Microencapsulation and electrostatic processing method

• US 6,103,271 A
• Filed: 05/15/1998
• Issued: 08/15/2000
• Est. Priority Date: 12/02/1994
• Status: Expired due to Term

• Current Assignee: National Aeronautics and Space Administration US Government As Represented By The Administrator of The
• Original Assignee: United States Of America As Represented By The Administrator Of The National Aeronautics And Space Administration
• Inventors: Mosier, Benjamin, Morrison, Dennis R.
• Primary Examiner(s): Spear, James M.
• Application Number:
  US09/079,770
• Time in Patent Office: 823 Days
• Field of Search: 424/489, 424/490, 424/450, 424/491, 424/497, 424/498, 427/213.3, 428/402.21, 428/402.24, 264/4.32, 264/4.33
• US Class Current: 424/490
• CPC Class Codes: A61K 41/0028 Disruption, e.g. by heat or ultrasounds, sonophysical or sonochemical activation, e.g. thermosensitive or heat-sensitive liposomes, disruption of calculi with a medicinal preparation and ultrasounds
• CPC Class Codes: A61K 9/1277 Processes for preparing; Proliposomes
• CPC Class Codes: A61K 9/5073 having two or more different coatings optionally including drug-containing subcoatings
• CPC Class Codes: A61K 9/5089 Processes
• CPC Class Codes: B01F 33/30 Micromixers
• CPC Class Codes: B01J 13/06 by phase separation
• CPC Class Codes: Y10T 428/2985 Solid-walled microcapsule from synthetic polymer
• CPC Class Codes: Y10T 428/2989 Microcapsule with solid core [includes liposome]

Abstract

Methods are provided for forming spherical multilamellar microcapsules having alternating hydrophilic and hydrophobic liquid layers, surrounded by flexible, semi-permeable hydrophobic or hydrophilic outer membranes which can be tailored specifically to control the diffusion rate. The methods of the invention rely on low shear mixing and liquid-liquid diffusion process and are particularly well suited for forming microcapsules containing both hydrophilic and hydrophobic drugs. These methods can be carried out in the absence of gravity and do not rely on density-driven phase separation, mechanical mixing or solvent evaporation phases. The methods include the process of forming, washing and filtering microcapsules. In addition, the methods contemplate coating microcapsules with ancillary coatings using an electrostatic field and free fluid electrophoresis of the microcapsules. The microcapsules produced by such methods are particularly useful in the delivery of pharmaceutical compositions.

Claims

1. A method for preparing a microcapsule comprising the steps of:

formulating a primary solution;

formulating a secondary solution;

adding said primary solution to a first chamber;

adding said secondary solution to a second chamber that is adjacent to said first chamber and separated from said first chamber by a porous barrier such that said secondary solution forms an interface with said primary solution at said porous barrier; and

allowing said primary and secondary solutions to become quiescent; and

moving said interface away from said porous barrier; and

allowing microcapsules to form; and

isolating said microcapsules by filtration through a porous barrier.

2. The method of claim 1 wherein said step for formulating a primary solution further comprises the steps of preparing a mixture comprising a polymer and at least 75% by volume of an organic solvent.

3. The method of claim 1 wherein said step for formulating a primary solution further comprises the steps of preparing a mixture comprising an organic solvent, a polymer and an oil.

4. The method of claim 2 wherein said step for formulating a primary solution further comprises the steps of preparing a mixture comprising an organic solvent to a final concentration of approximately 75% to 90% by volume and a polymer to a final concentration of approximately 1% to 5% by volume.

5. The method of claim 3 wherein said step for formulating a primary solution further comprises the steps of preparing a mixture comprising an organic solvent to a final concentration of approximately 75% to 90% by volume and a polymer to a final concentration of approximately 1% to 5% by volume and an oil to a concentration of about 1% to 10% by volume.

6. The method of claim 1 wherein said step for formulating a primary solution further comprises the steps of preparing a mixture comprising isopropyl alcohol and glycerol monostearate.

7. The method of claim 1 wherein said step for formulating a primary solution further comprises the step of preparing a mixture comprising a polymer that is insoluble in said secondary solution;

and wherein said step for formulating a secondary solution further comprises the step of preparing a mixture comprising a polymer that is insoluble in said polymer of said primary solution and is approximately insoluble in said primary solution.

8. The method of claim 1 wherein said step for formulating a primary solution further comprises the step of preparing a mixture comprising a polymer having an HLB value below 8 and has a hydrocarbon chain length of at least twelve (12) carbon atoms and wherein said step for formulating a secondary solution further comprises the step of preparing a mixture comprising a polymer of 400 to 100,000 Daltons and a surfactant having an HLB that is greater than 12.

9. The method of claim 1 wherein said step for formulating a primary solution further comprises the step of preparing a mixture comprising glycerol monostearate wherein said step for formulating a secondary solution further comprises the step of preparing a mixture comprising polyethylene glycol 1000 and ethoxylated sorbitan monooleate (20).

10. The method of claim 1 wherein said step for formulating a primary solution further comprises the step of preparing a mixture comprising a polymer having an HLB value below 8 and wherein said step for formulating a secondary solution further comprises the step of preparing a mixture comprising a polymer having an HLB value above 12 and a surfactant having an HLB value between 8 and 12.

11. The method of claim 1 wherein said step for formulating a primary solution further comprises the step of preparing a mixture comprising sorbitan monolaurate and wherein said step for formulating a secondary solution further comprises the step of preparing a mixture comprising ethoxylated (10) lanolin and ethoxylated glycerol trioleate.

12. The method of claim 1 wherein said step for formulating a primary solution further comprises the step of preparing a mixture comprising a polymer having an HLB value between 5 and 10 and a surfactant having an HLB value below 5 and wherein said step for formulating a secondary solution further comprises the step of preparing a mixture comprising a polymer having an HLB value above 10.

13. The method of claim 1 wherein said step for formulating a primary solution further comprises the step of preparing a mixture comprising a glycerol monoricinoleate monolaurate and a surfactant having an HLB value below 5 and wherein said step for formulating a secondary solution further comprises the step of preparing a mixture comprising polyethylene glycol 400.

14. The method of claim 1 wherein said step for formulating a primary solution further comprises the step of preparing a mixture comprising a polymer having an HLB value below 8 and wherein said step for formulating a secondary solution further comprises the step of preparing a mixture comprising a polymer of having an HLB value above 12 and a surfactant having an HLB value between the polymer of the primary solution and the polymer of the secondary solution.

15. The method of claim 1 wherein said step for formulating a primary solution further comprises the step of preparing a mixture comprising glycerol monooleate and wherein said step for formulating a secondary solution further comprises the step of preparing a mixture comprising polyvinyl pyrrolidone and ethoxylated (4) sorbitan monostearate.

16. The method of claim 1 wherein said step for formulating a primary solution further comprises the step of preparing an aqueous mixture comprising a polymer having an HLB value between 8 and 11 and wherein said step for formulating a secondary solution further comprises the step of preparing an aqueous mixture comprising a polymer having an HLB between 10 and 12 and a surfactant having an HLB value above 12.

17. The method of claim 1 wherein said step for formulating a primary solution further comprises the step of preparing an aqueous mixture comprising polyethylene glycol 400 distearate and wherein said step for formulating a secondary solution further comprises the step of preparing an aqueous mixture comprising polyethylene glycol monostearate and ethoxylated (20) oleyl ether.

18. The method of claim 1 wherein said step for formulating a primary solution further comprises the step of preparing an aqueous mixture comprising a polymer having an HLB value between 8 and 10 and wherein said step for formulating a secondary solution further comprises the step of preparing an aqueous mixture comprising a polymer having an HLB value greater than 10 and a surfactant having an HLB value of less than 6.

19. The method of claim 1 wherein said step for formulating a primary solution further comprises the step of preparing an aqueous mixture comprising polyethylene glycol 400 distearate and wherein said step for formulating a secondary solution further comprises the step of preparing an aqueous mixture comprising lanolin and diethylene glycerol monooleate.

20. The method of claim 1 wherein said step for formulating a primary solution further comprises the step of preparing a mixture comprising a polymer that dissolves in physiological body fluids.

21. The method of claim 1 further comprising carrying out within a single chamber said step of allowing said capsules to form;

and said step of isolating said microcapsules by filtration through a porous barrier; and

the additional step of washing said microcapsules by introducing a wash solution into said first chamber containing said microcapsules.

22. The method of claim 1 further comprising the steps of formulating a coating solution, adding said coating solution to microcapsules;

and applying electric field to said coating solution and generating a coating around a microcapsule to produce coated microcapsules.

23. The method of claim 22 further comprising the steps of formulating a coating solution by dissolving a cationic composition in said solution, adding said coating solution to said coated microcapsules, applying an electric field to said coating solution and generating a coating around said coated microcapsule.

24. The method of claim 22 further comprising the steps of formulating a coating solution by dissolving type I collagen in said solution, adding said coating solution to said coated microcapsules, applying an electric field to said coating solution and generating a coating around said coated microcapsule.

25. The method of claim 22 further comprising the steps of formulating a coating solution, by dissolving an anionic composition in said solution, adding said coating solution to said coated microcapsules, applying an electric field to said coating solution and generating a coating around said coated microcapsule.

26. The method of claim 22 further comprising the steps of formulating a coating solution, by dissolving a zwitterionic composition in said solution, adding said coating solution to said coated microcapsules, applying an electric field to said coating solution and generating a coating around said coated microcapsule.

27. The method of claim 22 further comprising the steps of formulating a coating solution, by dissolving polyvinyl pyrrolidone in said solution, adding said coating solution to said coated microcapsules, applying an electric field to said coating solution and generating a coating around said coated microcapsule.

28. The method of claim 22 further comprising the steps of formulating a coating solution, by dissolving polyvinyl acetate in said solution, adding said coating solution to said coated microcapsules, applying an electric field to said coating solution and generating a coating around said coated microcapsule.

29. The method of claim 22 further comprising the steps of formulating a coating solution, by dissolving vancomycin in said coating solution, adding said coating solution to said coated microcapsules, applying an electric field to said coating solution and generating a coating around said coated microcapsule.

30. The method of claim 22 further comprising the steps of formulating a coating solution, by dissolving stearylamine in said coating solution, adding said coating solution to said coated microcapsules, applying an electric field to said coating solution and generating a coating around said coated microcapsule.

31. The method of claim 1 wherein the step of moving said interface away from said permeable barrier further comprises moving said interface into said first chamber.

32. The method of claim 22 wherein said electric field is in the range of from approximately 1 to 500 volts/cm.

33. The method of claim 1 further comprising the step of supplying an amount of fluid shear to said interface of less than 100 dynes/cm² by flowing said primary solution into said first chamber.

34. The method of claim 1 further comprising the step of supplying a small amount of shear by flowing said secondary solution along the fluid interface.

35. The method of claim 1 further comprising the step of formulating an electrophoresis solution, adding said electrophoresis solution to microcapsules, applying an electric field sufficient to cause electrophoretic migration of said microcapsules, and collecting the microcapsules.

36. The method of claim 1 wherein said step for adding a second solution to a second chamber further comprises adding a secondary solution that is hydrophilic relative to said primary solution.

38. The method of claim 30 further comprising the steps of introducing a coating solution into said first chamber;

and applying an electric field into said chamber containing said microcapsules to produce a coating on said coated microcapsules; and

isolating said coated microcapsules.

40. The microcapsule of claim 32 wherein said method further comprises carrying out within a single chamber said step of allowing said capsules to form;

said step of isolating said microcapsules by filtration through a porous barrier; and

a step of washing said microcapsules by introducing a wash solution into said first chamber containing said microcapsules.

50. The method of claim 1 further comprising the step of formulating an electrophoresis solution, adding said electrophoresis solution to said microcapsules, applying an electric field to said electrophoresis solution, and collecting groups of microcapsules from the electrophoresis solution.

37. A method for preparing a microcapsule comprising the steps of:

formulating a primary solution;

formulating a secondary solution adding said secondary solution to a first chamber;

adding said primary solution to a second chamber that is adjacent to said first chamber and separated from said first chamber by a porous barrier, said primary solution being added to said second chamber so as to create an interface with said secondary solution at said porous barrier;

allowing said primary and secondary solutions to become quiescent;

moving said interface away from said porous barrier and into said second chamber;

allowing microcapsules to form;

isolating said microcapsules by filtration through a porous barrier;

washing said microcapsules by introducing a solution into the chamber containing said microcapsules;

introducing a coating solution into said first chamber; and

applying an electric field in the range of approximately 1 to 500 volts/cm into said first chamber.

39. A microcapsule produced by a method comprising the steps of:

adding a first solution to a first chamber; and

adding a second solution that is immiscible with said first solution to a second chamber that is adjacent to said first chamber and separated from said first chamber by a porous barrier, said second solution being added to said second chamber so as to create an interface with said first solution at said porous barrier;

allowing said first and second solutions to become quiescent and moving said interface away from said porous barrier; and

allowing microcapsules to form; and

isolating said microcapsules by filtration through a porous barrier.

41. The microcapsule of claim 39 wherein said method further comprises the steps of introducing a coating solution into said first chamber;

and applying an electric field in said first chamber to produce coated microcapsules.

42. The microcapsule of claim 39 wherein said step of moving said interface away from said permeable barrier further comprises moving said interface into said first chamber.

43. The microcapsule of claim 39 wherein said step of applying an electric field in said first chamber to produce coated microcapsules further comprises applying an electric field in the range of from approximately 1 to approximately 500 volts/cm.

44. The microcapsule of claim 39 wherein said step of forming microcapsules further includes supplying an amount of fluid shear to said interface of less than 100 dynes/cm² by flowing said secondary solution into said first chamber.

45. The microcapsule of claim 39 wherein said method further comprises the step of supplying a small amount of shear to said interface by flowing said primary solution along said fluid interface.

46. The microcapsule of claim 39 wherein said method further includes separating said microcapsules into groups by electrophoresis and harvesting said groups into a harvesting chamber.

47. The microcapsule of claim 39 wherein said step for adding a second solution to a second chamber that is adjacent to said first chamber and separated from said first chamber by a porous barrier further comprises adding a second solution to a second chamber that is adjacent to said first chamber and separated from said first chamber by a porous barrier that is hydrophobic if said secondary solution is hydrophobic relative to said primary solution or hydrophilic if said secondary solution is hydrophilic relative to said primary solution.

48. A microcapsule prepared by formulating a primary solution;

formulating a secondary solution that is hydrophilic relative to said primary solution;

adding said secondary solution to a first chamber; and

adding said primary solution to a second chamber that is adjacent to said first chamber and separated from said first chamber by a porous barrier that is hydrophobic if said secondary solution is hydrophobic relative to said primary solution or hydrophilic if said secondary solution is hydrophilic relative to said primary solution, said primary solution being added to said second chamber so as to create an interface with said secondary solution at said porous barrier;

allowing said primary and secondary solutions to become quiescent;

moving said interface away from said porous barrier and into said first chamber;

allowing microcapsules to form;

isolating said microcapsules by filtration through a porous barrier;

formulating a wash solution;

washing said microcapsules by introducing said wash solution into the chamber containing said microcapsules;

formulating a coating solution;

adding said coating solution to said microcapsules; and

generating coated microcapsules.

49. The microcapsule of claim 48 wherein said process further includes applying an electric field to said coating solution after said coating solution is added to said microcapsules.

51. A microcapsule prepared by formulating a primary solution by preparing a mixture containing 1 mg/ml Reglan, 1% polyethylene glycol-400, 5% dextran-40, 1% Tween 80, 0.5% polyvinyl pyrrolidone, 0.05% Cy-3 fluorescent dye;

formulating a secondary solution by preparing a mixture containing 5% glycerol monostearate, 92% isopropyl alcohol, 3% iodinated poppy seed oil, 2% water, 1.5% hexanol, 1.5% heptanol adding said secondary solution to a first chamber; and

adding said primary solution to a second chamber that is adjacent to said first chamber and separated from said first chamber by a porous barrier, said primary solution being added to said second chamber so as to create an interface with said secondary solution at said porous barrier;

allowing said primary and secondary solutions to become quiescent;

moving said interface away from said porous barrier and into said first chamber;

allowing microcapsules to form;

applying an electric field of 14 volts/cm to the microcapsule formation chamber for 1 minute and then reversing the polarity of the electrodes and applying an electric field of 14 volts/cm for a period of 30 seconds;

isolating said microcapsules by filtration through a porous barrier;

washing the coated microcapsules with water.

52. A microcapsule having a diameter of over 160 microns prepared by formulating a primary solution by preparing a mixture containing 2.5% myverol 1804, 2.5% vitamin E succinate, 88% isopropanol, 5% iodinated poppy seed oil, 2% water, 2.5% hexanol and 2.5% heptanol;

formulating a secondary solution by preparing a mixture containing 2% of a solution containing fluorocein isothiocyanate, 1% polyethylene glycol 4000, 5% dextran-40, 1% ethoxylated (20) sorbitan monooleate;

adding said secondary solution to a first chamber;

adding said primary solution to a second chamber that is adjacent to said first chamber and separated from said first chamber by a porous barrier, said primary solution being added to said second chamber so as to create an interface with said secondary solution at said porous barrier;

allowing said primary and said secondary solutions to become quiescent; and

moving said interface away from said porous barrier and into said second chamber; and

allowing microcapsules to form for one hour.