Process for preparing microparticles through phase inversion phenomena

• US 6,143,211 A
• Filed: 07/03/1996
• Issued: 11/07/2000
• Est. Priority Date: 07/21/1995
• Status: Expired due to Term

• Current Assignee: Brown University
• Original Assignee: Brown University
• Inventors: Mathiowitz, Edith, Jacob, Jules S., Jong, Yong S., Chickering, Donald III
• Primary Examiner(s): Mullis, Jeffrey C.
• Application Number:
  US08/686,928
• Time in Patent Office: 1,588 Days
• Field of Search: 427/213.36, 264/4, 264/4.1
• US Class Current: 264/4
• CPC Class Codes: A61K 48/00 Medicinal preparations containing genetic material which is inserted into cells of the living body to treat genetic diseases; Gene therapy
• CPC Class Codes: A61K 9/1641 obtained otherwise than by reactions only involving carbon-to-carbon unsaturated bonds, e.g. polyethylene glycol, poloxamers
• CPC Class Codes: A61K 9/1694 resulting in granules or microspheres of the matrix type containing more than 5% of excipient
• CPC Class Codes: A61K 9/5089 Processes
• CPC Class Codes: A61K 9/5138 obtained by reactions only involving carbon-to-carbon unsaturated bonds, e.g. polyvinyl pyrrolidone, poly(meth)acrylates
• CPC Class Codes: A61K 9/5146 obtained otherwise than by reactions only involving carbon-to-carbon unsaturated bonds, e.g. polyethylene glycol, polyamines, polyanhydrides
• CPC Class Codes: A61K 9/5153 Polyesters, e.g. poly(lactide-co-glycolide)
• CPC Class Codes: A61K 9/5192 Processes
• CPC Class Codes: B01J 13/04 by physical processes, e.g. drying, spraying
• CPC Class Codes: B01J 13/06 by phase separation

Abstract

A process for preparing nanoparticles and microparticles is provided. The process involves forming a mixture of a polymer and a solvent, wherein the solvent is present in a continuous phase and introducing the mixture into an effective amount of a nonsolvent to cause the spontaneous formation of microparticles.

Claims

1. A method for microencapsulating an agent to form a microencapsulated product, comprising:

dissolving a polymer in an effective amount of a solvent,

dissolving or dispersing said agent in said effective amount of said solvent, wherein said polymer, said agent and said solvent form a mixture having a continuous phase and wherein the solvent is said continuous phase, and

introducing said mixture into an effective amount of a nonsolvent to cause the spontaneous formation of said microencapsulated product, wherein said solvent and said nonsolvent are miscible and 0<

δ

solvent -δ

nonsolvent <

6 wherein the nonsolvent and solvent are used in effective amounts, wherein the effective amount of nonsolvent and solvent is an effective amount when the solvent;

nonsolvent volume ratio is between 1;

40 and 1;

1,000,000.

2. The method of claim 1 wherein the agent is dissolved in the solvent.

3. The method of claim 1 wherein the agent is dispersed as solid microparticles in the solvent.

4. The method of claim 1 wherein the agent is contained in microdroplets dispersed in the solvent.

5. The method of claim 1 wherein the agent is a liquid.

6. The method of claim 1 wherein the agent is a bioactive agent.

7. The method of claim 1 wherein the microencapsulated product consists of microparticles having an average particle size of between 10 nanometers and 10 microns.

8. The method of claim 1 wherein the microencapsulated product consists of microparticles having an average particle size between 100 nanometers and 5 microns.

9. The method of claim 1 wherein the microencapsulated product consists of microparticles having an average particle size of between 100 nanometers and 1 micron.

10. The method of claim 1 further comprising separating the microencapsulated product from the nonsolvent.

11. The method of claim 1 wherein the solvent:

nonsolvent volume ratio is between 1;

50 and 1;

200.

12. The method of claim 1 wherein the concentration of the polymer in the solvent is less than 20% weight per volume.

13. The method of claim 1 wherein the concentration of the polymer in the solvent is less than 10% weight per volume.

14. The method of claim 1 wherein the concentration of the polymer in the solvent is less than 5% weight per volume.

15. The method of claim 1 wherein the concentration of the polymer in the solvent is between 1 and 5% weight per volume.

16. The method of claim 1 wherein the mixture has a viscosity less than 6 centepoise.

17. The method of claim 1 wherein the mixture has a viscosity less than 4 centepoise.

18. The method of claim 1 wherein the mixture has a viscosity less than 3 centepoise.

19. The method of claim 1 wherein the mixture has a viscosity less than 2 centepoise.

20. The method of claim 1 wherein the solvent and nonsolvent are hydrophilic pairs.

21. The method of claim 1 wherein the concentration of polymer in the solvent is less than 10% weight per volume and wherein the viscosity of the solvent is less than 3.5 centepoise.

22. The method of claim 1 wherein the solvent:

nonsolvent ratio is greater than 1;

40 and wherein the viscosity of the mixture is less than 3.5 centepoise.

23. A method for microencapsulating an agent to form a microencapsulated product, comprising:

dissolving a polymer in a solvent at a concentration of less than 10% weight/volume,

dissolving or dispersing said agent in said solvent, wherein said polymer, said agent and said solvent form a mixture having a viscosity of less than 3.5 centipoise, and

introducing said mixture into a nonsolvent, wherein the volume ratio of solvent;

nonsolvent is at least 1;

40, to cause the spontaneous formation of said microencapsulated product, wherein said solvent and said nonsolvent are miscible and 0<

δ

solvent -δ

nonsolvent <

6.

24. The method of claim 23 wherein the concentration of the polymer in the solvent is between 0.5 and 5% weight per volume, and wherein the volume ration of solvent:

nonsolvent is between 1;

50 and 1;

200.

25. A method for microencapsulating an agent to form a microencapsulated product, comprising:

dissolving a polymer in an effective amount of a solvent,

dissolving or dispersing an agent in the effective amount of the solvent by freezing the mixture of the solvent, the polymer, and the agent to form a frozen mixture and drying by vacuum the frozen mixture, wherein the polymer, the agent and the solvent in the frozen mixture have a continuous phase,

redissolving the continuous phase frozen mixture in a solvent, and

introducing the mixture into an effective amount of a nonsolvent to cause the spontaneous formation of microencapsulated product, wherein the solvent and the nonsolvent are miscible and 0<

δ

solvent -δ

nonsolvent <

6.

26. The method of claim 25, wherein the solvent, the polymer, and the agent are frozen in liquid nitrogen.

27. The method of claim 25, wherein the microencapsulated product consists of microparticles having an average particle size of between 10 nm and 10 microns.

28. The method of claim 25, wherein the microencapsulated product consists of microparticles having an average particle size between 100 nm and 5 microns.

29. The method of claim 25, wherein the microencapsulated product consists of microparticles having an average particle size of between 100 nm and 1 micron.

30. The method of claim 25, wherein the solvent:

nonsolvent volume ratio is >

1;

40.

31. The method of claim 25, wherein the solvent:

nonsolvent volume ratio is >

1;

50.