Processes for manufacturing polymeric microspheres

• US 7,094,369 B2
• Filed: 03/29/2002
• Issued: 08/22/2006
• Est. Priority Date: 03/29/2002
• Status: Active Grant

• Current Assignee: Boston Scientific Scimed (Boston Scientific Corporation)
• Original Assignee: Scimed Life Systems Incorporated (Boston Scientific Corporation)
• Inventors: Buiser, Marcia, Baldwin, Samuel P.
• Primary Examiner(s): THEISEN, MARY LYNN F
• Application Number:
  US10/109,966
• Publication Number:
  US 20030183962A1
• Time in Patent Office: 1,607 Days
• Field of Search: 264/4.6, 264/5, 264/7, 264/15, 427/212
• US Class Current: 264/7
• CPC Class Codes: A61F 2/0036 implantable A61F2/0018 takes precedence
• CPC Class Codes: A61K 49/0452 Solutions, e.g. for injection
• CPC Class Codes: A61K 9/1635 obtained by reactions only involving carbon-to-carbon unsaturated bonds, e.g. polyvinyl pyrrolidone, poly(meth)acrylates
• CPC Class Codes: A61L 24/001 Use of materials characterised by their function or physical properties
• CPC Class Codes: A61L 24/0036 Porous materials, e.g. foams or sponges
• CPC Class Codes: A61L 24/06 obtained by reactions only involving carbon-to-carbon unsaturated bonds A61L24/043, A61L24/046 take precedence
• CPC Class Codes: A61L 2430/36 for embolization or occlusion, e.g. vaso-occlusive compositions or devices artificial blood vessels A61L27/507
• CPC Class Codes: A61L 27/16 obtained by reactions only involving carbon-to-carbon unsaturated bonds
• CPC Class Codes: A61L 27/50 Materials characterised by their function or physical properties , e.g. injectable or lubricating compositions, shape-memory materials, surface modified materials
• CPC Class Codes: A61L 31/048 obtained by reactions only involving carbon-to-carbon unsaturated bonds A61L31/041 takes precedence
• CPC Class Codes: B29B 2009/125 Micropellets, microgranules, microparticles
• CPC Class Codes: B29B 2009/166 Deforming granules to give a special form, e.g. spheroidizing, rounding
• CPC Class Codes: B29B 9/16 Auxiliary treatment of granules
• CPC Class Codes: C08J 2329/04 Polyvinyl alcohol; Partially hydrolysed homopolymers or copolymers of esters of unsaturated alcohols with saturated carboxylic acids
• CPC Class Codes: C08J 3/12 Powdering or granulating
• CPC Class Codes: C08J 3/24 Crosslinking, e.g. vulcanising, of macromolecules mechanical aspects B29C35/00; crosslinking agents C08K
• CPC Class Codes: C08L 29/04 Polyvinyl alcohol; Partially hydrolysed homopolymers or copolymers of esters of unsaturated alcohols with saturated carboxylic acids
• CPC Class Codes: Y10T 428/2985 Solid-walled microcapsule from synthetic polymer

Abstract

Processes of manufacturing polymeric microspheres facilitate the generation of polymeric microspheres of size ranges smaller than 600 microns diameter by forming beads of a predetermined size from a starting material which may include a template polymer, and subsequently contacting the beads with a structural polymer. After crosslinking of the structural polymer has taken place, the template polymer may be removed to form the finished microspheres.

Claims

1. A method for producing spherical polymeric particles, the method comprising the steps of:

generating spherical beads of a desired size from a starting material comprising a template polymer;

diffusing a structural polymer into the beads; and

crosslinking the structural polymer, thereby producing polymeric spherical particles.

2. The method of claim 1, wherein the generating step comprises use of a droplet generator.

3. The method of claim 1, wherein the generating step comprises spheronization.

4. The method of claim 1, wherein the beads are porous.

5. The method of claim 4, wherein the beads comprise a template polymer selected from the group consisting of alginate, polysaccharide, carrageenan, chitosan, hyaluronic acid, and carboxylic-, sulfate-, or amine-functionalized polymers.

6. The method of claim 2, wherein the generating step comprises (i) forming droplets by forcing a mixture comprising the template polymer and a solvent through the droplet generator, and (ii) depositing the droplets into a gelling solution comprising gelling ions to solidify the droplets into beads, the beads having a porosity gradient.

7. The method of claim 6, wherein the solvent does not affect crosslinking of the structural polymer.

8. The method of claim 6, wherein the gelling solution further comprises non-gelling ions to limit the porosity gradient.

9. The method of claim 6, wherein the gelling solution does not contain non-gelling ions so as not to limit the porosity gradient.

10. The method of claim 1, wherein diffusing comprises soaking the beads in a solution comprising the structural polymer.

11. The method of claim 1, further comprising the step of removing the template polymer subsequent to the crosslinking step by subjecting the spherical polymeric particles to a solvent selective for the template polymer only.

12. The method of claim 11, wherein the solvent comprises a solution of sodium hexametaphosphate.

13. The method of claim 11, wherein the solvent comprises a solution of ethylene diamine tetraacetic acid.

14. The method of claim 11, wherein the solvent comprises acetone.

15. The method of claim 1, wherein the resulting polymeric spherical particles are in the range of 1-50 microns diameter.

16. The method of claim 1, wherein the resulting polymeric spherical particles are in the range of 50-100 microns diameter.

17. The method of claim 1, wherein the resulting polymeric spherical particles are in the range of 100-600 microns diameter.

18. The method of claim 1, wherein the resulting polymeric spherical particles are in the range of 600-1000 microns diameter.

19. The method of claim 1, wherein the template polymer is a shape-forming agent.

20. The method of claim 1, wherein the structural polymer is selected from the group consisting of polyvinyl alcohol, polyacrylamide, polyethylene glycol, polyamides, polyureas, polyurethanes, and derivatives thereof.

21. The method of claim 1, wherein the crosslinking step comprises application of a crosslinking agent.

22. The method of claim 21, wherein the crosslinking agent forms covalent bonds with the structural polymer.

23. The method of claim 1, wherein the crosslinking step comprises application of radiation.

24. The method of claim 21, wherein the starting material comprises the crosslinking agent.

25. A method for producing spherical polymeric particles, the method comprising:

generating spherical beads of a desired size from a starting material comprising a methacrylate template polymer;

contacting the beads with a structural polymer; and

crosslinking the structural polymer, thereby producing spherical polymeric particles.

26. The method of claim 25, wherein the beads further comprise a filler agent.

27. The method of claim 26, wherein the filler agent is starch.

28. The method of claim 25, wherein the beads are substantially non-porous.

29. A method for producing spherical polymeric particles comprising the steps of:

generating ice beads;

contacting the beads with a structural polymer; and

crosslinking the structural polymer, thereby producing polymeric spherical particles.

30. The method of claim 29, further comprising the step of removing the ice subsequent to the crosslinking step by exposing the particles to an elevated temperature.

31. The method of claim 29, wherein the contacting step comprises coating the beads with the structural polymer.

32. The method of claim 29, wherein the structural polymer is selected from the group consisting of polyvinyl alcohol, polyacrylamide, polyethylene glycol, polyamides, polyureas, polyurethanes, and derivatives thereof.

33. A method, comprising:

contacting a template polymer with a structural polymer to form a particle comprising the template polymer and the structural polymer; and

removing at least a portion of the template polymer from the particle.

34. The method of claim 33, further comprising, after contacting the template polymer and the structural polymer but before removing the portion of the template polymer, cross-linking the structural polymer.

35. The method of claim 34, wherein cross-linking the structural polymer includes contacting the structural polymer with a cross-linking agent.

36. The method of claim 35, wherein the cross-linking agent is selected from the group consisting of formaldehyde and glutaraldehyde.

37. The method of claim 33, further comprising, before contacting the template polymer with the structural polymer, forming droplets of the template polymer.

38. The method of claim 37, wherein forming the droplets of the template polymer includes passing a solution containing the template polymer through a nozzle.

39. The method of claim 38, wherein passing the solution containing the template polymer through the nozzle forms a stream containing the template polymer.

40. The method of claim 39, further comprising subjecting the nozzle to a periodic disturbance to break up the stream containing the template polymer.

41. The method of claim 33, wherein the template polymer comprises a polysaccharide.

42. The method of claim 41, wherein the polysaccharide comprises alginate.

43. The method of claim 33, wherein the template polymer is selected from the group consisting of carrageenans, chitosan, hyaluronic acid, carboxylic-functionalized polymers, sulfate-functionalized polymers, amine-functionalized polymers, blends thereof, and derivatives thereof.

44. The method of claim 33, wherein the structural polymer is selected from the group consisting of vinyl polymers, polyacrylamides, polyethylene glycols, polyamides, polyureas, polyurethanes, polyvinyl alcohols, and derivatives thereof.

45. The method of claim 44, wherein the structural polymer comprises a polyvinyl alcohol.

46. The method of claim 33, wherein the particle has a diameter of less than 600 microns.

47. The method of claim 46, wherein the particle has a diameter of 1 to 50 microns.

48. The method of claim 46, wherein the particle has a diameter of 50 to 100 microns.

49. The method of claim 46, wherein the particle has a diameter of 100 to 600 microns.

50. The method of claim 33, wherein the particle has a diameter of 600 to 1000 microns.

51. The method of claim 33, wherein the template polymer comprises alginate, the structural polymer comprises a polyvinyl alcohol, and the particle has a diameter of less than 600 microns.

52. A method, comprising:

contacting a first polymer with a second polymer to form a particle comprising the first and second polymers; and

removing at least a portion of the first polymer from the particle,

wherein the particle has a diameter of about 1000 microns or less.

53. The method of claim 52, wherein the first polymer comprises a polysaccharide.

54. The method of claim 53, wherein the polysaccharide comprises alginate.

55. The method of claim 52, wherein the first polymer is selected from the group consisting of carrageenans, chitosan, hyaluronic acid, carboxylic-functionalized polymers, sulfate-functionalized polymers, amine-functionalized polymers, blends thereof, and derivatives thereof.

56. The method of claim 52, wherein the second polymer is selected from the group consisting of vinyl polymers, polyacrylamides, polyethylene glycols, polyamides, polyureas, polyurethanes, polyvinyl alcohols, and derivatives thereof.

57. The method of claim 52, wherein the second polymer comprises a polyvinyl alcohol.