkylenes, silica and combinations thereof.

11. The method of claim 7, wherein said polymer is functionalized with an ionic functional group.

12. The method of claim 11, wherein said functional group is anionic and is selected from the group consisting of carboxyl and sulfate.

13. The method of claim 1, further comprising transferring said colloidosomes into a second fluid and recovering intact colloidosomes, wherein said second fluid is substantially identical to said first fluid.

14. The method of claim 1, wherein at least about 99% of said colloidosomes remain intact after transferring said colloidosomes from said first solvent into a second solvent substantially the same as said first fluid.

15. The method of claim 1, wherein said stabilizing is performed by adding a polyelectrolyte to said first fluid.

16. The method of claim 15, wherein said polyelectrolyte is a polycationic agent.

17. The method of claim 16, wherein said polycationic agent is polylysine.

18. The method of claim 16, wherein said polyelectrolyte is added to said first fluid prior to formation of said emulsion.

19. The method of claim 1, wherein said stabilizing is performed by swelling said particles by adding a second solvent to said first solvent.

20. The method of claim 16, wherein said second solvent is a combination of at least two solvents.

21. The method of claim 1, wherein said stabilizing is performed by a sintering process.

22. The method of claim 1, further comprising isolating said colloidosomes by centrifuging said colloidosomes from said first solvent into a second solvent substantially the same as said first fluid.

23. A method of forming a colloidosome, comprising:

(a) providing substantially spherical particles formed from a biocompatible polymer in a first solvent;

(b) forming an emulsion by adding a first fluid to said first solvent, said emulsion defined by droplets of said first fluid surrounded by said first solvent;

(c) coating the surface of said droplets with said spherical particles; and

(d) stabilizing said particles on said surface of said droplets to form colloidosomes having a yield strength of at least about 20 Pascals.

24. The method of claim 23, wherein said stabilizing is performed by a sintering process.

25. The method of claim 23, wherein said stabilizing is performed by addition of an agent to said first solvent selected from the group consisting of a polycationic agent, a chemical crosslinking agent and a combination thereof.

26. The method of claim 23, wherein said first solvent is an organic solvent and said first fluid is an aqueous solvent.

27. The method of claim 23, wherein said first solvent is an aqueous solvent and said first fluid is an organic solvent.

28. The method of claim 23, wherein said first solvent is an aqueous solvent or an organic solvent and said first fluid is a gas.

29. The method of claim 23, wherein said biocompatible polymer is a hydrophilic polymer.

30. The method of claim 23, wherein said biocompatible polymer is a hydrophobic polymer.

31. The method of claim 30, wherein said hydrophobic polymer is selected from the group consisting of polystyrene, polymethylmethacrylate, polyalkylenes, silica and combinations thereof.

32. A method of encapsulating an active agent, comprising:

(a) providing particles formed from a biocompatible material in a first solvent;

(b) forming an emulsion by adding a second solvent containing said active agent to said first solvent, said emulsion defined by droplets of said second solvent surrounded by said first solvent;

(c) coating the surface of said droplets with said particles; and

(d) stabilizing said particles on said surface of said droplet to form colloidosomes having a yield strength of at least about 20 Pascals.

33. The method of claim 32, wherein said first solvent is an aqueous solvent and said second solvent is an organic solvent.

34. The method of claim 32, wherein said first solvent is an organic solvent and said second solvent is an aqueous solvent.

35. The method of claim 32, wherein said particles are substantially spherical.

36. The method of claim 32, wherein said biocompatible material is a polymer.

37. The method of claim 32, wherein said polymer is hydrophobic.

38. The method of claim 37, wherein said hydrophobic polymer is polymethylmethacrylate.

39. The method of claim 37, wherein said hydrophobic polymer is polystyrene.

40. The method of claim 37, wherein said hydrophobic polymer is selected from the group consisting of polystyrene, polymethylmethacrylate, polyalkylenes, silica and combinations thereof

41. The method of claim 37, wherein said polymer is functionalized with an ionic functional group.

42. The method of claim 41, wherein said functional group is anionic and is selected from the group consisting of carboxyl and sulfate.

43. The method of claim 32, wherein at least about 95% of said colloidosomes remain intact after transferring said colloidosomes from said first solvent into a third solvent substantially the same as said second solvent.

44. The method of claim 32, wherein at least about 99% of said colloidosomes remain intact after transferring said colloidosomes from said first solvent into a third solvent substantially the same as said second solvent.

45. The method of claim 32, wherein said stabilizing is performed by adding a polyelectrolyte to said first solvent.

46. The method of claim 45, wherein said polyelectrolyte is a polycationic agent.

47. The method of claim 46, wherein said polycationic agent is polylysine.

48. The method of claim 32, wherein said stabilizing is performed by swelling said particles by adding a fourth solvent to said first solvent.

49. The method of claim 48, wherein said fourth solvent is a combination of at least two solvents.

50. The method of claim 32, wherein said stabilizing is performed by a sintering process.

51. The method of claim 32, wherein said active agent is selected from the group consisting of a chemical agent or biological agent.

52. The method of claim 51, wherein said chemical agent is selected from the group consisting of a drug, a flavoring agent, a fragrance-producing chemical and a combination thereof.

53. The method of claim 51, wherein said biological agent is a biological macromolecule.

54. The method of claim 51, wherein said macromolecule is selected from the group consisting of a protein, a nucleic acid, a carbohydrate, a lipid and a combination thereof.

55. The method of claim 52, wherein said biological agent is a biological cell.

56. A method of encapsulating an active agent, comprising:

(a) providing substantially spherical particles formed from a biocompatible polymer in a first solvent;

(b) forming an emulsion by adding a second solvent containing said active agent to said first solvent, said emulsion defined by droplets of said second solvent surrounded by said first solvent;

(c) coating the surface of said droplets with said spherical particles; and

(d) stabilizing said particles on said surface of said droplet to form a colloidosome.

57. The method of claim 56, wherein said biocompatible material is selected from the group consisting of polystyrene, polymethylmethacrylate, polyalkylenes, silica and combinations thereof.

58. The method of claim 56, wherein said active agent is a chemical agent or biological agent.

59. The method of claim 58, wherein said chemical agent is selected from the group consisting of a drug, a flavoring agent, a fragrance-producing chemical and a combination thereof.

60. The method of claim 58, wherein said biological agent is a biological macromolecule.

61. The method of claim 60, wherein said macromolecule is selected from the group consisting of a protein, a nucleic acid, a carbohydrate, a lipid and a combination thereof.

62. The method of claim 58, wherein said biological agent is a biological cell.

63. A colloidosome, comprising:

a shell formed of biocompatible, substantially spherical particles, each of said particles linked to neighboring particles, said shell defining an inner chamber and having a plurality of pores extending therethrough, said chamber sized for housing an active agent, said colloidosome having a yield strength of at least about 20 Pascals.

64. The colloidosome of claim 63, wherein said colloidosomes have a yield strength of at least about 50 Pascals.

65. The colloidosome of claim 63, wherein said shell is a monolayer.

66. The colloidosome of claim 63, wherein an active agent in a solvent is disposed within said chamber.

67. The colloidosome of claim 66, wherein said active agent is a biological agent or chemical agent.

68. The colloidosome of claim 67, wherein said chemical agent is selected from the group consisting of a drug, a flavoring agent, a fragrance-producing chemical and a combination thereof.

69. The colloidosome of claim 67, wherein said biological agent is a biological macromolecule.

70. The colloidosome of claim 69, wherein said macromolecule is selected from the group consisting of a protein, a nucleic acid, a carbohydrate, a lipid and a combination thereof.

71. The colloidosome of claim 67, wherein said biological agent is a biological cell.

72. The colloidosome of claim 63, wherein each of said particles are linked to neighboring particles by coalescence of regions of the particles.

73. The colloidsome of claim 63, wherein each of said particles is linked to a neighboring particle by chemical cross-linking.

74. A colloidosome suspension, comprising:

a colloidosome suspended in a first solvent, said colloidosome having a shell formed of biocompatible, substantially spherical particles, each of said particles linked to neighboring particles, said shell defining an inner chamber and having a plurality of pores extending therethrough, said chamber sized for housing an active agent and filled with a second solvent that is substantially similar to said first solvent.

75. The colloidosome of claim 74, wherein said colloidosome has a yield strength of at least about 50 Pascals.